Lamotrigine

Inhibition of Voltage-Sensitive Sodium Channels

A key mechanism of this compound involves the inhibition of voltage-sensitive sodium channels (VGSCs). These channels are essential for the initiation and propagation of action potentials in excitable cells. patsnap.comdrugbank.com By interacting with VGSCs, this compound helps to stabilize neuronal membranes and reduce excessive neuronal firing. patsnap.comdroracle.ai

Electrophysiological studies have provided significant insights into how this compound interacts with sodium channels. Research has shown that this compound blocks sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations relevant to therapeutic use in human seizures. wikipedia.org this compound has been demonstrated to inhibit the opening of voltage-gated sodium channels, leading to a reduction in the spread of electrical activity in neurons. nih.gov In vitro and in vivo studies have consistently shown a reduction in sodium channel activity following this compound treatment. nih.govmdpi.com

This compound selectively binds to and inhibits voltage-gated sodium channels, stabilizing presynaptic neuronal membranes and inhibiting the release of excitatory neurotransmitters like glutamate and aspartate. nih.govdroracle.ai This blockage is thought to occur preferentially when the sodium channels are in their inactivated state, preventing them from returning to an active state. patsnap.comresearchgate.net This state-dependent interaction is crucial for its therapeutic effect, as it allows for the preferential inhibition of pathologically overactive neurons while sparing normal neuronal activity. mdpi.comphysiology.org

This compound exhibits use-dependent or frequency-dependent inhibition of neuronal firing. researchgate.netnih.govif-pan.krakow.pl This means that the degree of channel blockade increases with increased neuronal activity and rapid repetitive stimulation. researchgate.netif-pan.krakow.plresearchgate.net During high-frequency firing, a larger proportion of sodium channels enter the inactivated state, and this compound's preferential binding to this state leads to enhanced inhibition. if-pan.krakow.plresearchgate.netnih.gov This use-dependent property is considered important for its ability to attenuate supranormal neuronal activities associated with conditions like epilepsy and bipolar disorder. nih.gov Studies using electrophysiological techniques on rat hippocampal slices have shown that the inhibition of compound action potentials by this compound is increased at higher stimulation frequencies. if-pan.krakow.pl

This compound shares a similar mechanism of inhibiting voltage-sensitive sodium channels with other anticonvulsant drugs like phenytoin and carbamazepine. drugbank.commdpi.comphysiology.org These drugs also block the repetitive activation of sodium channels. mdpi.com However, there are notable differences in their interactions with the channels. Studies comparing the effects of this compound, carbamazepine, and phenytoin on human brain sodium channel alpha-subunits (NaV1.1, NaV1.2, NaV1.3, and NaV1.6) expressed in HEK293 cells have revealed distinctions. nih.govnih.gov this compound evokes a larger maximal shift of the steady-state inactivation relationship compared to carbamazepine or phenytoin. nih.govnih.gov While carbamazepine shows the highest binding rate to the alpha-subunits, this compound's unbinding from the alpha-subunits is slower than that of carbamazepine and phenytoin. nih.gov These differences in binding kinetics and effects on inactivation may contribute to their distinct clinical profiles. nih.gov

A comparative study on rat hippocampal slices found that this compound and carbamazepine inhibited hippocampal backpropagated compound action potentials with similar concentration-response relationships at a low stimulation frequency (0.5 Hz), with interpolated IC50 values of 210 µM for both. Phenytoin had an extrapolated IC50 of 400 µM in this model. if-pan.krakow.pl However, at higher frequencies (≥ 30 Hz), this compound produced a marked concentration-dependent additional inhibition of the response amplitude. if-pan.krakow.pl

Note: IC50 values are interpolated or extrapolated from the provided data in the source.

The inhibition of voltage-sensitive sodium channels by this compound plays a crucial role in stabilizing neuronal membranes and reducing hyperexcitability. patsnap.comdroracle.ai By blocking sodium channels, particularly in their inactivated state during periods of high-frequency firing, this compound limits the rapid influx of sodium ions required for action potential generation and propagation. patsnap.comresearchgate.net This action attenuates the excessive electrical activity that underlies seizures and mood instability in conditions like epilepsy and bipolar disorder. droracle.aidroracle.ainih.gov The stabilization of neuronal membranes also contributes to the inhibition of the release of excitatory neurotransmitters such as glutamate and aspartate, which are implicated in neuronal hyperexcitation. droracle.aiwikipedia.orgnih.govdroracle.ai

Comparison with Phenytoin and Carbamazepine

Modulation of Voltage-Gated Calcium Channels

Beyond its well-established effects on sodium channels, this compound has also been reported to modulate voltage-gated calcium channels (VGCCs). patsnap.comwikipedia.orgnih.gov Calcium channels are critical for various neuronal functions, including neurotransmitter release and the regulation of neuronal excitability. patsnap.com While the primary focus of this compound's mechanism has been on sodium channels, some studies suggest that its effects on calcium channels may contribute to its broader spectrum of activity. patsnap.comwikipedia.org

This compound has been shown to inhibit native and recombinant high voltage-gated calcium channels (N- and P/Q/R-types) at therapeutic concentrations. wikipedia.org It has been suggested that this compound modulates intracellular calcium signaling by inhibiting the release of calcium ions from intracellular stores and reducing the influx of calcium ions through VGCCs. nih.govmdpi.com The reduction of calcium influx can influence calcium-dependent signaling pathways. nih.govmdpi.com An in vivo study provided evidence that this compound inhibits Cav2.3 (R-type) calcium currents, potentially contributing to its anticonvulsant effects. drugbank.com

Inhibition of L-, N-, and P-type Calcium Channels

Research indicates that this compound blocks voltage-gated calcium channels, including L-, N-, and P-type channels. wikipedia.orgresearchgate.netscielo.brpharmgkb.org This action is thought to contribute to its broader spectrum of activity compared to some other sodium channel blockers. wikipedia.org The inhibition of calcium influx through these channels can influence various calcium-dependent signaling pathways and reduce the release of neurotransmitters. nih.govnih.gov Studies have shown that this compound reduces calcium currents. mdpi.com

Interaction with Vesicular Release of Neurotransmitters

This compound's modulation of voltage-gated sodium and calcium channels leads to an interaction with the vesicular release of neurotransmitters. pharmgkb.orgoup.comfabad.org.tr By stabilizing presynaptic neuronal membranes and reducing calcium influx, this compound inhibits the release of excitatory amino acids from presynaptic vesicles. nih.govoup.comfabad.org.trahajournals.org This is considered a key mechanism by which it reduces neuronal excitability. mims.comdrugbank.compatsnap.commdpi.comnih.govdroracle.ai

Hyperpolarization-Activated Cyclic Nucleotide (HCN) Channels Modulation

This compound has been shown to modulate hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, also known as h-channels or pacemaker channels. nih.govresearchgate.netaginganddisease.org These channels are involved in setting the resting membrane potential and regulating neuronal excitability and rhythmic firing. nih.govaginganddisease.org this compound has been described as a non-specific modulator or agonist of HCN channels, potentially enhancing the h-current mediated by these channels in pyramidal neurons. researchgate.netaginganddisease.orgjneurosci.orgfrontiersin.orgmdpi.com This modulation may contribute to its effects on neuronal activity and potentially impact brain functions beyond its primary indications. nih.govaginganddisease.org

Glutamatergic System Modulation

A significant aspect of this compound's mechanism of action is its modulation of the glutamatergic system. patsnap.comdovepress.com By influencing ion channel activity, this compound reduces the excessive release of excitatory amino acids. wikipedia.orgmims.comdrugbank.commdpi.comnih.govdroracle.ai

