Current Neuropharmacology - Volume 24, Issue 3, 2026

One of the accepted factors of antiseizure medication resistance is the action of P-glycoprotein (P-gp), limiting the access of drugs to the nervous system. But if we ask which antiseizure medications are substrates of P-gp and which are not, the available bibliography will not allow us to obtain a clear answer. In this review, we focus on clarifying this response. The reviewed studies have been conducted both in cell lines and in mice that have been administered a P-gp inhibitor, artificially induced with drug-resistant epilepsy, or had a P-gp gene knockout. A limited number of studies have been conducted in dogs, primates, brain sections of known epilepsies, or human volunteers, including pharmacokinetic studies in healthy volunteers and symptomatic response to treatment. Notably, in human cases, allele variation studies check if having one allele or another of P-gp varies the pharmacokinetics in question. As we see, the approach to P-gp and antiseizure medication can be done using very different methods, which undoubtedly complicates the interpretation of the findings. We cannot be categorical in our results, but we can mention probabilities. Regarding the weighting of studies, we will consider those conducted in humans as more important, followed by animal studies, and we will give less weight to studies showing contradictory results compared to the general bibliographic base. Based on the published bibliography, we propose that, among the anti-crisis medications, the following are likely substrates of P-glycoprotein: Phenytoin, Phenobarbital, Oxcarbazepine, Lamotrigine, Topiramate, and Lacosamide (less evidence). The following are probably not substrates: Brivaracetam, Zonisamide, Valproic acid, Perampanel, Gabapentin, and Vigabatrin. We have not obtained enough information about: Carbamazepine, Eslicarbazepine, Levetiracetam, Tiagabine, Felbamate, Pregabalin, Rufinamide, Ezogabine, and Retigabine.

Autophagy relates to the mechanism underlying the intracellular constituents’ breakdown by lysosomes. Autophagy plays an essential role in preserving and regulating cellular homeostasis by mediating the degradation of intracellular components and recycling their decomposition products. It was demonstrated that autophagy operates in-vivo in the starving reaction, initial growth, internal control of quality, and cell division. Autophagy malfunction is perhaps connected with cancer and neurological conditions, as demonstrated by current research. In conjunction with the identification of specific mutations associated with autophagy-related disorders and deeper knowledge of the pathophysiology of disorders caused by aberrant disintegration of particular autophagy substrates, autophagy activation serves a vital part in prolonging lifespans and suppressing the process of aging. To safeguard the homeostasis within a cell, cells have developed sophisticated quality-control procedures for organelles and proteins. These quality-control mechanisms maintain cellular integrity through degradation by the autophagy-lysosome or ubiquitin-proteasome systems, as well as through protein folding assistance (or refolding of misfolded proteins) provided by molecular chaperones. A great deal of neurodegenerative illnesses are indicated by the development of intracellular inclusions formed from misfolded proteins, which are believed to be an outcome of defective autophagy. Additionally, it was recently discovered that neurodegenerative illnesses are also linked with mutations in key autophagy-related genes. However, pathogenic proteins like α-synuclein and amyloid β cause damage to the autophagy system. This paper examines the recent advancements in our understanding of the link between autophagic abnormalities and the development of neurological disorders, and proposes that activating autophagy could serve as a potential therapeutic strategy.

Depression is a chronic and recurrent psychiatric condition believed to result from an interaction between genetic susceptibility and environmental stimuli. Although current therapies prescribed for depression can be effective, it will take several weeks to demonstrate their full effectiveness and is often accompanied by side effects and withdrawal symptoms. In this regard, the discovery of new antidepressant drugs with unique, higher curative effects and fewer adverse reactions is the pursuit of pharmaceuticals. Trace amine-associated receptor 1 (TAAR1), a G-protein coupled receptor (GPCR) that is broadly expressed in the mammalian brain, especially within cortical, limbic, and midbrain monoaminergic regions and activated by “trace amines” (TAs). It is allegedly involved in modulating dopaminergic, serotonergic, and glutamatergic transmission, which makes TAAR1 a new drug target for the treatment of dysfunction of monoamine-related disorders. Moreover, TAAR1 agonists have attracted interest as potential treatments for depression due to their role in regulating monoamine neurotransmission. In fact, Ulotaront (a TAAR1 agonist) is reported to be currently undergoing phase 2/3 clinical trials in order to test its safety and efficacy in the treatment of major depressive disorder (MDD). However, the final results of this Phase 2/3 clinical study have not been announced yet, and the efficacy and safety of Ulotaront in the treatment of depression still need further observation and research. Thus, this article aims to review evidence of the potential role of TAAR1 in the pathophysiology and treatment of depression. Moreover, we briefly summarize the recent findings in the elucidation of behavioral and physiological properties of TAAR1 agonists both in clinical trials and preclinical animal studies. Collectively, these studies will provide a solid foundation for TAAR1 as a novel therapeutic target for depression.

