Ivermectin 12mg ► 100 and 200 capsules

General support for well-being and immune modulation

This protocol is designed for those seeking to support the natural processes of immune response and promote the balance of cell signaling pathways related to communication between cells of the immune system.

• Dosage: It is recommended to begin with a 3- to 5-day adaptation phase using 12 mg (1 capsule) every other day to assess individual tolerance. Subsequently, a maintenance dose of 12 mg (1 capsule) every 3 to 4 days can be increased for the first two weeks. After this initial period, some users opt for a dose of 12–24 mg (1–2 capsules) once a week as a long-term maintenance protocol. Given ivermectin's pharmacokinetic profile, with a prolonged half-life (approximately 18 hours) and accumulation in adipose tissue with gradual release, continuous daily administration is neither necessary nor recommended. For individuals with a higher percentage of body fat, adjusting toward the higher end of the range may be considered, always within the context of responsible use.

• Administration frequency: It is suggested to take the capsules with food, preferably with a meal containing healthy fats, as the lipophilic nature of ivermectin favors its intestinal absorption in the presence of lipids. Administration can be done at any time of day, although some users prefer to take it in the morning with breakfast to facilitate adherence to the protocol. It is important to maintain consistency in the administration schedule when establishing a weekly pattern. Since ivermectin is a substrate of intestinal P-glycoprotein, avoiding simultaneous administration with known inhibitors of this transporter (such as grapefruit juice) may be prudent unless specifically seeking to increase bioavailability.

• Cycle duration: Typical cycles for this purpose range from 8 to 12 weeks of use with the established weekly protocol, followed by a 4- to 6-week break to allow for complete elimination of the compound and its metabolites from the body. After the break, the cycle can be restarted, again following the initial adaptation phase before resuming the maintenance protocol. Some users implement seasonal protocols, using 12-week cycles two or three times a year during periods when they seek greater immune support, always respecting the appropriate breaks between cycles.

Support for cell renewal processes and autophagy

This protocol is designed to support the natural mechanisms of cellular cleansing, recycling of damaged components, and maintenance of cellular homeostasis by modulating autophagic pathways.

• Dosage: Begin with a conservative 5-day adaptation phase using 12 mg (1 capsule) every 4 days to assess individual response. After completing this initial phase, progress to a maintenance dose of 12 mg (1 capsule) every 3 days for the first two weeks of the active protocol. For users seeking more consistent support for cell renewal processes and who have confirmed good tolerance, a dose of 24 mg (2 capsules) once weekly may be considered as an alternative to the 12 mg twice-weekly protocol. The choice between these options may be based on personal preference regarding administration frequency, considering that both provide similar exposure over time given the compound's pharmacokinetic profile.

• Administration frequency: To optimize the effects on autophagy and cell renewal, some protocols suggest taking ivermectin on an empty stomach or at least 2 hours after the last meal, as the fasted state can synergistically enhance the activation of autophagic pathways through the concurrent inhibition of mTOR by nutritional restriction and pharmacological action. However, this practice must be balanced with the needs for optimal absorption, so an alternative is to take the dose with a light meal containing moderate fat. Administration can be scheduled on specific days of the week (e.g., Mondays and Thursdays, or only Sundays for the weekly protocol) to facilitate adherence and consistency of the regimen.

• Cycle duration: The recommended cycles for this goal range from 10 to 14 weeks of active use, implementing the established dosing protocol, followed by a 6- to 8-week rest period. This pattern allows the cellular renewal processes supported during the active cycle to stabilize, and the body to return to its baseline autophagic regulation patterns before restarting. For long-term maintenance goals related to healthy aging and cellular quality, some users implement 2 to 3 cycles per year with their respective rest periods, adjusting the schedule according to their individual wellness objectives.

Modulation of inflammatory responses and immune balance

This protocol is designed for those seeking to support the balance of the body's natural inflammatory processes and promote the modulation of signaling pathways related to cytokines and inflammatory transcription factors.

• Dosage: Begin with a 3- to 5-day adaptation phase using 12 mg (1 capsule) every 5 days to establish a baseline tolerance. Subsequently, during the first two weeks of the active protocol, use 12 mg (1 capsule) every 3 days. For the sustained maintenance protocol, 12 mg (1 capsule) twice a week, evenly spaced (e.g., Tuesday and Friday), is suggested, or alternatively, 24 mg (2 capsules) once a week for greater convenience. In situations where more intensive support is sought during specific, limited periods, 12 mg (1 capsule) every 2 days for up to 2-3 weeks could be considered, followed immediately by a return to the standard maintenance protocol or the start of the rest period.

• Frequency of administration: It is recommended to take the capsules with fatty foods to optimize absorption, preferably during the main meal of the day. Administration can be done at any time, although some protocols suggest nighttime administration based on the fact that certain repair and immune modulation processes intensify during the rest period. It is important to avoid simultaneous administration with supplements or compounds that may compete for the same hepatic metabolism pathways (CYP3A4 system) or intestinal transport, spacing their intake by at least 4-6 hours when possible.

• Cycle duration: Cycles for this purpose typically extend from 8 to 12 weeks of continuous use with the established protocol, followed by a 4- to 6-week break. During the break, the body allows inflammatory signaling pathways to return to their endogenous regulatory patterns without pharmacological modulation. Some users implement shorter 6-week cycles with 3- to 4-week breaks when seeking support during specific periods of increased demand on the immune system, potentially completing up to 3-4 cycles per year with this structure. The adaptation phase should always be restarted after each break.

Support for cellular metabolism and mitochondrial function

This protocol is designed to support cellular bioenergetics processes, modulation of mitochondrial function, and support the mechanisms by which cells generate and manage their metabolic energy.

• Dosage: Begin with an extended 5-day adaptation phase using 12 mg (1 capsule) every 5 days, allowing the body to adjust to the compound's effects on energy metabolism. After completing this phase, progress to 12 mg (1 capsule) every 4 days for the first two weeks of the active cycle. The standard maintenance protocol consists of 12 mg (1 capsule) twice a week with at least 3 days between doses (e.g., Monday and Friday). Since the effects on mitochondrial function can be cumulative and ivermectin accumulates in tissues with repeated use, maintaining a moderate and consistent dosage is preferable to higher, less frequent doses for this particular purpose.

• Administration frequency: It is suggested to take the capsules with the first meal of the day containing healthy fats, as this promotes absorption and coincides with the period when cellular energy demands are increasing after the overnight fast. Some alternative protocols suggest administration in the early afternoon with a balanced meal, allowing the effects on metabolism to develop during the remaining active hours of the day and night. It is recommended to maintain adequate hydration throughout the protocol, as optimal metabolic processes require proper fluid balance. Avoid administration too close to bedtime in sensitive individuals who may experience changes in energy patterns.

• Cycle Length: Recommended cycles range from 10 to 14 weeks of continuous use following the established dosing protocol, followed by a 6- to 8-week break. This pattern allows for the assessment of how changes in energy metabolism and mitochondrial function are maintained after discontinuing the compound and provides time for the body's enzyme systems to readjust. For long-term metabolic support, 2 to 3 cycles per year can be implemented with this structure, adjusting the schedule to coincide with periods of increased physical or mental demand where energy metabolism support might be particularly relevant.

Modulation of epithelial barriers and intestinal homeostasis

This protocol is designed for those seeking to support the integrity of the body's epithelial barriers, particularly the intestinal barrier, and to promote the balance of processes that regulate the selective permeability of these tissues.