This compound is known to inhibit the release of the excitatory amino acids glutamate and aspartate. wikipedia.orgnih.govmims.compatsnap.commdpi.comnih.govdroracle.aioup.comfabad.org.trjrespharm.comoup.com This inhibition is a direct consequence of its effects on voltage-gated sodium and calcium channels, which are crucial for the depolarization-evoked release of these neurotransmitters. wikipedia.orgnih.govoup.comfabad.org.trjrespharm.comoup.comnih.gov Studies in rat brain slices and synaptosomes have demonstrated that this compound reduces the release of glutamate and aspartate evoked by stimuli that promote sodium channel activity or calcium influx. wikipedia.orgnih.govjrespharm.comoup.comnih.gov

Data illustrating the effect of this compound on excitatory amino acid release has been observed in experimental settings. For example, studies using rat cerebral cortex slices in vitro showed that this compound inhibited the veratrine-evoked release of glutamate and aspartate in a concentration-dependent manner. wikipedia.org Another study using isolated cerebrocortical nerve terminals (synaptosomes) demonstrated that this compound inhibited 4-aminopyridine (4AP)-evoked glutamate release, which was associated with a reduction in the depolarization-evoked increase in cytoplasmic free Ca2+ concentration. nih.gov

This compound's inhibitory effect on glutamate release is primarily mediated by its actions at the presynaptic terminal. wikipedia.orgdrugbank.compatsnap.comnih.govnih.govoup.comahajournals.orgdovepress.com By blocking voltage-gated sodium channels in their inactivated state, this compound stabilizes the presynaptic membrane and reduces the sustained repetitive firing of neurons. wikipedia.orgdrugbank.compatsnap.commdpi.comnih.govdroracle.ai This, in turn, reduces the influx of calcium through voltage-gated calcium channels, which is a critical step in the process of vesicular neurotransmitter release. nih.govoup.comfabad.org.tr Therefore, this compound's presynaptic actions on sodium and calcium channels converge to inhibit the release of glutamate into the synaptic cleft. wikipedia.orgnih.govoup.comfabad.org.trahajournals.org

Here is a summary of the effects of this compound on ion channels and neurotransmitter release:

Role in Anti-Glutamatergic Effects

A significant aspect of this compound's mechanism is its role in anti-glutamatergic effects. This compound is thought to reduce the release of glutamate, the principal excitatory neurotransmitter in the mammalian brain mdpi.comdrugbank.comwikipedia.orgepilepsysociety.org.uk. This is primarily achieved through the inhibition of voltage-sensitive sodium channels, which stabilizes neuronal membranes and consequently reduces the release of excitatory amino acids like glutamate and aspartate drugbank.comwikipedia.orgdergipark.org.trjrespharm.com. Studies using rat cortical slices have shown that this compound inhibits the veratrine-stimulated release of glutamate wikipedia.orgnih.gov. This reduction in glutamate release is considered a key contributor to its anticonvulsant and potentially its mood-stabilizing effects mdpi.comwikipedia.orgscielo.br. Multiple studies have demonstrated a decrease in glutamate levels in brain tissue and synaptic fluid following this compound treatment nih.govmdpi.com.

GABAergic System Modulation

This compound also interacts with the GABAergic system, although the nature and extent of this modulation appear complex and have been the subject of conflicting findings. GABA is the major inhibitory neurotransmitter in the brain, and its activity is crucial for regulating neuronal excitability jrespharm.comneurology.orgajnr.org.

Enhancement of Gamma-Aminobutyric Acid (GABA) Release

Some research indicates that this compound may enhance the release of GABA. Studies in the rat entorhinal cortex using whole-cell patch clamp techniques observed that this compound increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs), suggesting a presynaptic effect that enhances GABA release nih.govresearchgate.net. Similar effects were noted with miniature IPSCs recorded in the presence of TTX, further supporting a presynaptic mechanism independent of sodium channel blockade nih.govresearchgate.net. An increase in GABA levels in brain tissue and synaptic fluid following this compound treatment has been reported in several studies nih.govmdpi.com.

Attenuation of GABA Release

Conversely, other studies suggest that this compound can attenuate GABA release or GABAergic transmission. Neurochemical studies have indicated that while this compound inhibits glutamate release, at slightly higher concentrations, it can also reduce the release of GABA nih.gov. Studies in rat hippocampal slices have shown that this compound decreased GABAergic inhibition in certain neuronal populations, such as CA3 cells, and reduced spontaneous GABA synaptic activity mdpi.com. It has also been reported that this compound suppresses GABAA-mediated neurotransmission in rat amygdala cells, potentially by affecting presynaptic Ca2+ influx dergipark.org.trjrespharm.com.

GABA Levels in Brain Tissue and Synaptic Fluid

Measurements of GABA levels in brain tissue and synaptic fluid following this compound administration have yielded varied results. Some studies utilizing techniques like microdialysis in rats have shown that acute this compound treatment can elevate GABA levels in cerebrospinal fluid dergipark.org.trjrespharm.comresearchgate.net. Multiple studies have demonstrated an increase in GABA levels in brain tissue and synaptic fluid following this compound treatment nih.govmdpi.com. However, one study using MR spectroscopy in healthy adults did not observe a significant acute change in cerebral GABA concentrations with this compound, although a significant increase was detected after four weeks of chronic dosing neurology.org. This suggests that the effects on GABA levels may be more pronounced with chronic administration dergipark.org.trjrespharm.comneurology.org.

Detailed research findings on the effects of this compound on GABA levels in brain tissue and synaptic fluid are summarized in the table below:

Note: The interactive nature of the table is dependent on the platform rendering this markdown.

Monoaminergic System Modulation

This compound has been investigated for its effects on monoaminergic neurotransmission, which includes serotonin, dopamine, and noradrenaline systems. These interactions are generally considered weak compared to its effects on voltage-gated sodium channels. wikipedia.orgfda.gov

Inhibition of Serotonin 5-HT3 Receptor (Weak)

Studies have indicated that this compound has a weak inhibitory effect on the serotonin 5-HT3 receptor. medex.com.bdfda.govnih.govdrugbank.comebmconsult.comnih.gov In laboratory binding assays, this compound demonstrated an inhibitory effect on the 5-HT3 receptor with an IC50 value of 18 µM. fda.govebmconsult.com

Apparent Inhibition of Serotonin, Dopamine, and Noradrenaline Uptake

This compound has been reported to exhibit apparent inhibitory effects on the synaptosomal uptake of serotonin, noradrenaline, and dopamine in rat brain studies. nih.govmdpi.comfrontiersin.org However, in vitro studies using rat synaptosomes and/or human platelets did not show inhibition of the uptake of norepinephrine, dopamine, or serotonin at IC50 values greater than 200 µM. fda.govebmconsult.com This suggests that while some in vivo observations might indicate an effect on monoamine uptake, direct inhibitory effects in isolated systems appear weak or absent at concentrations typically studied in these assays. fda.govebmconsult.com

The following table summarizes some reported IC50 values related to this compound's effects on monoamine uptake:

Other Neurotransmitter Receptor Binding (Weak Inhibitory Effects)

In addition to its primary actions and effects on the monoaminergic system, this compound has been shown to interact weakly with a variety of other neurotransmitter receptors in laboratory binding assays. medex.com.bdfda.govnih.govdrugbank.comebmconsult.com These interactions are generally characterized by low affinity, with IC50 values typically exceeding 100 µM. medex.com.bdnih.govdrugbank.com

Adenosine A1/A2 Receptors

This compound has been reported to bind weakly to Adenosine A1 and A2 receptors. medex.com.bdfda.govnih.govdrugbank.comebmconsult.com In receptor binding assays, this compound does not exhibit high affinity binding to these receptors, with IC50 values greater than 100 µM. fda.govebmconsult.com

Alpha-1/Alpha-2/Beta Adrenergic Receptors

This compound also demonstrates weak binding to alpha-1, alpha-2, and beta adrenergic receptors. medex.com.bdfda.govnih.govdrugbank.comebmconsult.com Similar to adenosine receptors, this compound does not show high affinity binding to these adrenergic receptor subtypes, with reported IC50 values exceeding 100 µM in binding assays. fda.govebmconsult.com