The exploration of consciousness and the elucidation of the mechanisms underlying general anesthesia are two intertwined endeavors that have significantly advanced our understanding of the neural correlates of awareness. Both fields converge on the neural systems that regulate consciousness. Frontoparietal networks, known for their involvement in executive functions, attention, and cognitive control, emerge as key players in the transition from wakefulness to anesthesia-induced unconsciousness. This review synthesizes recent findings highlighting the pivotal role of fronto-parietal connectivity in the induction and maintenance of unconsciousness by general anesthetics. By examining functional neuroimaging studies and neurophysiological data, we elucidate how disruptions in fronto-parietal interactions contribute to the loss of responsiveness and altered states of awareness associated with anesthesia. Additionally, we further explain the underlying mechanism at both the neuronal and molecular levels. Furthermore, we discuss the implications of these findings for advancing our understanding of the neural correlates of consciousness and the development of novel anesthetic agents with more predictable and targeted effects on consciousness. This review decisively bridges the gap between consciousness research and anesthetic pharmacology, providing a robust framework for future investigations into the neural mechanisms that control transitions between conscious states.

Schizophrenia remains a therapeutic challenge. For much of its long history, the physiological basis of its symptoms and clinical presentation remained elusive. However, in recent decades, consistent anatomical and metabolic changes have been documented that can also serve as therapeutic targets. An insult to the developing nervous system in the prenatal or neonatal period appears to set the schizophrenic syndrome in motion by preventing the development of the normal circuit balance between inhibitory and excitatory neurons. In time, a reduction in the volume of frontal and temporal grey matter and a decrease in the density of dendritic spines on pyramidal neurons becomes apparent. These anatomical findings are accompanied by a reduced capacity to synthesize GABA, an increased capacity to synthesize and release dopamine, and an increased level of blood cortisol. Treatment with sodium oxybate (SO) (gammahydroxybutyrate) may make it possible to reverse these pathological features of the schizophrenic syndrome, given SO’s potential to increase neuronal levels of GABA, inhibit dopamine release and reduce blood cortisol levels. SO can also serve as a source of energy to promote the growth of the dendritic arbor on excitatory pyramidal neurons and as an antioxidant to enhance the activity of GABAergic inhibitory neurons. In this way, SO may restore the balance between the excitatory pyramidal neurons and the inhibitory GABAergic neurons in schizophrenia. In a short clinical trial, the use of SO to improve the sleep of patients with chronic schizophrenia led to a significant clinical improvement.

Neutrophil Extracellular Traps (NETs) are complexes containing DNA fibrils and antimicrobial peptides that are released by neutrophils in response to pathogen stimulation. At the time of their discovery, the neutrophil extracellular trap contained active substances such as Neutrophil Elastase (NE) and myeloperoxidase (MPO). Although NETs were initially thought to be a means for the innate immune system to fight microbial invasion, now they have been observed to have a broader impact throughout the body. In recent studies, NETs have been linked to several neurological disorders and have been found to have varying roles in a number of diseases. In addition to their role in thrombosis, NETs have been identified in various autoimmune diseases. NETs play a significant role in the body when they are produced at the correct time and place; however, when the generation and removal of NETs are out of equilibrium, there can be important implications for human health. Here, the impact of NETs is reviewed in various neurological disorders and their potential clinical applications.

Ischemic stroke, triggered by the interruption of cerebral blood flow, initiates a complex inflammatory process involving both brain-resident and peripheral immune cells. Microglia, the primary brain-resident immune cells of high heterogeneity, regulate central nervous system inflammation upon activation. Activated microglia are commonly classified into two predominant phenotypes (pro-inflammatory M1 and anti-inflammatory M2), which exert dual effects through the secretion of distinct cytokine profiles. Peripheral immune cells, including monocytes, macrophages, and neutrophils, contribute to stroke pathogenesis and progression via diverse inflammatory mechanisms. Multiple microRNAs regulate the inflammatory dynamics of ischemic stroke across all phases by modulating both brain-resident and peripheral immune cells. MicroRNAs play a pivotal role in the activation and polarization of microglia, as well as cytokine release. Furthermore, microRNAs modulate the activation and extravasation processes of peripheral leukocytes by enhancing or attenuating signaling pathways. These mechanisms suggest that microRNA alterations could be biomarkers for predicting, diagnosing, and prognosticating ischemic stroke. Additionally, microRNA modulation offers potential as a therapeutic strategy for the treatment of ischemic stroke.