• Dosage: Begin with a conservative 5-day adaptation phase using 12 mg (1 capsule) every 6 days to allow the body to gradually adjust to the compound's effects on epithelial tight junctions and the intestinal microenvironment. After this initial phase, progress to 12 mg (1 capsule) every 4 days for the first two weeks. The maintenance protocol consists of 12 mg (1 capsule) once a week, as for this particular goal, less frequent but consistent doses over time may be sufficient given the compound's long half-life and tissue accumulation. In cases where more active support is sought for a limited period, 12 mg (1 capsule) every 3 days for 3-4 weeks may be considered before returning to the weekly protocol.

• Administration frequency: It is recommended to take the capsule with food to minimize any direct effects on the gastrointestinal mucosa on an empty stomach, preferably with a meal containing soluble fiber and healthy fats that can promote both the absorption of the compound and provide substrate for the gut microbiome. Administration can be performed at any time of day, although some protocols suggest taking it with dinner to allow the effects on epithelial junctions to develop during the nighttime period of tissue repair and renewal. It is important to maintain a balanced diet rich in nutrients that support the integrity of the intestinal mucosa (such as zinc, vitamin A, L-glutamine) throughout the protocol.

• Cycle duration: Typical cycles for this goal range from 8 to 12 weeks of continuous use with the established weekly dosing protocol, followed by a 6- to 8-week break. During the break, it is the ideal time to assess how the changes in barrier function are maintained without active pharmacological modulation and to implement complementary dietary and lifestyle strategies that support gut health. The cycle can be restarted after the break, always beginning again with the adaptation phase. For long-term support of intestinal homeostasis, some users implement 2 to 3 cycles per year with this structure.

Support for cellular quality control processes and apoptotic regulation

This protocol is designed to support the natural mechanisms by which the body eliminates damaged or dysfunctional cells, promoting a balance between survival signals and programmed cell death.

• Dosage: Begin with a 3- to 5-day adaptation phase using 12 mg (1 capsule) every 5 days to establish tolerance to the compound's effects on apoptotic pathways. After completing this phase, progress to a dose of 12 mg (1 capsule) every 3 days for the first two weeks of the active cycle. The standard maintenance protocol consists of 12-24 mg (1-2 capsules) once a week, with the specific dose adjusted according to body weight, body composition (particularly body fat percentage, since the compound accumulates in adipose tissue), and individual response observed during the initial phase. For individuals with lower body weight or a lower percentage of body fat, maintain 12 mg weekly; for individuals with higher body mass or a higher percentage of body fat, consider 24 mg weekly.

• Administration frequency: It is suggested to take the capsules with foods containing fats to optimize absorption and systemic bioavailability, preferably during a main meal. Administration can be performed at any time, although some protocols experiment with nighttime administration, considering that certain cell renewal processes and the elimination of senescent cells intensify during the rest period. It is important to maintain consistency in the chosen day of the week for administration (for example, always on Sundays) to facilitate adherence to the protocol and allow cellular response patterns to stabilize at a predictable rate.

• Cycle duration: The recommended cycles for this purpose range from 10 to 14 weeks of continuous use following the established weekly dosing protocol, followed by a longer rest period of 8 to 10 weeks. This extended rest period allows the body's apoptotic regulatory systems to fully return to their baseline functioning patterns without external modulation and provides sufficient time for the complete elimination of the compound and its metabolites, given their long half-life and tissue accumulation. For long-term maintenance of cellular quality control, two annual cycles with this structure can be implemented, ideally spaced in opposite halves of the year.

Did you know that ivermectin can cross the blood-brain barrier at specific concentrations and modulate neuronal ion channels?

This compound interacts with glutamate receptors and ligand-gated chloride channels in the nervous system of various organisms. In mammals, the blood-brain barrier normally limits its passage into the brain thanks to efflux proteins such as P-glycoprotein, but under certain conditions or concentrations, it can reach peripheral nervous tissue and modulate GABAergic neurotransmission. This ability to interact with ion channels has sparked research interest in its potential to influence cell signaling pathways beyond its conventional applications.

Did you know that ivermectin comes from a bacterium discovered in the soil of a Japanese golf course?

The bacterium Streptomyces avermitilis, the natural source of avermectins (precursors to ivermectin), was first isolated from a soil sample collected near a golf course in Japan during the 1970s. Scientists were searching for new compounds with biological activity in soil microorganisms, and this bacterium produced macrocyclic lactones with unique properties. This discovery exemplifies how the microbial biodiversity of soil represents a valuable source of bioactive compounds that can subsequently be modified and studied for diverse applications in science and health.

Did you know that ivermectin selectively binds to glutamate-dependent chloride channels present in invertebrate cells but absent in mammals?

This biochemical selectivity explains why the compound exhibits a differential action profile among organisms. Glutamate-gated chloride channels are abundant in the nervous and muscular systems of invertebrates, where ivermectin induces sustained cellular hyperpolarization by increasing chloride ion permeability. In mammals, these specific channels are absent, and the compound primarily interacts with GABAergic and glycine receptors in the peripheral nervous system, contributing to its differential therapeutic window. This molecular specificity has been studied to better understand evolutionary differences in neurotransmission between species.

Did you know that ivermectin can accumulate in adipose tissue and be released gradually over several weeks?

Due to its lipophilic nature, this compound has a high affinity for body lipids and tends to be distributed and stored in adipose tissue after administration. This pharmacokinetic characteristic results in a prolonged half-life in the body, with gradual release from fat deposits into the systemic circulation over extended periods. Accumulation in adipose tissue also means that individuals with a higher percentage of body fat may experience different pharmacokinetics compared to leaner individuals, which has generated interest in studies on personalized dosing based on body composition.

Did you know that ivermectin inhibits importin-mediated nuclear transport, interfering with the movement of proteins between the cytoplasm and the cell nucleus?

Importins are transport proteins that facilitate the entry of specific molecules into the cell nucleus through nuclear pores. Ivermectin can bind to the importin alpha/beta complex and block its nuclear transport function, potentially affecting the localization of various regulatory proteins, transcription factors, and cell signaling components that rely on this mechanism to perform their functions. This property has sparked interest in research on the regulation of gene expression and cell signaling pathways, particularly in the context of cellular responses to various biological stimuli.

Did you know that ivermectin can modulate autophagy, a cellular process of recycling and degradation of damaged components?

Autophagy is a fundamental mechanism by which cells break down and recycle damaged proteins, dysfunctional organelles, and other cellular components, contributing to the maintenance of cellular homeostasis. In vitro studies have observed that ivermectin can influence the signaling pathways that regulate this process, particularly through the modulation of the mTOR (mechanistic target of rapamycin) pathway and the activation of autophagy-related proteins. This ability to interact with cell renewal processes has generated interest in research on cellular longevity and adaptive responses to metabolic stress.

Did you know that ivermectin can inhibit the helicase enzyme, which unwinds DNA during replication and transcription?

Helicases are essential enzymes that separate the two strands of the DNA double helix, allowing other molecular components to access the genetic information for replication, repair, and transcription processes. Biochemical studies have shown that ivermectin can interfere with certain helicases, potentially affecting these fundamental processes of genetic information management. This property has opened lines of research into how small compounds can modulate the activity of enzymes that manipulate nucleic acids, contributing to our understanding of cell cycle regulation and gene expression.

Did you know that ivermectin can affect mitochondrial function by altering the membrane potential of these energy-producing organelles?

Mitochondria maintain an electrochemical gradient across their inner membrane that is essential for ATP synthesis via oxidative phosphorylation. In vitro studies have shown that ivermectin can influence this mitochondrial membrane potential, affecting cellular energy production and potentially triggering signaling pathways related to metabolic stress. This interaction with mitochondrial function has also been linked to the generation of reactive oxygen species and the activation of cellular response mechanisms to changes in energy status—aspects relevant to understanding cellular metabolism in different physiological contexts.

Did you know that ivermectin can modulate the inflammatory response by interfering with the NF-κB signaling pathway?