The following table summarizes some reported binding affinities (or lack thereof) for this compound at other neurotransmitter receptors:

Dopamine D1/D2 Receptors

This compound does not appear to have pronounced effects on dopamine D1 and D2 receptors. wikipedia.org Laboratory binding assays indicate weak binding to dopamine D1/D2 receptors with an IC50 > 100 µM. nih.gov However, some research suggests that chronic administration of this compound may enhance extracellular concentrations of dopamine in the rat hippocampus. researchgate.netmdpi.com One hypothesis posits that this compound might boost dopamine release through weak direct binding to D1/D2 receptors and indirectly via serotonergic modulation of dopaminergic transmission. researchgate.net Another study in rats suggested that this compound reduces extracellular dopamine in the hippocampus, which could potentially precipitate dopaminergic hypofunction. psychiatryonline.org Studies in mice have shown that this compound can potentiate motor responses mediated by dopamine D2 receptors but not dopamine D1 receptors, an interaction profile noted as being opposite to that seen with glutamate receptor antagonists. nih.gov

Histamine H1 Receptors

Similar to its effects on dopamine receptors, this compound does not have pronounced effects on histaminergic H1 receptors. wikipedia.org In laboratory binding assays, this compound shows weak binding to histamine H1 receptors with an IC50 > 100 µM. nih.gov

Muscarinic Receptors

This compound does not have pronounced effects on muscarinic receptors. wikipedia.org Laboratory binding assays indicate weak binding to mACh receptors with an IC50 > 100 µM. nih.gov

N-methyl-D-aspartate (NMDA) Receptors

While this compound does not have pronounced direct effects on NMDA receptors in the same way it affects sodium channels, it is reported to interfere with glutamatergic neurotransmission involving NMDA receptors. wikipedia.orgresearchgate.netscielo.br this compound has been shown to block NMDA receptor-initiated arachidonic acid signaling in rat brain. wikipedia.orgmdpi.comresearchgate.net This action may contribute to its efficacy, particularly in bipolar disorder, as an up-regulated brain arachidonic acid cascade and a hyperglutamatergic state are thought to characterize the condition. researchgate.net Studies in healthy volunteers have shown that this compound can attenuate the hyperglutamatergic consequences of NMDA receptor dysfunction, such as cognitive dysfunction and psychomimetic effects induced by the NMDA antagonist ketamine. scielo.brjnjmedicalconnect.com The antidepressant effect of this compound has also been attributed to NMDA blockade. mdpi.com

Kappa-Opioid Receptor (KOR)

This compound demonstrates weak binding to the κ-opioid receptor (KOR) with an IC50 > 100 µM in laboratory binding assays. nih.gov

Neuroprotective Properties and Mechanisms

This compound has demonstrated neuroprotective properties in various models. wikipedia.orgpatsnap.comahajournals.orgnih.gov These effects are thought to be linked to its ability to inhibit glutamate release by blocking voltage-sensitive sodium channels, as glutamate plays a significant role in excitotoxicity and neuropathology observed in conditions like ischemia. wikipedia.orgpatsnap.comahajournals.orgmims.com However, the inhibition of glutamate release may not fully explain all observed neuroprotective effects. ahajournals.org

This compound's neuroprotective mechanisms may also involve antioxidant properties, contributing to reduced oxidative stress and increased cell viability. patsnap.comnih.gov Studies have shown that this compound administration can reduce levels of malondialdehyde (MDA) and increase the activity of antioxidants such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in brain tissue. nih.gov Additionally, this compound has been shown to reduce the activation of microglia, the central nervous system's resident immune cells, which are involved in neuroinflammation. nih.gov

Further research indicates that this compound can protect against neurotoxicity induced by substances like kainic acid, which is dependent on neuronally released glutamate. ahajournals.org In models of cerebral ischemia, this compound has been shown to protect against cognitive deficits and reduce neuronal damage, particularly in hippocampal regions. ahajournals.org

The potential neuroprotective effects through the inhibition of apoptotic pathways have also been suggested as a contributor to this compound's ability to stabilize mood. patsnap.com

Neuroprotective Effects of this compound in a Gerbil Model of Global Cerebral Ischemia ahajournals.org

Note: This table summarizes findings from a gerbil model and may not directly translate to human outcomes.

Protection Against Glutamate Excitotoxicity

Glutamate is a primary excitatory neurotransmitter in the central nervous system, and excessive glutamate activity can lead to excitotoxicity, a process implicated in neurodegenerative disorders and neuronal death. researchgate.net this compound has demonstrated neuroprotective effects against glutamate-induced excitotoxicity. nih.govoup.com This protective effect is time- and concentration-dependent, with higher concentrations providing more significant protection in experimental models. nih.govoup.comnih.gov this compound is thought to inhibit glutamate excitotoxicity by blocking voltage-gated sodium channels, which in turn modulates the release of presynaptic excitatory neurotransmitters like glutamate. psychscenehub.comdrugbank.com This action helps to stabilize neuronal membranes and reduce excessive neuronal firing. drugbank.com Studies in rat cerebellar granule cells (CGCs) have shown that this compound pretreatment significantly inhibits glutamate excitotoxicity. nih.govoup.com

Table 1: Effect of this compound Pretreatment on Cell Viability Against Glutamate Excitotoxicity in Rat CGCs

Data derived from research findings indicating time- and concentration-dependent inhibition of glutamate excitotoxicity by this compound in rat cerebellar granule cells. nih.govoup.comnih.gov

Chromatin Remodeling and Histone Deacetylase (HDAC) Inhibition

Epigenetic modifications, such as histone acetylation, play a crucial role in regulating gene expression and neuronal function. Histone deacetylases (HDACs) remove acetyl groups from histones, leading to chromatin condensation and reduced gene transcription. Inhibition of HDACs can promote chromatin remodeling and alter gene expression. researchgate.net Research indicates that this compound influences chromatin remodeling through the inhibition of HDAC activity. nih.govoup.comoup.com Studies have shown that this compound treatment increases the levels of acetylated histone H3 and H4. nih.govoup.com While the inhibition of HDAC activity by this compound may be moderate and less robust compared to other mood stabilizers like valproate, it contributes to its neuroprotective effects. oup.comnih.gov This modulation of histone acetylation is associated with changes in gene expression conducive to cell survival. consensus.app

Table 2: Effect of this compound on Histone Acetylation and HDAC Activity in CGCs

Data compiled from studies examining the impact of this compound on histone acetylation and HDAC activity in cerebellar granule cells. nih.govoup.comoup.com

Induction of Anti-Apoptotic Protein Bcl-2

Apoptosis, or programmed cell death, is a significant factor in neurodegenerative processes. The B-cell lymphoma-2 (Bcl-2) protein is a key regulator of apoptosis, acting as an anti-apoptotic factor. This compound has been shown to induce the expression of the anti-apoptotic protein Bcl-2. nih.govoup.comnih.gov This induction occurs in a dose- and time-dependent manner, leading to increased levels of both Bcl-2 mRNA and protein. nih.govnih.govnih.gov The increase in Bcl-2 expression is linked to the up-regulation of Bcl-2 promoter activity and its association with acetylated histone H3, suggesting a connection between chromatin remodeling and Bcl-2 induction. nih.gov Silencing of Bcl-2 expression using shRNA has been shown to reduce both this compound-induced Bcl-2 up-regulation and its neuroprotective effects against glutamate excitotoxicity, highlighting the importance of Bcl-2 in this compound's protective mechanisms. nih.govoup.com

Table 3: Effect of this compound on Bcl-2 Expression in CGCs

Data derived from studies investigating the effects of this compound on Bcl-2 mRNA and protein expression in cerebellar granule cells. nih.govnih.govnih.gov

Brain-Derived Neurotrophic Factor (BDNF) Regulation

Brain-Derived Neurotrophic Factor (BDNF) is a crucial protein involved in neuronal survival, growth, and plasticity. Dysregulation of BDNF has been implicated in the pathophysiology of mood disorders. This compound has been shown to regulate BDNF levels in the brain, contributing to its therapeutic effects. nih.govoup.comnih.govoup.com