Nuclear factor kappa B (NF-κB) is a central transcription factor in the regulation of genes related to the immune response and inflammatory processes. Studies have shown that ivermectin can inhibit the nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory cytokines and other immune signaling molecules. This ability to modulate inflammatory pathways has generated interest in research on how naturally occurring compounds or derivatives can influence cell communication within the immune system and the body's responses to various stimuli that trigger inflammatory cascades.

Did you know that ivermectin is primarily metabolized in the liver by the cytochrome P450 enzyme system?

Cytochrome P450 is a family of liver enzymes responsible for metabolizing a wide variety of endogenous and exogenous compounds. Ivermectin is a substrate of the CYP3A4 and CYP3A5 isoforms, which carry out oxidation reactions that transform the compound into more water-soluble metabolites to facilitate its elimination. This dependence on the CYP450 system means that substances that inhibit or induce these enzymes can significantly alter the pharmacokinetics of ivermectin, prolonging or shortening its duration of action in the body. Understanding these metabolic interactions is relevant to comprehending how different factors can influence the bioavailability and elimination of the compound.

Did you know that ivermectin can inhibit the replication of certain viruses by blocking the nuclear transport of viral proteins?

Some viruses rely on the host cell's nuclear import mechanism to transport their proteins and genetic material to the nucleus, where they can complete their replication cycle. Since ivermectin interferes with the importins that facilitate this transport, in vitro studies have shown that the compound can hinder the replication of certain viruses dependent on this mechanism. This property has spurred research into the molecular mechanisms by which small compounds can interfere with specific viral processes that depend on the host cell's machinery, contributing to our understanding of virus-cell interactions.

Did you know that ivermectin has a dose-dependent effect on the permeability of the blood-brain barrier?

At conventional doses, P-glycoprotein in the endothelial cells of cerebral capillaries effectively pumps ivermectin out of the central nervous system, maintaining low brain concentrations. However, at higher doses or in the presence of P-glycoprotein inhibitors, saturation of this efflux mechanism allows greater penetration of the compound into brain tissue. This dose-dependent phenomenon illustrates how active transport systems protect the brain from lipophilic substances, and how these protective mechanisms have a limited capacity that can be exceeded under certain conditions—a relevant principle in central nervous system pharmacology.

Did you know that ivermectin can sensitize cells to apoptosis by modulating proteins of the Bcl-2 family?

The Bcl-2 family of proteins regulates the permeability of the outer mitochondrial membrane and determines whether a cell undergoes programmed cell death (apoptosis) or survives in response to stress stimuli. Research has shown that ivermectin can alter the balance between pro-apoptotic and anti-apoptotic proteins in this family, favoring, in certain contexts, the release of mitochondrial cytochrome c and the activation of caspases, enzymes that trigger apoptosis. This ability to influence cell survival or death decisions has motivated studies on the molecular mechanisms that determine cell fate in response to different bioactive compounds.

Did you know that ivermectin can affect the function of P-glycoprotein, an efflux pump that protects the body from foreign substances?

P-glycoprotein (P-gp) is an ABC transporter located in the membranes of intestinal, hepatic, renal, and blood-brain barrier cells. It actively pumps various compounds out of cells, limiting their absorption and tissue distribution. Ivermectin is both a substrate and a potential modulator of P-gp, and its interaction with this transporter can influence the bioavailability of other compounds that are also substrates of this efflux pump. This complex relationship between ivermectin and cellular transport systems illustrates how the body's defense mechanisms can be influenced by external compounds, an important aspect in the study of interactions between different substances.

Did you know that ivermectin can modulate the expression of genes related to lipid metabolism and cholesterol homeostasis?

Transcriptomic studies have revealed that exposure to ivermectin can alter the expression of genes involved in lipid synthesis, transport, and metabolism, as well as the regulation of nuclear receptors such as LXR (liver X receptor), which controls cholesterol homeostasis. These observations suggest that the compound may influence metabolic pathways related to lipid handling at the cellular and systemic levels. The ability to modulate gene expression related to lipid metabolism has generated interest in understanding how compounds with macrocyclic lactone structures can interact with metabolic regulatory systems.

Did you know that ivermectin can interfere with Wnt/β-catenin signaling, a crucial pathway for cell renewal and differentiation?

The Wnt/β-catenin pathway regulates fundamental processes such as cell proliferation, differentiation, and stem cell maintenance in various tissues. Ivermectin has demonstrated in experimental models the ability to modulate this signaling pathway, affecting the stability and localization of β-catenin, a key protein that, when it accumulates in the nucleus, activates the transcription of Wnt target genes. This interference with a signaling pathway so fundamental to tissue development and maintenance has opened lines of research into how small compounds can influence cell renewal and differentiation processes.

Did you know that ivermectin can enhance the effects of inhibitory neurotransmitters such as GABA and glycine in the peripheral nervous system?

In addition to its action on specific chloride channels in invertebrates, ivermectin can bind to GABAergic and glycinergic receptors in mammals, increasing the opening of chloride channels activated by these inhibitory neurotransmitters. This potentiating effect on inhibitory neurotransmission in the peripheral nervous system contributes to modifying neuronal excitability and signal transmission. The compound's ability to act as a positive allosteric modulator of these receptors illustrates how certain molecules can amplify endogenous neurochemical signals without directly activating the receptors.

Did you know that ivermectin undergoes enterohepatic recirculation, prolonging its presence in the body?

After being metabolized in the liver, ivermectin and its metabolites are excreted in the bile into the small intestine. A portion of these compounds can be reabsorbed from the intestine back into the bloodstream, creating a cycle of elimination and reabsorption known as enterohepatic recirculation. This process contributes to the compound's prolonged half-life in the body and explains why its effects can last for an extended period. Enterohepatic recirculation is a relevant pharmacokinetic phenomenon that affects the duration of action of various lipophilic compounds and their metabolites.

Did you know that ivermectin can modulate macrophage function by altering the polarization between M1 and M2 phenotypes?

Macrophages can adopt different functional states: the M1 phenotype promotes pro-inflammatory responses, while the M2 phenotype is associated with the resolution of inflammation and tissue repair. Research has suggested that ivermectin can influence macrophage polarization, favoring, in certain experimental contexts, changes in the expression of surface markers and in the cytokine profile secreted by these immune cells. This ability to modulate the function of phagocytic cells represents an additional mechanism by which the compound could influence complex immune responses and the resolution of inflammatory processes.

Did you know that ivermectin can affect intestinal permeability by modulating tight junction proteins between epithelial cells?

Tight junctions between intestinal epithelial cells regulate the selective permeability of the intestinal barrier, controlling the passage of molecules, ions, and microorganisms from the intestinal lumen into the bloodstream. In vitro studies have shown that ivermectin can influence the expression and organization of proteins such as claudins, occludins, and ZO-1 that form these tight junctions, potentially altering the integrity of the intestinal barrier. This interaction with structural components of the epithelial barrier illustrates how compounds can modulate tissue permeability and the defense mechanisms that separate different compartments of the body.

Support for the natural immune response

Ivermectin has been investigated for its ability to modulate various aspects of the body's immune function. This compound can influence communication between immune system cells by interacting with signaling pathways such as nuclear factor kappa B (NF-κB), a central regulator of the expression of genes related to the immune response. By modulating the activity of this transcription factor, ivermectin could help balance the production of messenger molecules that coordinate the body's defensive responses. Additionally, studies have observed that this compound can influence the function of macrophages, cells specialized in detecting and responding to various biological stimuli. Ivermectin's ability to support immune cell communication processes is one of the most studied aspects of this compound, particularly in the context of how the body coordinates its natural defense mechanisms against different biological challenges.

It promotes cell renewal and cleansing processes

Research has shown that ivermectin can modulate autophagy, a fundamental process by which cells break down and recycle damaged components, misfolded proteins, and dysfunctional organelles. This "cellular cleanup" mechanism is essential for maintaining cell health and function, allowing cells to eliminate defective material and renew their internal components. Ivermectin can influence the signaling pathways that regulate this process, particularly through its interaction with the mTOR pathway, a central sensor of cellular nutritional and energy status. By promoting these cell renewal processes, the compound could support the natural mechanisms by which the body maintains the quality and function of its cells over time. This support for cellular homeostasis represents an important aspect of overall well-being at the molecular level.

It contributes to the balance of inflammatory processes.

Research has revealed that ivermectin can participate in modulating the body's inflammatory responses through multiple molecular mechanisms. This compound can interfere with pro-inflammatory signaling pathways, reducing the expression of cytokines and other messenger molecules that amplify inflammatory responses. By modulating the NF-κB pathway and other transcription factors related to inflammation, ivermectin could contribute to maintaining an appropriate balance between activating and resolving responses. It is important to understand that inflammation is a natural and necessary process for the body's repair and defense, but its appropriate regulation is fundamental for overall well-being. Ivermectin's ability to support the balance of these processes, without completely suppressing them, represents a relevant aspect of its biological profile that has generated interest in the field of research on the modulation of physiological responses.

Supports mitochondrial function and communication

Mitochondria are the powerhouses of cells, responsible for producing most of the ATP that fuels cellular processes. Studies have shown that ivermectin can influence various aspects of mitochondrial function, including maintaining mitochondrial membrane potential and regulating signaling pathways related to energy metabolism. This compound can affect the production of mitochondrial reactive oxygen species, molecules that, at appropriate levels, function as important cell signaling pathways for metabolic adaptation. By modulating mitochondrial function, ivermectin could support cellular energy efficiency and the mechanisms by which cells respond to changes in metabolic demands. Mitochondrial health is fundamental to overall well-being, as virtually all cellular processes depend on an adequate energy supply.

It promotes cell cycle regulation mechanisms.

Ivermectin has demonstrated the ability to interact with various signaling pathways that regulate cell division, differentiation, and survival. This compound can modulate the Wnt/β-catenin pathway, a fundamental signaling system for tissue renewal and the maintenance of stem cell populations in various organs. Additionally, ivermectin can influence proteins of the Bcl-2 family, which determine the balance between cell survival and programmed cell death (apoptosis), a process essential for eliminating damaged or dysfunctional cells. By participating in the regulation of these cellular quality control mechanisms, ivermectin could contribute to the natural processes by which the body maintains tissue integrity. The compound's ability to influence fundamental cellular decisions represents an aspect of its biological action that has generated considerable interest in tissue homeostasis research.

It supports the integrity of the body's protective barriers.

Ivermectin can influence the function of epithelial barriers that separate different compartments of the body and regulate the selective exchange of substances. Research has shown that this compound can modulate the expression and organization of tight junction proteins that connect adjacent epithelial cells, particularly in the intestinal epithelium. These tight junctions are essential for maintaining the integrity of the intestinal barrier, controlling which substances can pass from the intestinal lumen into the bloodstream. By influencing structural components such as claudins, occludins, and ZO proteins, ivermectin may support the mechanisms by which the body maintains the selectivity of its protective barriers. Proper function of these barriers is essential to prevent the uncontrolled passage of potentially problematic substances and maintain the balance between different systems of the body.

It contributes to the modulation of lipid metabolism

Gene expression studies have revealed that ivermectin can influence the activity of genes related to lipid metabolism and cholesterol homeostasis. This compound can modulate the activity of nuclear receptors such as the liver X receptor (LXR), which acts as a sterol sensor and regulates the expression of genes involved in cholesterol transport, synthesis, and elimination. Additionally, ivermectin can affect the expression of genes related to fatty acid synthesis and oxidation, processes fundamental to cellular energy management. By participating in the regulation of lipid metabolic pathways, this compound could contribute to the mechanisms by which the body maintains balance in the levels of different types of lipids. It is important to understand that lipid metabolism is a complex and interconnected system, and ivermectin's ability to influence multiple aspects of this metabolism represents an area of ​​ongoing research.

It supports peripheral neuroprotective mechanisms.

Ivermectin can interact with components of the peripheral nervous system, particularly through its ability to modulate GABAergic and glycinergic receptors, which mediate inhibitory signaling in nervous tissue. By acting as a positive allosteric modulator of these receptors, ivermectin can potentiate the effects of natural inhibitory neurotransmitters, which could contribute to maintaining the balance between excitatory and inhibitory signals in peripheral nervous circuits. Additionally, this compound's ability to influence neuronal ion channels and modulate neurotransmission represents a mechanism by which it could support proper nervous system function. Importantly, these effects are primarily observed peripherally, as the blood-brain barrier significantly limits ivermectin's access to the central nervous system under normal conditions, providing a significant safety margin.

It promotes the modulation of nuclear protein transport

Ivermectin possesses the unique ability to interfere with the importin system, transport proteins that facilitate the movement of specific molecules from the cytoplasm to the cell nucleus. By binding to the importin alpha/beta complex, this compound can block the nuclear transport of various regulatory proteins, transcription factors, and cell signaling components that rely on this mechanism to perform their functions. This ability to modulate nucleocytoplasmic trafficking represents a sophisticated mechanism by which ivermectin can influence gene expression and cell signaling processes. Nuclear transport is a fundamental process for regulating cellular responses to various stimuli, and the ability to selectively modulate this mechanism has generated interest in understanding how compounds can influence the subcellular localization of regulatory molecules.

It contributes to the balance of cellular oxidative stress

Ivermectin can influence the production and handling of reactive oxygen species (ROS) at the cellular level. These molecules, at appropriate concentrations, function as important signaling molecules, but in excess, they can contribute to oxidative stress. This compound can modulate the generation of mitochondrial ROS by affecting the function of the electron transport chain and can also influence signaling pathways that respond to cellular redox status. By participating in the regulation of oxidative balance, ivermectin could contribute to the mechanisms by which cells maintain an appropriate equilibrium between the production of oxidizing molecules and endogenous antioxidant systems. It is important to understand that ROS are not simply harmful molecules, but rather important signals for cellular adaptation processes, and their proper regulation is fundamental for normal cellular function.

It supports the function of cellular defense and transport systems.

Ivermectin interacts with P-glycoprotein (P-gp), an efflux pump located in cell membranes of various tissues that actively expels foreign substances from cells. This transporter is part of the body's defense system against potentially problematic compounds and is found in strategic locations such as the intestine, liver, kidneys, and blood-brain barrier. Ivermectin is both a substrate and a potential modulator of P-gp, meaning it can influence the function of this transport system. This interaction with cellular defense mechanisms illustrates the complex relationship between foreign compounds and the systems the body has developed to regulate which substances can accumulate in different tissues. Modulating transporters like P-gp represents an important aspect of how the body controls the distribution and elimination of various molecules.

It promotes cell signaling processes and intercellular communication

Ivermectin can influence multiple signaling pathways that cells use to communicate with each other and respond to changes in their environment. Beyond its effects on the specific pathways already mentioned, this compound can modulate the activity of kinases, phosphatases, and other regulatory enzymes that control cell signaling cascades. By affecting the phosphorylation of key proteins and the activity of second messengers, ivermectin can influence how cells interpret and respond to extracellular signals. This ability to modulate cell communication networks represents one mechanism by which the compound can have broad effects on cell and tissue function. Appropriate cell signaling is essential for coordinating complex physiological responses involving multiple cell types and systems in the body.