Up-regulation of Frontal and Hippocampal BDNF Protein Expression

Chronic administration of this compound has been observed to up-regulate BDNF protein expression in specific brain regions, particularly the frontal cortex and hippocampus. nih.govoup.comoup.comresearchgate.net This effect is seen in both naive animals and those subjected to stress, where this compound can restore stress-induced down-regulation of BDNF levels. nih.govoup.comoup.com Studies in rats have demonstrated a significant increase in frontal and hippocampal BDNF protein levels following chronic this compound treatment. oup.comoup.com

Table 4: Effect of Chronic this compound Treatment on BDNF Protein Expression in Rat Brain Regions

Data compiled from studies examining the impact of chronic this compound treatment on BDNF protein levels in the frontal cortex and hippocampus of rats under stressed and non-stressed conditions. nih.govoup.comoup.com

Mediation of Antidepressant Effects

The regulation of BDNF by this compound is considered an essential mediator of its antidepressant effects. nih.govoup.comoup.com Studies using animal models of depression, such as the chronic unpredictable stress (CUS) model, have shown that this compound treatment ameliorates behavioral deficits and that this is associated with the up-regulation of BDNF in the frontal cortex and hippocampus. nih.govoup.comoup.com Furthermore, inhibiting BDNF signaling has been shown to block the antidepressant effects of this compound in these models, providing strong evidence for the role of BDNF as a mediator. nih.govoup.comoup.com

Dissociation from Protein Kinase C (PKC) and MARCKS Down-regulation

Unlike some other mood stabilizers, such as lithium and valproate, this compound does not appear to reduce the expression or activity of Protein Kinase C (PKC) or down-regulate Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS). nih.govkarger.com PKC is a family of enzymes involved in various cellular signaling pathways, and MARCKS is a major substrate for PKC in the brain, implicated in cytoskeletal restructuring and neurotransmitter release. karger.comnih.gov While lithium and valproate have been shown to modulate PKC activity and down-regulate MARCKS, this compound's mechanism of action does not involve these specific pathways. nih.govkarger.comucl.ac.ukcambridge.org This suggests that this compound utilizes different intracellular mechanisms to exert its long-term effects on neurobiology compared to lithium and valproate. nih.gov

Arachidonic Acid Signaling Cascade Down-regulation

The arachidonic acid cascade is a critical pathway in the brain involved in various physiological and pathophysiological processes, including inflammation and neurotransmission. nih.govfrontiersin.org Dysregulation of this cascade, characterized by an upregulated state, has been implicated in conditions such as bipolar disorder. nih.govfrontiersin.orgnih.gov The cascade begins with the release of arachidonic acid from membrane phospholipids, primarily catalyzed by phospholipase A₂ (PLA₂), particularly the calcium-dependent cytosolic phospholipase A₂ (cPLA₂). nih.govresearchgate.netresearchgate.net Once released, AA can be metabolized by enzymes such as cyclooxygenases (COX) and lipoxygenases (LOX) into various bioactive lipids, including prostaglandins (PGs) and thromboxanes (TXs), which act as signaling molecules. nih.govoaepublish.comoup.com

Studies have demonstrated that this compound exerts a down-regulatory effect on the brain AA cascade. researchgate.netmdpi.com This action appears to be linked, at least in part, to its interference with glutamatergic neurotransmission involving N-methyl-D-aspartate receptors (NMDARs). nih.govfrontiersin.orgnih.gov NMDARs play a role in stimulating cPLA₂ activity by allowing calcium influx into the cell, thereby promoting AA release. nih.govresearchgate.net Chronic treatment with this compound has been shown to block NMDA-mediated signaling involving the AA metabolic cascade in rat brain. nih.govnih.govgrantome.com

Research findings indicate that chronic administration of this compound can reduce the activity of key enzymes in the AA cascade. Specifically, studies in rats have shown that chronic this compound treatment reduces brain cyclooxygenase (COX) activity and decreases the concentration of prostaglandin E₂ (PGE₂), a major product of COX activity. nih.govnih.gov Furthermore, this compound has been found to decrease the DNA binding activity of NF-κB, a transcription factor that regulates the expression of COX-2. nih.govnih.govfrontiersin.org This suggests that this compound may down-regulate COX-2 expression at the transcriptional level. nih.gov

Detailed research findings support the impact of chronic this compound administration on COX-2 expression. In one study, chronic treatment of rats with a therapeutically relevant dose of this compound (10 mg/kg daily for 42 days) significantly decreased both protein and mRNA levels of COX-2 in the frontal cortex compared to vehicle-treated rats. nih.gov Interestingly, this study did not observe significant alterations in the protein levels of PLA₂ isoforms. nih.gov This suggests that while this compound impacts the downstream metabolism of AA via COX-2, its effect on the initial release of AA by PLA₂ might be less pronounced or occur through different mechanisms.

The down-regulation of the AA cascade by this compound is considered a potential mechanism contributing to its therapeutic efficacy, particularly in conditions associated with an upregulated AA cascade and neuroinflammation. nih.govfrontiersin.orgoaepublish.commdpi.com This effect aligns with observations that other mood stabilizers also target the brain AA cascade. nih.govresearchgate.netgrantome.comeurekaselect.com

The following table summarizes key findings regarding this compound's effects on markers of the arachidonic acid cascade in rat brain:

This data highlights the consistent finding across multiple studies regarding this compound's ability to reduce COX activity and COX-2 expression, along with decreased levels of the downstream product PGE₂ and the regulatory transcription factor NF-κB.

Role of UGT Enzymes

Effects of Enzyme-Inducing Antiepileptic Drugs (e.g., Carbamazepine, Phenytoin, Phenobarbital)

Enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine, phenytoin, and phenobarbital are known to induce hepatic enzymes, including UGTs. gsk.comnih.gov Coadministration of this compound with these inducers results in increased this compound clearance and a reduction in its half-life. gsk.comdrugbank.comnih.gov Studies have shown that enzyme-inducing AEDs can decrease this compound serum concentrations by approximately 40%. drugs.comdrugs.com The mean half-life of this compound can be reduced to approximately 13.5 to 15 hours when administered with these inducers, compared to a mean half-life of 22.8 to 37.4 hours in healthy volunteers or patients on this compound monotherapy. nih.gov This accelerated metabolism necessitates adjustments in this compound dosing to maintain therapeutic levels. gsk.comdrugs.com

While enzyme-inducing AEDs significantly impact this compound pharmacokinetics, this compound itself generally does not significantly influence the plasma concentrations of these concomitant AEDs, with the exception of a potential increase in carbamazepine-10,11-epoxide, an active metabolite of carbamazepine. nih.govdrugs.com However, the clinical significance of this increase and whether the interaction with carbamazepine is primarily pharmacokinetic or pharmacodynamic remains a subject of investigation. nih.govdrugs.com

Table 1: Effects of Enzyme-Inducing AEDs on this compound Pharmacokinetics

Note: Values are approximate and based on reported study findings. gsk.comdrugbank.comnih.govdrugs.comdrugs.com

Effects of Valproic Acid (Inhibition of Metabolism)

In contrast to enzyme inducers, valproic acid is an inhibitor of this compound metabolism, primarily through the inhibition of UGT enzymes responsible for glucuronidation. pharmgkb.orgnih.govpsychiatrienet.nl Coadministration with valproic acid leads to a significant decrease in this compound clearance and a substantial increase in its elimination half-life and plasma concentrations. gsk.comdrugbank.comnih.govnih.govpsychiatrienet.nl Valproic acid can more than double the elimination half-life of this compound, increasing it to a range of 48 to 59 hours. drugbank.comnih.govdrugs.com This inhibitory effect can result in an approximate twofold increase in serum this compound levels. nih.govdrugs.com The inhibition of this compound metabolism by valproic acid appears to be dose-dependent and can occur even at relatively low doses of valproate. researchgate.netpsychiatrienet.nldrugs.com This interaction is clinically significant and necessitates a lower this compound starting dose and a slower dose escalation when co-administered with valproic acid to mitigate the risk of adverse effects. psychiatrienet.nldrugs.com