It contributes to the modulation of DNA enzymatic activity

Ivermectin has demonstrated the ability to inhibit certain helicases, enzymes that unwind the DNA double helix to allow access to genetic information during replication, transcription, and repair processes. By interfering with these nucleic acid-manipulating enzymes, ivermectin can influence fundamental processes of genetic information management at the cellular level. This interaction with DNA enzymes represents a molecular mechanism by which the compound can affect gene expression and cell division processes. It is important to understand that the regulation of helicase activity is a complex aspect of cell cycle control and genomic stability, and the ability of compounds to modulate these enzymes has generated interest in the field of molecular and cellular biology.

Supports the homeostasis of the peripheral nervous system

Ivermectin may contribute to maintaining functional balance in the peripheral nervous system through its interaction with various components of neurotransmission. By modulating ligand-gated ion channels and potentiating the action of inhibitory neurotransmitters such as GABA and glycine, this compound can influence neuronal excitability and signal transmission in peripheral nerves. This ability to modulate inhibitory neurotransmission represents a mechanism by which ivermectin could support the proper function of neural circuits that control various bodily functions. The balance between excitatory and inhibitory signals is fundamental to the coordinated functioning of the nervous system, and compounds that can influence this balance have been the subject of considerable research in neuroscience.

It promotes cellular adaptation to metabolic changes

Ivermectin can influence the ability of cells to adapt to changes in their metabolic and nutritional environment. Through its interaction with the mTOR pathway, a central sensor of cellular energy and nutrient status, this compound can modulate adaptive responses that cells implement in response to variations in the availability of energy and building blocks. The mTOR pathway integrates signals from multiple sources, including growth factors, amino acids, and cellular energy status, to coordinate processes such as protein synthesis, cell growth, and metabolism. By modulating this signaling pathway, ivermectin could contribute to the mechanisms by which cells adjust their metabolism to maintain homeostasis in the face of changing conditions. This ability to influence cellular adaptive responses represents an important aspect of how the compound can affect metabolism at a fundamental level.

A molecule with multiple keys for cell doors

Imagine your body as a vast and complex city, with millions of buildings that are your cells. Each cell has special doors called receptors and channels, which only open when the correct key arrives. Ivermectin is like a set of master keys that can open several different types of doors in this cellular city. When this molecule enters your body, it travels through the bloodstream like a special messenger, carrying these keys to different locations. What's fascinating is that these keys don't work the same way in all living things: in some small organisms, such as certain invertebrate parasites, ivermectin's keys open doors that cause a flood of charged particles called chloride ions, which paralyzes their nerve and muscle cells. But in mammals like us, these same keys interact with different doors and in a more subtle way, because our cellular city has a different architecture. This selectivity is as if ivermectin knows exactly which doors to open depending on the type of building it's in.

The guardian of the brain's border

Our brain is like the command center of the body's city, protected by a special barrier called the blood-brain barrier. This barrier isn't a simple brick wall, but rather a smart filter with microscopic security guards called P-glycoproteins, acting as very strict gatekeepers. These gatekeepers have an important job: when they detect certain foreign substances, including ivermectin, they immediately expel them before they can enter the brain's command center. It's as if the guards say, "This molecule isn't authorized to enter here," and send it back to the rest of the city. That's why, under normal conditions, ivermectin works primarily in the peripheral neighborhoods of the nervous system, not in the control center. However, if too many ivermectin molecules arrive at the same time, or if the guards are busy with other tasks, some can slip through. This is one of the reasons why dosages are so important: maintaining the correct number of molecules ensures that the guards can do their protective job effectively.

The internal mail system that connects the cytoplasm to the nucleus

Within each cell, there is a highly organized mail system. The cell nucleus, where all genetic information is stored like a central library, is separated from the rest of the cell by a membrane with special gates. For instructions from the nucleus to reach the rest of the cell, or for messages from the outside to reach the nucleus, molecular messengers called importins are needed. These importins are like postal workers carrying important packages (proteins and other molecules) through the nuclear gates. Here's the interesting part: ivermectin can act as an obstacle in the path of these messengers. When ivermectin binds to importins, it's as if it puts an extra lock on their backpacks, preventing them from delivering their cargo to the nucleus. This means that certain instructions and signals that would normally enter the central library to modify what information is read and used are now stranded outside. By blocking this mail system, ivermectin can influence which genes are turned on or off, subtly changing how the entire cell functions.

The power plant and its smoke signals

Mitochondria are the power plants of our cells, tiny energy factories that convert the fuel we eat into ATP, the energy currency that everything in our body needs to function. Think of these power plants as factories that keep the lights on throughout the cellular city. Ivermectin can enter these power plants and adjust some of their controls, affecting how they maintain their internal voltage—that special electrical gradient they need to produce energy efficiently. When ivermectin modifies this voltage, it's like adjusting the power plant's thermostats, which can change not only how much energy is produced but also how many "smoke signals" are released. These smoke signals are reactive oxygen molecules, which, in the right amounts, act as important messages telling the cell how its metabolism is functioning and whether it needs to make adjustments. By influencing mitochondrial function, ivermectin participates in fundamental conversations about the cell's energy status and how it should respond to different demands.

The cellular cleaning team that recycles and renews

Inside every cell is a fascinating recycling and cleaning system called autophagy, which literally means "self-eating." But don't worry, this is a good thing. Imagine that each cell has a team of workers with special garbage trucks that constantly patrol, looking for things that are old, broken, or no longer useful: damaged proteins, pieces of worn-out membranes, or even mitochondria that no longer function properly. This team collects all this waste, takes it to cellular recycling centers called lysosomes, where everything is broken down into basic parts that can be reused to build new things. It's like a circular economy system inside each cell. Ivermectin can modify the signals that control when and how much this cleaning team works, particularly by influencing a signaling pathway called mTOR, which acts as the supervisor that decides whether it's time to build new things or clean up and recycle the old. By modulating this pathway, ivermectin could help cells keep their interiors cleaner and more organized, eliminating damaged components before they cause problems.

The messengers of the immune system and its molecular megaphone

The immune system is like a defense force with many different types of cellular soldiers that constantly communicate with each other using chemical messengers called cytokines. These cytokines are like text messages that immune cells send to coordinate their responses. Some messages say, "Something's wrong here, we need more troops," while others say, "Everything's fine, you can relax." For these messages to occur, the cell needs to activate certain molecular commanders, one of the most important being nuclear factor kappa B, or NF-κB for short. This commander normally lives in the cytoplasm, but when it detects something that requires attention, it travels to the nucleus to activate the genes that produce alarm messages. Ivermectin can interfere with this journey of the commander to the nucleus, preventing it from activating as many alarm genes. It's as if it turns down the volume of the megaphone that broadcasts the alarm signals, helping to keep immune responses at a balanced level instead of turning into an overreaction involving too many cells and too many inflammatory messages.

The close ties that protect internal borders

Imagine the lining of your intestine as a brick wall, where each brick is a cell. But unlike a normal wall, this one needs to let certain good things in (nutrients, water, vitamins) while keeping out other things that could be problematic (bacteria, toxins, undigested food fragments). To accomplish this, the cell-bricks are held together with a special molecular cement called tight junctions, made up of proteins with names like claudins, occludins, and ZO proteins. These junctions determine how tight or permeable the wall is. Ivermectin can modify how these junction proteins are organized and expressed, potentially changing how selective the intestinal barrier is. It's as if it adjusts the amount and quality of cement between the bricks, which could influence how many substances can slip between the cells instead of having to pass through them. This ability to modulate the integrity of protective barriers represents one way ivermectin can influence how the body controls what goes in and what stays out in its different compartments.

The molecular ballet of cell survival or sacrifice

Every cell in your body constantly faces an existential decision: continue living or self-destruct for the good of the organism? This process of controlled self-destruction is called apoptosis, and it's essential for eliminating damaged, infected, or simply outdated cells. It's not a bad thing; it's like urban renewal for the cellular city, where old buildings are demolished in a controlled manner to make room for new and better ones. Cells have a committee of proteins from the Bcl-2 family that votes on this decision: some proteins vote for survival, while others vote for self-destruction. Ivermectin can influence this molecular committee, shifting the balance between votes for survival and votes for sacrifice. In particular, it can affect how these proteins control the membranes of mitochondria, those powerhouses we mentioned earlier. If the vote favors sacrifice, the mitochondrial membranes become permeable and release molecules that activate the "molecular scissors" called caspases, which systematically dismantle the entire cell. By participating in these fundamental cellular decisions, ivermectin contributes to the quality control mechanisms that maintain healthy cell populations.

The roadmap that guides tissue development and renewal

There is an ancient signaling pathway called Wnt/β-catenin that acts like a GPS navigation system for cells, telling them when to divide, differentiate into specialized cell types, or maintain their juvenile stem cell state. At the heart of this system is a protein called beta-catenin, which is normally rapidly broken down in the cytoplasm. But when the correct Wnt signals arrive, it stabilizes and travels to the nucleus, where it activates genes important for cell growth and renewal. Ivermectin can interfere with this navigation system, affecting how much beta-catenin accumulates and where it ends up in the cell. It's as if it modifies the GPS instructions, potentially changing where cells are headed on their developmental journey. This ability to modulate the Wnt pathway has fascinating implications for tissue renewal processes, stem cell maintenance, and how tissues decide when they need to create new cells to replace old ones or repair damage.

The amplifiers of tranquilizing signals of the nervous system

The nervous system functions with a delicate balance between "go!" (excitatory) and "stop!" (inhibitory) signals. Two of the main neurotransmitters that send "stop" signals are GABA and glycine, which open special gates in neurons to allow chloride ions to enter, making it harder for the neuron to fire. Ivermectin acts as an amplifier of these calming signals, not by directly activating them, but by causing the gates that GABA or glycine open to remain open a little longer. It's as if it turns up the volume of a calming message that was already being transmitted. This occurs primarily in the peripheral nervous system, the network of nerve fibers that runs throughout the body, connecting the brain and spinal cord to the rest of the body. By enhancing these natural inhibitory signals, ivermectin can influence the balance between excitation and inhibition in nerve circuits that control various bodily functions, promoting the transmission of electrical signals in a more regulated and balanced manner.

Lipid metabolism and its master regulators

The fats in your body aren't just stored as energy reserves; they participate in complex molecular conversations about the body's overall metabolic state. Molecular sensors called nuclear receptors, such as the liver's X receptor (LXR), detect levels of cholesterol and other lipids and respond by turning genes on or off that control how cholesterol is produced, transported, and eliminated. It's like a thermostat that measures fat levels and adjusts production and elimination to maintain the right balance. Ivermectin can influence these sensors and the genes they control, potentially altering how cells handle different types of fat. This includes genes that determine how much cholesterol is produced inside cells, how much is transported out, and how fatty acids are metabolized for energy. By participating in the regulation of these lipid metabolic pathways, ivermectin could contribute to the complex systems by which the body maintains balance in its fat and cholesterol economy.

The molecular gatekeepers who decide what goes in and what goes out

In the membranes of your cells are incredible molecular pumps called ABC transporters, with P-glycoprotein (P-gp) being one of the most important. Imagine these pumps as special revolving doors that only swing in one direction: outward. Their job is to recognize foreign or potentially problematic substances that have entered the cell and actively expel them, using energy in the form of ATP. These pumps are strategically located in places like the gut (reducing how much you absorb of certain substances), the liver and kidneys (helping to eliminate them from the body), and the blood-brain barrier (protecting the brain). Ivermectin has a complex relationship with these pumps: it's both a passenger that the pumps try to expel and a modulator that can affect their function. It's as if ivermectin can sometimes occupy the gatekeepers, giving other substances that are also passengers on these pumps a better chance of staying inside. This interaction with cellular transport systems illustrates the sophisticated defense mechanisms the body has developed to control which substances can accumulate in different tissues.

A molecular orchestra with multiple instruments

If we had to summarize how ivermectin works with a single image, it would be that of a molecular conductor who doesn't play just one instrument, but rather modulates the volume and rhythm of multiple sections of the orchestra simultaneously. It doesn't replace the body's natural musicians—its own hormones, neurotransmitters, and signaling molecules—but instead adjusts how and when they play. It lowers the volume of some inflammatory signals while boosting the calming whispers of the peripheral nervous system. It interferes with the messengers that carry messages to the cell nucleus, changing which genetic instructions are executed. It adjusts the thermostats of the mitochondrial power plants and oversees the cleanup crew that recycles old cellular components. It modulates the guards at the borders between different compartments of the body and participates in decisions about when a cell should renew itself or retire. This entire symphony of molecular effects works together, creating a complex pattern of modulation that affects multiple systems simultaneously, from energy metabolism to cell communication, from the integrity of protective barriers to the regulation of immune responses, demonstrating that the most fascinating molecules are those that can play multiple notes in the complex composition that is cellular life.

Modulation of glutamate-dependent chloride channels and GABAergic receptors

Ivermectin exerts its primary action by selectively and with high affinity binding to glutamate-gated chloride channels present in nerve and muscle cells of invertebrates. These channels, belonging to the Cys-loop ionotropic receptor superfamily, are activated by the neurotransmitter glutamate in invertebrate organisms and mediate inhibitory neurotransmission through the influx of chloride ions. Ivermectin binds to allosteric sites at the interface between channel subunits, stabilizing their open conformation and significantly increasing the probability of opening and the time spent in the open state. This potentiation of chloride influx results in sustained hyperpolarization of the cell membrane, reducing neuronal excitability and synaptic transmission. In mammals, where glutamate-dependent chloride channels are absent, ivermectin interacts with GABAergic (gamma-aminobutyric acid type A) and glycinergic receptors in the peripheral nervous system, acting as a positive allosteric modulator that potentiates the chloride current mediated by these endogenous inhibitory neurotransmitters. Selectivity for peripheral versus central receptors is determined by the differential expression of P-glycoprotein in the blood-brain barrier, which actively limits ivermectin penetration into the central nervous system via ATP-dependent efflux transport. This substrate specificity and the tissue distribution of transporters contribute to the differential safety profile observed between species and explain the therapeutic window based on fundamental structural differences in neurotransmission between invertebrates and vertebrates.

Inhibition of nuclear transport mediated by importins alpha and beta

Ivermectin can interfere with the nucleocytoplasmic transport system by specifically inhibiting the importin alpha/beta complex, an essential component of the cellular machinery responsible for trafficking cargo proteins between the cytoplasm and the nucleus. Importins recognize nuclear localization sequences (NLS) on target proteins and facilitate their translocation through the nuclear pore complex, a fundamental process for regulating gene expression, cell signaling, and the response to external stimuli. Ivermectin binds to the cargo-binding domain of importin alpha, sterically blocking its interaction with proteins containing classical NLS signals. This competitive inhibition mechanism prevents the formation of the ternary importin alpha-cargo-importin beta complex necessary for nucleoporin recognition and passage through the nuclear pore. The functional consequence of this inhibition is the cytoplasmic retention of transcription factors, cell cycle regulatory proteins, signaling pathway components, and viral proteins that depend on nuclear import to perform their functions. Structural studies have revealed that ivermectin occupies the NLS-binding groove of importin alpha, establishing hydrophobic interactions and hydrogen bonds with critical residues of the recognition site. This inhibition of nuclear transport represents a versatile mechanism of action that can affect multiple cellular processes simultaneously, from the activation of transcriptional responses to the replication of intracellular pathogens that utilize the host's import machinery.