Table 2: Effects of Valproic Acid on this compound Pharmacokinetics

Note: Values are approximate and based on reported study findings. gsk.comdrugbank.comnih.govnih.govpsychiatrienet.nldrugs.com

Oral Contraceptive Interactions

Combined oral contraceptives, which typically contain estrogen and progestin, have been shown to interact with this compound pharmacokinetics. womensmentalhealth.orgdrugs.compsychscenehub.com The estrogen component, particularly ethinyl estradiol, is considered the primary factor responsible for this interaction due to its ability to induce UGT enzymes involved in this compound glucuronidation. womensmentalhealth.orgdrugs.compsychscenehub.com Coadministration of this compound with combined oral contraceptives can significantly increase this compound clearance, leading to decreased plasma concentrations and reduced systemic exposure. womensmentalhealth.orgdrugs.compsychscenehub.com Studies have demonstrated that oral contraceptives can decrease this compound concentration by about 50% after approximately one week of co-administration. womensmentalhealth.org Conversely, during the pill-free week of oral contraceptive therapy, this compound levels can rise. womensmentalhealth.orgdrugs.com While this interaction primarily affects this compound levels, some studies suggest that this compound at higher doses may cause a small reduction in the concentration of the progestin component (e.g., levonorgestrel) in oral contraceptives, although the clinical significance of this effect on contraceptive efficacy is not fully established. womensmentalhealth.orgdrugs.compsychscenehub.com

Table 3: Effects of Oral Contraceptives on this compound Pharmacokinetics

Note: Values are approximate and based on reported study findings. womensmentalhealth.orgdrugs.compsychscenehub.com

Linear Pharmacokinetics within Therapeutic Range

Within the typical therapeutic dose range, this compound generally exhibits linear pharmacokinetics. nih.govfabad.org.trnih.govmdpi.comfrontiersin.org This means that the drug's concentration in the plasma increases proportionally with an increase in the administered dose. fabad.org.trmdpi.com Studies in healthy volunteers and patients have shown a linear relationship between this compound dose and parameters such as peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) over a range of doses. fabad.org.trmdpi.comhres.cafda.gov This linearity simplifies dose adjustments within the therapeutic window, as changes in dose are expected to result in predictable proportional changes in plasma concentration. mdpi.comaesnet.org The elimination half-life and volume of distribution generally remain independent of the dose within this linear range. hres.ca

Non-linear Kinetics at Elevated Concentrations

While this compound typically follows linear kinetics within the therapeutic range, there is some evidence suggesting that its elimination may become non-linear at elevated serum concentrations. aesnet.orgnih.gov Observations in some patients have shown disproportionate increases in this compound serum concentrations, sometimes leading to toxicity, in response to minor or no changes in dose, particularly when baseline concentrations are already in the upper therapeutic or supratherapeutic range (e.g., > 10-20 mg/L). aesnet.orgnih.gov This suggests that at higher concentrations, the metabolic pathways responsible for this compound elimination may approach saturation, leading to a less predictable increase in plasma levels with dose increases. mdpi.comnih.gov This potential for non-linear kinetics at elevated concentrations underscores the importance of careful monitoring of this compound levels in some individuals, especially when approaching or exceeding the typical therapeutic range. aesnet.orgnih.gov

Table 4: this compound Pharmacokinetic Linearity

Note: Non-linearity at elevated concentrations is suggested by some clinical observations. aesnet.orgnih.gov

Relationship Between Plasma and Brain Profiles

This compound demonstrates rapid penetration of the blood-brain barrier (BBB) after administration. jrespharm.comnih.gov Studies in rats have shown that this compound appears quickly in both plasma and brain tissue following administration. nih.govdergipark.org.tr A linear relationship has been observed between this compound concentrations in plasma and brain tissue once the plasma-brain system has reached equilibrium. nih.govuc.pt This suggests that the distribution of this compound from plasma into the brain is primarily limited by blood flow and that the drug crosses the BBB via simple diffusion. jrespharm.comuc.pt The parallel decline of this compound concentrations in the brain and plasma further supports this, indicating no significant retention of the drug in brain tissue. jrespharm.comuc.pt

The mechanism by which this compound crosses the BBB is not fully understood, but it is thought to involve organic cation transporters (OCT). pharmgkb.org Specifically, in vitro studies suggest that this compound is a substrate for SLC22A1 (OCT1), an influx transporter found in brain endothelial cells. pharmgkb.orgresearchgate.net Polymorphisms in the SLC22A1 gene have been linked to differences in this compound plasma concentrations in patients with epilepsy. pharmgkb.org While some studies have indicated that this compound is also a substrate for efflux transporters like P-glycoprotein (P-gp) and ABCG2 (BCRP) at the BBB, other research has presented conflicting evidence regarding the role of these transporters in this compound efflux. pharmgkb.orgresearchgate.netnih.govdovepress.com

Studies have investigated the ratio of this compound concentration in cerebrospinal fluid (CSF) to plasma. One study reported a CSF:plasma concentration ratio of 0.43. conicet.gov.ar Another study found a steady-state CSF to total serum concentration ratio of 0.61 in rats. nih.gov The concentration of this compound in CSF is considered similar to the free, non-protein-bound concentration in plasma. conicet.gov.ar

Acute Seizure Models

Acute seizure models involve inducing a single seizure event in naive animals. These models are often used for initial rapid-throughput screening of potential ASMs. frontiersin.orgoup.com

Maximal Electroshock Seizure (MES) Model

The Maximal Electroshock Seizure (MES) model is a widely used preclinical screening test that involves delivering an electrical stimulus through electrodes, typically auricular or corneal, to induce a generalized tonic-clonic seizure in rodents. nih.govresearchgate.net This model is considered a valid test for identifying drugs effective against generalized tonic-clonic seizures in humans. researchgate.net Lamotrigine has demonstrated activity in the MES model. researchgate.net Studies have investigated the interaction of this compound with other ASMs in this model. For instance, one study found that a specific compound (C-11) did not enhance the anticonvulsant action of this compound in the MES test in mice. mdpi.com Another study indicated that nicardipine, a calcium channel blocker, potentiated the anticonvulsant effect of this compound in the MES model in rats. ijbcp.com Conversely, docosahexaenoic acid (DHA) did not show anticonvulsant effect in the MES model alone, but it significantly increased the potency of this compound in the kindling model. nih.gov

Subcutaneous Pentylenetetrazole (s.c. PTZ)-Induced Seizure Model

The subcutaneous Pentylenetetrazole (s.c. PTZ) model involves administering the chemoconvulsant pentylenetetrazole to induce seizures in animals. nih.gov PTZ is a central nervous system stimulant that causes convulsions at high doses. wikipedia.org This model is useful for identifying compounds that may be effective against myoclonic and generalized spike-wave seizures in patients. nih.gov While some ASMs are effective in the s.c. PTZ test, others, including this compound, have shown preclinical inefficacy in this model, despite being effective against human generalized absence seizures. nih.gov However, other reports suggest that this compound can be effective against PTZ-induced seizures in zebrafish. researchgate.net Acute treatment with this compound has been shown to significantly decrease the levels of excitatory amino acids like glutamate and aspartate in the hippocampus of PTZ-kindled rats, suggesting a role in its antiepileptic efficacy in this model. nih.gov

6 Hz Psychomotor Seizure Model

The 6 Hz psychomotor seizure model involves inducing acute, secondarily generalized focal seizures in rodents using low-frequency electrical stimulation (6 Hz) through corneal electrodes. oup.comresearchgate.net This model has shown promise as a screening model for pharmacoresistant seizures. aesnet.orgoup.com The 6 Hz model, particularly at higher stimulation intensities, can display a degree of pharmacoresistance to some standard ASMs. oup.comresearchgate.net Studies have shown that increasing the current intensity in the 6 Hz seizure model can decrease the sensitivity to this compound. researchgate.netnih.gov Despite this reduced sensitivity at higher intensities, the 6 Hz model is considered useful for differentiating investigational drugs based on efficacy and potency. oup.com