Modulation of the NF-κB signaling pathway and inflammatory response

Ivermectin interferes with the activation and function of nuclear factor kappa B (NF-κB), a pleiotropic transcription factor that regulates the expression of more than 500 genes involved in immune responses, inflammation, cell survival, and proliferation. In its basal state, NF-κB remains sequestered in the cytoplasm by binding to inhibitory IκB proteins. Upon stimulation with various pro-inflammatory stimuli, the IKK (IκB kinase) complex phosphorylates IκB, marking it for proteasomal degradation and releasing NF-κB for nuclear translocation. Ivermectin can modulate this pathway through multiple convergent mechanisms: first, by inhibiting importin-mediated nuclear transport, it directly blocks the entry of NF-κB into the nucleus even after its release from IκB; Second, it can interfere with the phosphorylation and activation of the IKK complex, reducing IκB degradation and maintaining NF-κB in a cytoplasmic inactive state; third, it modulates the expression of negative regulators of the pathway such as A20 and CYLD, establishing a negative feedback loop. The functional consequence of this multilevel modulation is the reduction in the transcription of NF-κB target genes, including proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8, chemokines, adhesion molecules, inducible enzymes such as COX-2 and iNOS, and anti-apoptotic factors of the Bcl-2 family. This ability to modulate the NF-κB pathway without completely suppressing it allows for fine-tuning of inflammatory responses, promoting the resolution of excessive inflammatory processes while preserving essential immune responses.

Interference with mitochondrial function and energy homeostasis

Ivermectin exerts pleiotropic effects on mitochondrial function, affecting multiple aspects of cellular bioenergetics and redox signaling. The compound can accumulate in the mitochondrial membrane due to its lipophilic nature and the negative electrochemical gradient of the mitochondrial matrix, where it interferes with components of the electron transport chain. Specifically, ivermectin partially inhibits complexes I and III of the respiratory chain, reducing the efficiency of oxidative phosphorylation and altering the mitochondrial membrane potential (ΔΨm). This mitochondrial depolarization has multiple consequences: first, it reduces ATP synthesis by activating energy stress sensors such as AMPK (AMP-activated protein kinase); second, it increases the production of reactive oxygen species (ROS) by promoting electron leakage from the respiratory chain, particularly at complex I; and third, it disrupts mitochondrial calcium homeostasis, which is closely linked to the membrane potential. The generated ROS act as oxidative stress signals that activate adaptive response pathways, including the induction of endogenous antioxidants through activation of the transcription factor Nrf2. Furthermore, ivermectin-induced mitochondrial dysfunction can trigger the activation of selective mitochondrial autophagy (mitophagy), a process by which damaged mitochondria are secreted and degraded to maintain the quality of the mitochondrial pool. Modulation of mitochondrial function also affects signaling pathways dependent on mitochondrial metabolites, such as the NAD+/NADH ratio that regulates sirtuin activity, and the production of Krebs cycle intermediate metabolites that function as epigenetic signals.

Induction and modulation of autophagy by mTOR regulation

Ivermectin acts as a modulator of macroautophagy, a catabolic process by which cytoplasmic components, aggregated proteins, and dysfunctional organelles are sequestered in double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation and recycling. The primary mechanism by which ivermectin induces autophagy involves the inhibition of the mTOR (mechanistic target of rapamycin) signaling pathway, a central regulator of cellular metabolism that integrates signals for nutrient availability, growth factors, and energy status. mTOR exists in two distinct complexes: mTORC1, which primarily regulates protein synthesis, lipogenesis, and autophagy; and mTORC2, which controls cytoskeleton organization and cell survival. Ivermectin preferentially inhibits mTORC1, resulting in the dephosphorylation and activation of ULK1 (Unc-51-like kinase 1), a key initiator of the autophagic process that phosphorylates components of the PI3K class III complex necessary for phagophore nucleation. Simultaneously, mTORC1 inhibition derepresses the transcription of autophagy-related genes by activating the transcription factor TFEB (transcription factor EB), which translocates to the nucleus and induces the expression of genes encoding ATG proteins (autophagy-related genes), lysosomal components, and degradative enzymes. Ivermectin also activates AMPK through its effect on mitochondrial energy metabolism, and activated AMPK directly phosphorylates ULK1 and TSC2, indirectly inhibiting mTORC1 via a feedback loop. This induction of autophagy has implications for protein quality control, the elimination of toxic aggregates, organelle renewal, and the cellular response to metabolic and nutritional stress.

Modulation of Bcl-2 family proteins and regulation of apoptosis

Ivermectin influences programmed cell death, or apoptosis, by modulating the balance between pro-apoptotic and anti-apoptotic proteins of the Bcl-2 family, which control outer mitochondrial membrane permeabilization (MOMP), an event involved in the intrinsic pathway of apoptosis. The Bcl-2 family includes anti-apoptotic members such as Bcl-2, Bcl-xL, and Mcl-1, which reside in the outer mitochondrial membrane and prevent MOMP, as well as pro-apoptotic members such as Bax and Bak, which oligomerize to form pores in the membrane, and BH3-only proteins such as Bid, Bim, and Puma, which act as stress sensors and activators of Bax/Bak. Ivermectin alters this balance through multiple mechanisms: it induces the expression of BH3-only proteins through stress pathways, including p53, which responds to mitochondrial and genotoxic stress induced by the compound; It reduces the expression of anti-apoptotic proteins by inhibiting NF-κB and modulating mRNA stability; and it facilitates the conformational activation of Bax, promoting its insertion into the mitochondrial membrane and oligomerization. When the balance shifts toward pro-apoptotic signals, MOMP occurs, resulting in the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. The released cytochrome c associates with Apaf-1 and procaspase-9 to form the apoptosome, a complex that activates initiator caspase-9, which in turn activates effector caspases 3 and 7 that carry out cell dismantling by cleaving hundreds of protein substrates. This mechanism of apoptotic sensitization may be particularly relevant in cells with a high proliferative rate or with dysregulated anti-apoptotic systems.

Interference with the Wnt/β-catenin signaling pathway

Ivermectin modulates the canonical Wnt/β-catenin pathway, an evolutionarily conserved signaling system that regulates fundamental processes of development, tissue homeostasis, stem cell renewal, and cell proliferation. In the absence of Wnt signals, cytoplasmic β-catenin is sequentially phosphorylated by the destruction complex composed of the scaffold proteins Axin and APC, along with the kinases CK1α and GSK3β. This phosphorylation marks β-catenin for ubiquitination by the E3 ligase β-TrCP complex and subsequent proteasomal degradation. When Wnt ligands bind to Frizzled receptors and LRP5/6 coreceptors, a cascade is initiated that inhibits the destruction complex, allowing the accumulation and nuclear translocation of β-catenin, where it interacts with TCF/LEF transcription factors to activate target genes, including c-Myc, cyclin D1, and Axin2. Ivermectin interferes with this pathway through multiple checkpoints: it stabilizes the destruction complex and promotes GSK3β-mediated phosphorylation of β-catenin, increasing its degradation; it inhibits the nuclear translocation of β-catenin both by increased degradation and by blocking importin-mediated nuclear transport; and it can modulate the expression of negative regulators of the pathway such as Dickkopf-1 (DKK1). The functional consequence of this multilevel inhibition is a reduction in the transcription of Wnt/β-catenin target genes, affecting cell proliferation, stemness maintenance, epithelial-mesenchymal transition, and cell metabolism. This modulation of Wnt signaling has implications for tissue renewal, cell differentiation, and cell cycle control in various physiological contexts.