Chronic Epilepsy Models

Chronic epilepsy models aim to replicate the enduring changes in brain excitability that characterize human epilepsy, including spontaneous recurrent seizures and pharmacoresistance. oup.com These models are generally more labor-intensive than acute seizure models but are considered more aligned with the actual condition of epilepsy. oup.com

Kindling Models (Amygdala, Hippocampal, Corneal)

Kindling is a phenomenon where repeated administration of subconvulsive stimuli, either electrical or chemical (like PTZ), leads to a progressive increase in seizure severity, eventually resulting in generalized tonic-clonic seizures. oup.comumsu.ac.ir Kindling models, including those involving stimulation of the amygdala, hippocampus, or cornea, are considered chronic models of network hyperexcitability. oup.combiorxiv.org

The amygdala kindling model in rats has been used to study this compound. Exposure to a low dose of this compound during the acquisition of amygdala kindling can lead to a state of pharmacoresistance to this compound in the fully kindled animals. oup.comaesnet.org This this compound-resistant amygdala-kindled rat model has been used to assess cross-tolerance to other ASMs, showing resistance to carbamazepine but not valproate in some studies. oup.com

Pentylenetetrazole (PTZ) kindling is another model where repeated PTZ injections lead to kindled seizures. umsu.ac.ir Similar to amygdala kindling, pretreatment with a low dose of this compound during PTZ kindling in mice did not prevent the development of kindling but resulted in subsequent resistance to a therapeutic dose of this compound. researchgate.net This this compound-resistant PTZ kindling model has also shown resistance to phenytoin and carbamazepine. nih.gov

Corneal kindling in mice is a well-established model of chronic seizures that is suitable for moderate-throughput screening. biorxiv.orgtandfonline.com While traditionally not considered pharmacoresistant, modifications have been developed to create this compound-resistant corneal kindled mouse models. aesnet.orgtandfonline.com These models, elicited by chronic this compound administration early in the epileptogenesis process, exhibit a highly drug-resistant profile, including resistance to carbamazepine and retigabine. aesnet.orgtandfonline.com Interestingly, seizures in the this compound-resistant corneal kindled mouse can be worsened by sodium channel-blocking drugs like phenytoin, carbamazepine, and this compound itself. nih.gov

Research findings in kindling models suggest that this compound may also possess antiepileptogenic properties, influencing the process of epileptogenesis itself, although studies have yielded mixed results. mdpi.com this compound pretreatment in the rat PTZ kindling model has been shown to decrease seizure stages and generalized seizure durations and eliminate heightened population spike amplitude in the hippocampus. mdpi.com

Here is a summary of this compound's effects in various animal models:

This compound-Resistant Kindled Rodent Models

Kindling is a process in which repeated subconvulsive electrical or chemical stimuli to a brain region, such as the amygdala, lead to the development of progressively more severe seizures, eventually resulting in generalized tonic-clonic seizures. springernature.com this compound-resistant kindled rodent models are developed by administering this compound during the kindling process, which diminishes the subsequent response to the drug in fully kindled animals. mdpi.com This approach aims to create animal models that mimic the phenomenon of drug-resistant epilepsy observed in some patients.

In the rat amygdala kindling model, administering a low dose of this compound (e.g., 5 mg/kg, i.p.) before each amygdala stimulation during the kindling acquisition phase results in a state of pharmacoresistance to this compound in fully kindled animals. mdpi.comoup.com One week after achieving the fully kindled state, these rats are challenged with a higher dose of this compound (e.g., 15 mg/kg, i.p.) to confirm resistance, meaning seizures persist despite the treatment. mdpi.com Approximately 31% of rats completing this kindling paradigm may still show sensitivity to this compound despite daily treatment and stimulation, and only resistant animals are used for evaluating novel compounds. nih.gov

These this compound-resistant kindled animals are considered models of drug-resistant epilepsy (DRE). mdpi.com Studies using this model have shown that other antiseizure drugs (ASDs) like carbamazepine, phenytoin, and topiramate are also ineffective in these animals. mdpi.com This model has been incorporated into screening programs for novel compounds with potential activity against pharmacoresistant seizures. nih.gov For instance, the compound KM-568 has demonstrated efficacy in the this compound-resistant amygdala kindled seizure model. mdpi.com

The this compound-resistant kindled mouse model also exists and offers advantages such as easily identifiable Racine stage seizures, a clinically relevant monotherapy paradigm to induce pharmacoresistance during epileptogenesis, and the ability to detect seizure worsening with certain ASDs. nih.gov Notably, in the this compound-resistant corneal kindled mouse, seizure severity can be worsened by sodium channel-blocking drugs like phenytoin, carbamazepine, and this compound itself. nih.gov

Post-Status Epilepticus Seizure Models

Post-status epilepticus (SE) models are created by inducing a prolonged seizure (status epilepticus) in animals, typically through chemical or electrical means. These models often develop spontaneous recurrent seizures (SRSs) and reproduce characteristics of human temporal lobe epilepsy (TLE). mdpi.com They are increasingly used to study the pharmacology of SRSs and for developing new antiepileptogenic or disease-modifying therapies. mdpi.commdpi.com

In the lithium-pilocarpine model of TLE in rats, this compound administration has been shown to decrease the frequency of SRSs in a dose-dependent manner and limit neuronal loss and astrogliosis in the hippocampus. mdpi.com While this compound treatment in this model did not significantly differ in the number and duration of seizures compared to untreated animals, the severity of seizures was significantly reduced. mdpi.com this compound, alone or in combination with anakinra, significantly reduced neuronal loss in the CA1 hippocampus. mdpi.com

Studies in post-SE models have also investigated drug resistance. For example, in a model where SRSs develop after SE induced by sustained electrical stimulation of the basolateral amygdala, prolonged treatment with phenobarbital can result in responder and non-responder subgroups. doi.org Subsequent treatment of phenobarbital non-responders with this compound showed that all phenobarbital non-responders and 60% of phenobarbital responders exhibited a greater than 75% reduction in seizure frequency, classifying them as this compound responders. doi.org This suggests that this compound can be effective in some seizures uncontrolled by phenobarbital in this model. Plasma levels of this compound did not significantly differ between responders and non-responders in this study. doi.org

In the pilocarpine model, a dose of this compound given after the onset of SE appeared to have little effect on the duration of limbic status during three hours of observation but resulted in fewer generalized tonic-clonic convulsions. aesnet.org this compound treatment also appeared to play a neuroprotective role 24 hours following pilocarpine injection, reducing the severity of changes in apparent diffusion coefficient (ADC) and T2 values in the piriform cortex, which are associated with cytotoxic and vasogenic edema, respectively. aesnet.org

Evaluation of Antiseizure Potentials of Novel Compounds

Animal models are crucial platforms for evaluating the antiseizure potential of novel compounds before clinical trials. mdpi.com A common screening program involves initial evaluation in acute seizure models like the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole (s.c. PTZ) test. mdpi.com Compounds showing activity in these rapid screening models may then be tested in other models, including drug-resistant models like the this compound-resistant kindled rat. mdpi.com

The this compound-resistant amygdala-kindled rat model is considered important for evaluating novel compounds with potential activity against pharmacoresistant seizures. nih.gov A comprehensive evaluation of prototype ASDs in this model revealed that only clonazepam, ezogabine, and valproate were found to be effective among the tested compounds. nih.gov This finding supports the utility of the model for identifying compounds with potential efficacy against pharmacoresistant seizures, particularly those resistant to sodium channel blockers. nih.gov