Modulation of ABC transporters and P-glycoprotein

Ivermectin interacts in a complex manner with the ABC (ATP-binding cassette) transporter superfamily, particularly with P-glycoprotein (P-gp/MDR1/ABCB1), an ATP-dependent efflux transporter located in the plasma membranes of various tissues with barrier and excretory functions. P-gp recognizes a broad spectrum of hydrophobic and amphipathic substrates, extracting them from the cell membrane or cytoplasm and expelling them to the extracellular space, a process that consumes energy through ATP hydrolysis. Ivermectin is both a substrate and a modulator of P-gp: as a substrate, it is recognized and transported by P-gp, which limits its intracellular accumulation in tissues that express high levels of the transporter, particularly endothelial cells of the blood-brain barrier, intestinal enterocytes, and renal tubular epithelial cells. The functional expression of P-gp at these biological barriers determines the pharmacokinetics of ivermectin, limiting its intestinal absorption, promoting its biliary secretion, and restricting its access to the central nervous system. As a modulator, ivermectin can alter P-gp activity, potentially affecting the transport of other substrates that share this efflux system. The mechanism of this modulation may involve prolonged occupation of the substrate-binding site, alteration of ATPase activity, or conformational changes that affect transport kinetics. Additionally, ivermectin can affect ABCB1 gene expression by modulating transcription factors such as PXR (pregnane X receptor), which regulates the transcription of transporter genes in response to xenobiotics. This bidirectional interaction with efflux transport systems has important implications for the bioavailability, tissue distribution, and elimination of ivermectin, as well as for potential pharmacokinetic interactions with other compounds that are substrates, inhibitors, or inducers of P-gp.

Inhibition of helicases and modulation of nucleic acid processes

Ivermectin exhibits the ability to inhibit the activity of certain helicases, essential enzymes that catalyze the ATP-dependent separation of complementary nucleic acid strands during DNA replication, transcription, repair, and recombination. Helicases translocate along the nucleic acid chain in a defined direction, using ATP hydrolysis energy to break the hydrogen bonds between complementary bases and unwind the double helix. Ivermectin can bind to the ATP-binding site or motor domain of certain helicases, competitively inhibiting their catalytic activity. This inhibition has multiple potential consequences: during replication, the inhibition of helicases such as MCM2-7 can slow the progression of replication forks; during transcription, it can impair the unwinding of DNA necessary for RNA polymerase access; and in repair processes, it can compromise the processing of DNA structures that require unwinding for resolution. Furthermore, certain viral helicases, which are essential for the replication of viral DNA or RNA genomes, may be sensitive to inhibition by ivermectin, providing a potential mechanism for interfering with viral replication cycles. The specificity of this inhibition depends on particular structural characteristics of each helicase, including the sequence and conformation of its catalytic site, the presence of accessory domains, and its coupling mechanism between ATP hydrolysis and translocation. This ability to modulate the activity of enzymes that manipulate nucleic acids represents a mechanism of action that can influence gene expression, genomic integrity, and potentially the replication of certain intracellular pathogens.

Modulation of lipid metabolism and nuclear receptors

Ivermectin influences metabolic pathways related to lipid and cholesterol metabolism by modulating nuclear receptors, ligand-activated transcription factors that regulate the expression of metabolic genes in response to lipids and other metabolites. Specifically, ivermectin can modulate the activity of the liver X receptor (LXR), an oxysterol sensor that regulates cholesterol homeostasis, fatty acid metabolism, and inflammatory responses. LXR exists in two isoforms, LXRα (predominant in the liver, intestine, kidney, and adipose tissue) and LXRβ (ubiquitously expressed), which, upon activation by endogenous oxysterols, form heterodimers with the retinoid X receptor (RXR) and bind to LXR response elements (LXREs) in the promoters of target genes. The target genes of LXR include ABCA1 and ABCG1 (cellular cholesterol transporters involved in cholesterol efflux), SREBP-1c (master regulator of lipogenesis), ApoE (a lipoprotein component), and CYP7A1 (the rate-limiting enzyme in bile acid synthesis from cholesterol). Ivermectin can act as an LXR modulator, altering the transcription of these genes and consequently affecting multiple aspects of lipid metabolism: reverse cholesterol transport from peripheral tissues, de novo fatty acid synthesis in the liver, the production and secretion of triglyceride-rich lipoproteins, and the conversion of cholesterol to bile acids. Additionally, LXR modulation can have anti-inflammatory effects independent of its metabolic effects, through the transrepression of inflammatory genes via mechanisms involving SUMOylation of LXR and its interference with NF-κB. Ivermectin can also affect other nuclear receptors such as PPARs (peroxisome proliferator-activated receptors), which regulate fatty acid oxidation, insulin sensitivity, and adipocyte differentiation, thus expanding its metabolic modulation profile.

Alteration of the permeability of epithelial tight junctions

Ivermectin modulates the structural and functional integrity of tight junctions, multiprotein complexes that seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport of ions, solutes, and water. Tight junctions are composed of transmembrane proteins (claudins, occludin, JAMs) that form the intercellular seal, and cytoplasmic scaffolding proteins (ZO-1, ZO-2, ZO-3) that connect the transmembrane proteins to the actin cytoskeleton and signaling pathways. The specific composition of claudin isoforms determines the selective permeability properties of each epithelium. Ivermectin can alter epithelial barrier function through multiple mechanisms: it modulates the transcriptional expression of tight junction proteins, particularly by reducing the expression of barrier-forming claudins and increasing the expression of pore-forming claudins; It induces changes in the phosphorylation of tight junction proteins mediated by kinases such as PKC and MLCK, affecting their assembly and stability; it alters the organization of the actin cytoskeleton to which tight junctions are anchored, by modulating Rho GTPases that regulate actin dynamics; and it can promote the internalization of tight junction proteins from the plasma membrane via clathrin- or caveolin-dependent endocytosis. These effects on tight junctions have implications for the paracellular permeability of epithelial barriers in various tissues, particularly the intestinal epithelium, where they can affect nutrient absorption and the exclusion of luminal antigens, the blood-brain barrier, where they regulate the access of substances to the brain parenchyma, and renal and pulmonary epithelial barriers that control the movement of fluids and solutes between compartments.

Modulation of kinase-dependent signaling pathways

Ivermectin interferes with multiple signaling cascades mediated by protein kinases, enzymes that catalyze the transfer of phosphate groups from ATP to serine, threonine, or tyrosine residues in substrate proteins, modifying their activity, location, or interactions. Reversible protein phosphorylation is a fundamental regulatory mechanism for virtually all cellular processes. Ivermectin can modulate the activity of several key kinases: it inhibits Akt (PKB), a central kinase in the PI3K/Akt pathway that regulates cell survival, glucose metabolism, and protein synthesis, through multiple mechanisms, including the inhibition of mTORC2, which phosphorylates Akt at Ser473, and the activation of phosphatases such as PHLPP, which dephosphorylate Akt; it activates AMPK in response to the mitochondrial energy stress it induces, and activated AMPK phosphorylates numerous substrates, including ACC, TSC2, and ULK1, coordinating a metabolic shift toward catabolism and energy conservation. It modulates MAP kinases (ERK, JNK, p38) that transduce signals from cell surface receptors to the nucleus, affecting proliferation, differentiation, and apoptosis; and it can influence cell cycle checkpoint kinases such as CDKs (cyclin-dependent kinases), affecting progression through specific cell cycle phases. Modulation of these phosphorylation networks has pleiotropic effects that propagate through interconnected signaling circuits, altering gene expression patterns, protein localization, protein complex stability, and flux through metabolic pathways, illustrating how a single molecule can generate complex and context-dependent effects by perturbing critical nodes in cell signaling networks.