Other novel compounds, such as KM-568 and KRM-II-81, have also demonstrated commendable efficacy in DRE models, including the this compound-resistant amygdala kindled seizure model. mdpi.com C-11, another compound, showed broad-spectrum antiseizure activities in several preclinical models, including MES, s.c. PTZ, and the 6 Hz psychomotor seizure model, and attenuated kindling progression in a PTZ-induced chronic kindling model. mdpi.com MTL-1 effectively protected mice against s.c. PTZ-induced seizures and reduced evoked seizure severity in a chronic PTZ-induced kindled rat model. mdpi.com

Translational Validity and Limitations of Animal Models

While animal models have been instrumental in the discovery of many clinically useful antiseizure drugs, including this compound, they have limitations regarding translational validity, particularly for drug-resistant epilepsy. frontiersin.orgresearchgate.netaltex.org A significant proportion of patients with epilepsy remain refractory to available AEDs discovered using these models, suggesting potential differences in pharmacological efficacy between spontaneous unprovoked seizures (epilepsy) and induced/provoked seizures used in traditional models. frontiersin.org

There is ongoing debate about the translational validity of some current epilepsy models. focusonseveresuffering.co.uk Some clinically effective ASDs show efficacy in some animal models but not others, indicating potential limitations in their predictive capacity for clinical efficacy. focusonseveresuffering.co.uk For instance, this compound, effective against human generalized absence seizures, is inactive in the s.c. PTZ test, a model sometimes used for absence seizures. nih.gov This divergence might be explained by this compound's hypothesized additional mechanism on h-channels, which could be relevant in the thalamocortical network involved in absence seizures. nih.gov

Differences exist between the pathologies observed in animal models and human epilepsy. focusonseveresuffering.co.uk For example, experimental rats subjected to status epilepticus rarely exhibit the typical pattern of human hippocampal sclerosis and may suffer more extensive brain damage. focusonseveresuffering.co.uk

Despite these limitations, animal models remain valuable tools. Kindling models, while labor-intensive, represent a chronic model of network hyperexcitability that is more aligned with actual epilepsy. oup.com Drug-resistant kindling models and post-SE models are particularly useful for studying pharmacoresistance. nih.govmdpi.com The recent approval of cenobamate, an ASD with efficacy in the 6 Hz test and significant clinical efficacy in focal onset seizures, suggests that existing animal models can still identify new drugs for pharmacoresistance. oup.com Efforts to identify biomarkers of drug resistance and further elucidate resistance mechanisms may help improve the selection and utility of animal models. nih.gov

Antidepressant Effects in Rodent Models of Depression

This compound has demonstrated antidepressant effects in patients with bipolar disorder, and preclinical studies in rodent models of depression have sought to explore these effects and their underlying mechanisms. oup.comnih.gov

Studies using the forced swim test (FST), a behavioral despair model, have yielded inconsistent results regarding this compound's antidepressant effects, potentially due to variations in drug dose and treatment duration. oup.com Higher doses (e.g., >10 mg/kg) of this compound have been reported to significantly reduce immobility time in the FST, while lower doses may not. oup.com Both acute and subchronic this compound treatments at higher doses have shown antidepressant actions in the FST. oup.com

In the learned helplessness (LH) model of depression, subchronic treatment with this compound (e.g., 30 mg/kg daily for 7 days) reduced escape failures in rats that had developed LH symptoms. oup.comnih.gov

This compound's antidepressant effects in rodent models may involve the brain-derived neurotrophic factor (BDNF) signaling pathway. oup.comnih.gov Chronic administration of this compound (30 mg/kg) in rats subjected to chronic unpredictable stress (CUS) ameliorated behavioral deficits in the sucrose preference test (SPT) and novelty-suppressed feeding test (NSFT). oup.com This treatment also up-regulated frontal and hippocampal BDNF protein expression in both naive and stressed animals and restored stress-induced down-regulation of BDNF levels. oup.comnih.gov Inhibition of BDNF signaling by infusing a TrkB receptor inhibitor blocked the antidepressant effects of this compound in SPT, NSFT, and FST, suggesting BDNF is an essential mediator. oup.com

Other studies have explored the involvement of the noradrenergic system. This compound's reduction of immobility time in the FST in mice may be mediated by an interaction with the noradrenergic system, possibly involving postsynaptic α1- and α2-adrenoreceptors. frontiersin.org Pretreatment with prazosin (an α1 antagonist) and yohimbine (an α2 antagonist) reversed the decrease in immobility time evoked by this compound in the FST. frontiersin.org this compound's antidepressant effects might also involve inactivation of sodium channels and modulation of monoaminergic neurotransmission. frontiersin.org

Data from studies on antidepressant effects in rodent models:

Effects on Learning and Memory (e.g., Memory Bias)

This compound's effects on learning and memory have been investigated in both animal and human studies, with some reports suggesting positive effects, potentially related to its influence on glutamate neurotransmission. medrxiv.orgresearchgate.net

In mice, this compound administration has been reported to positively affect memory acquisition and spatial memory retrieval. medrxiv.orgresearchgate.net Studies using models like the modified elevated plus maze (mEPM) and passive avoidance tests have indicated that this compound can facilitate the acquisition of learning. researchgate.net

However, some studies in albino rats using the Morris water maze (MWM) and elevated plus maze (EPM) have indicated that this compound can cause significant impairment in learning compared to control groups. scispace.com In one study, this compound caused significant learning impairment compared to the levetiracetam group in the MWM, and no statistically significant impairment compared to the phenytoin group in either MWM or EPM, except on day 5 in the EPM. scispace.com Interestingly, this study did not find statistically significant impairment in memory compared to the control group on either MWM or EPM. scispace.com The discrepancy with previous studies suggesting no significant cognitive effects of this compound in healthy volunteers or epilepsy patients highlights the need for further research. scispace.com The authors suggested that the similar mechanism of action between this compound and phenytoin (blocking Na+ channels) might explain the comparable impairment observed in their study. scispace.com

In healthy human volunteers, a single dose of this compound has been shown to induce a positive memory bias, where participants recalled significantly more positive than negative self-referential words in an emotional recall task compared to a placebo group. medrxiv.org This positive shift in memory is similar to effects reported with conventional antidepressant drugs in experimental medicine studies. medrxiv.org

This compound has also been associated with attenuating the effects of corticosteroids on memory in humans, consistent with findings in animal models suggesting that agents decreasing glutamate release can block the effects of stress or corticosteroids on the hippocampus. escholarship.org While this compound was associated with less decline in declarative memory performance in corticosteroid-treated patients, significant differences in hippocampal subfield volumes were not observed within a 48-week period. escholarship.org

Sodium Channel Blocking Activity and Antiarrhythmic Potential

In vitro studies have consistently demonstrated that this compound inhibits cardiac voltage-gated sodium channels, specifically the human cardiac sodium channel isoform Naᵥ1.5 frontiersin.orgnih.govhres.cailae.orgmdpi.comnih.gov. This inhibition exhibits characteristics consistent with Class IB antiarrhythmic agents, including rapid onset and offset kinetics and strong voltage dependence nih.govhres.cailae.orgnih.gov.

Quantifying the potency of this compound's sodium channel blockade, in vitro studies using HEK-293 cells stably expressing the hNaᵥ1.5 channel have reported half-maximal inhibitory concentration (IC₅₀) values. One study found IC₅₀ values of 280.2 μM and 28.8 μM at holding voltages of –120 mV and –95 mV, respectively frontiersin.org. Another study reported an average IC₅₀ of 142 ± 36 μM for this compound's inhibitory effects on the Naᵥ1.5 current density mdpi.com. These findings suggest that this compound is capable of blocking Naᵥ1.5 channels at concentrations that may be observed within or above its therapeutic range frontiersin.orgmdpi.com.

While the in vitro data points to a Class IB antiarrhythmic profile, the translational implications for antiarrhythmic potential in vivo are complex and appear model-dependent. In an experimental whole-heart model using rabbit hearts, this compound showed antiarrhythmic effects in a setting of increased arrhythmia susceptibility induced by an IKr-blocker researchgate.net. However, studies in murine hearts have suggested a proarrhythmic potential, specifically promoting reentrant ventricular tachycardia nih.govresearchgate.net. This proarrhythmic effect in murine models was associated with anisotropic slowing of conduction nih.govresearchgate.net.

Effects on Cardiac Conduction and Repolarization

Preclinical studies have investigated this compound's effects on cardiac conduction parameters. In murine hearts, this compound decreased ventricular conduction velocity (CV), with a preferential impact along the longitudinal direction of propagation compared to the transverse direction, particularly at faster pacing frequencies nih.govresearchgate.net. This anisotropic slowing of CV is hypothesized to contribute to the formation of a functional substrate for reentrant ventricular tachycardia observed in this model nih.gov.

Regarding cardiac repolarization, preclinical data are less extensive and sometimes appear to contrast with findings from studies in healthy human subjects. While some preclinical data suggest that this compound might inhibit the cardiac rapid-delayed rectifier potassium ion current (IKr) in vitro researchgate.net, which could theoretically lead to QT prolongation, studies in healthy individuals have generally shown no clinically meaningful prolongation of the QT interval nih.govilae.org. In fact, a mild QT shortening has been observed at high doses in healthy subjects, consistent with a Class IB property nih.govilae.org. An in vitro study using rabbit ventricular cardiomyocytes found that this compound (at 100 µM) prolonged the action potential refractory period mdpi.com.

Neuropathic Pain

This compound is being investigated for its potential in managing neuropathic pain, a chronic condition resulting from damage to the nervous system. nih.govtandfonline.com Studies have suggested that this compound may be effective in reducing pain intensity and improving quality of life in patients with various neuropathic pain conditions, such as diabetic neuropathy and post-herpetic neuralgia. nih.gov It is considered a second-line treatment in specific cases, and research has shown its efficacy in reducing pain in patients with trigeminal neuralgia who did not respond to other medications. nih.gov The proposed mechanism for its analgesic effects in neuropathic pain states is its binding to sodium channels, similar to local anesthetics. drugbank.com While some studies have indicated efficacy in treating a number of painful syndromes and neuropathic pain conditions including central pain, trigeminal neuralgia, and HIV-associated neuropathy, further research is required to fully establish its role in conditions like spinal cord injury pain and neuralgia after nerve section. tandfonline.comresearchgate.net

Post-Traumatic Stress Disorder (PTSD)

The potential utility of this compound in the management of Post-Traumatic Stress Disorder (PTSD) is also being explored. nih.govresearchgate.net Given that glutamate appears to be a key moderator in PTSD, and this compound acts as a glutamate release inhibitor, it has been proposed as a potential treatment option for PTSD symptoms. nih.govfrontiersin.orgfrontiersin.org Preliminary studies have suggested that this compound may be useful for symptom management in PTSD, with some research indicating improvement in symptoms such as re-experiencing and avoidance/numbing. duke.educonsultant360.com While some studies have shown symptom reduction in adults with PTSD treated with this compound compared to placebo, further large-scale, double-blind, placebo-controlled trials are warranted to confirm these promising results and establish its effectiveness as a primary psychopharmacologic treatment or as an adjunct therapy for PTSD. frontiersin.orgduke.educonsultant360.com

Major Depressive Disorder and Unipolar Depression

Some research indicates that patients with more treatment-resistance, comorbid anxiety, or borderline personality disorder may be more likely to benefit from this compound in the context of unipolar depression. researchgate.net For instance, studies have supported its use in unipolar depression with comorbid anxiety. researchgate.net

However, other randomized controlled trials (RCTs) evaluating this compound as an add-on to antidepressants for major depressive disorder (MDD) have not demonstrated superiority over placebo on primary outcome measures. psychiatrictimes.com Some of these studies included patients with bipolar disorder, which can confound the interpretation of results specifically for unipolar depression due to potential differences in treatment response between the conditions. psychiatrictimes.com

Data Table 1: Summary of this compound Research in Unipolar Depression

Alzheimer's Disease and Schizophrenia

The potential role of this compound in the treatment of Alzheimer's disease and schizophrenia has been explored, although further research is needed to confirm its efficacy in these areas. nih.govresearchgate.net

In the context of Alzheimer's disease, this compound has been investigated for its potential to manage behavioral and psychological symptoms of dementia (BPSD) and treat associated seizures. A preliminary open-label trial suggested that this compound administration to patients with severe Alzheimer's disease with BPSD might be effective and could potentially reduce the need for increasing antipsychotic medication dosages. nih.gov Specifically, a significant decrease in the Neuropsychiatric Inventory (NPI) agitation subscale was observed in the this compound group compared to a control group. nih.gov

Regarding the treatment of epilepsy in people with Alzheimer's disease, a Cochrane review of one RCT found no significant differences in seizure freedom rates when comparing this compound, levetiracetam, and phenobarbital. cochrane.org The certainty of this evidence was considered very low. cochrane.org The same review noted that this compound seemed to relieve depression in this population, but also seemed to worsen cognition, although these findings were based on very low-certainty evidence. cochrane.org Another study indicated that this compound monotherapy was effective in controlling seizures in a proportion of patients with Alzheimer's disease. researchgate.net

For schizophrenia, this compound has been listed as an off-label use, but controlled trials specifically evaluating its efficacy in this disorder appear to be lacking in the search results. nih.govpsychiatrist.com

Data Table 2: Summary of this compound Research in Alzheimer's Disease

Trigeminal Neuralgia

This compound has been investigated for its potential in managing trigeminal neuralgia, a condition characterized by severe facial pain. nih.govmstrust.org.ukoup.com It has been used experimentally in multiple sclerosis to reduce pain associated with trigeminal neuralgia. mstrust.org.uk

A double-blind, placebo-controlled crossover trial in 14 patients with refractory trigeminal neuralgia demonstrated that this compound was superior to placebo based on a composite efficacy index. dovepress.comnih.gov Eleven out of 13 eligible patients showed better efficacy on this compound compared to placebo. nih.gov Global evaluations also suggested better outcomes with this compound. nih.gov

This compound is considered a second-line treatment option for trigeminal neuralgia and can be used alone or as add-on therapy, particularly in patients who cannot tolerate first-line treatments like carbamazepine and oxcarbazepine or to enhance efficacy. bmj.com It is generally associated with fewer side effects compared to carbamazepine and oxcarbazepine. bmj.com

Data Table 3: Summary of this compound Research in Trigeminal Neuralgia

Depersonalization-Derealization Disorder

Research into the use of this compound for depersonalization-derealization disorder (DPDR) has explored its potential, partly based on the hypothesis that glutamate hyperactivity may be relevant to the neurobiology of depersonalization. nih.govgenderanalysis.net this compound's mechanism of reducing glutamate release has been a focus of this investigation. nih.govgenderanalysis.netcambridge.org

Early studies of this compound monotherapy in a small number of patients with primary depersonalization showed substantial benefits in some cases. cambridge.org However, a subsequent placebo-controlled crossover study involving nine patients with DSM-IV depersonalization disorder did not find this compound to be significantly superior to placebo. nih.govgenderanalysis.netcambridge.org None of the patients in this study were considered responders to this compound monotherapy. nih.gov

Despite the lack of clear efficacy as monotherapy in controlled trials, clinical experience and open-label trials suggest that this compound may benefit some patients with primary depersonalization, particularly when used in conjunction with a selective serotonin reuptake inhibitor (SSRI). genderanalysis.netcambridge.orgtandfonline.com This approach is supported by the idea that both serotonergic and glutamatergic mechanisms might be involved in depersonalization. genderanalysis.net A case series of patients treated with this compound, most of whom were also taking an antidepressant, showed a notable proportion of responders, with a higher response rate observed in those combining this compound with an SSRI compared to this compound alone or with an SNRI. genderanalysis.net

Data Table 4: Summary of this compound Research in Depersonalization-Derealization Disorder