Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.

Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration.

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.

[Application of Ultra-High-Field Magnetic Resonance Imaging to the Central Nervous System].

The development of high-performance magnetic resonance imaging (MRI) scanners is ongoing. The strength of the magnetic field is the most important factor in the use of this technology. Ultra-high magnetic fields provide many benefits, including high spatial and temporal resolution. In this chapter, we describe the characteristics and images obtained using ultra-high-field MRI.

Injectable shear-thinning hydrogels promote oligodendrocyte progenitor cell survival and remyelination in the central nervous system.

Cell therapy for the treatment of demyelinating diseases such as multiple sclerosis is hampered by poor survival of donor oligodendrocyte cell preparations, resulting in limited therapeutic outcomes. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection. Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of primary human oligodendrocyte progenitor cells (hOPCs) to the brain of a shiverer/rag2 mouse, a model of congenital hypomyelinating disease. The STHs enabled immobilization of prosurvival signals, including a recombinantly designed bidomain peptide and platelet-derived growth factor. Notably, STHs reduced the death rate of hOPCs significantly, promoted the production of myelinating oligodendrocytes, and enhanced myelination of the mouse brain 12 weeks post-implantation. Our results demonstrate the potential of STHs loaded with biological cues to improve cell therapies for the treatment of devastating myelopathies.

SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system in vitro.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with neurological sequelae including haemorrhage, thrombosis and ischaemic necrosis and encephalitis. However, the mechanism by which this occurs is unclear. Neurological disease associated with COVID-19 has been proposed to occur following direct infection of the central nervous system and/or indirectly by local or systemic immune activation. We evaluated the expression of angiotensin-converting enzyme-2 and transmembrane protease, serine 2 (TMPRSS2) in brain tissue from five healthy human donors and observed low-level expression of these proteins in cells morphologically consistent with astrocytes, neurons and choroidal ependymal cells within the frontal cortex and medulla oblongata. Primary human astrocytes, neurons, choroid plexus epithelial cells and pericytes supported productive SARS-CoV-2 infection with ancestral, Alpha, Delta and Omicron variants. Infected cells supported the full viral life cycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 can infect human brain cells, and the mechanism of viral entry warrants further investigation.

Effects of Chronic Exposure to Low Doses of Rotenone on Dopaminergic and Cholinergic Neurons in the CNS of Hemigrapsus sanguineus.

Rotenone, as a common pesticide and insecticide frequently found in environmental samples, may be present in aquatic habitats worldwide. Exposure to low concentrations of this compound may cause alterations in the nervous system, thus contributing to Parkinsonian motor symptoms in both vertebrates and invertebrates. However, the effects of chronic exposure to low doses of rotenone on the activity of neurotransmitters that govern motor functions and on the specific molecular mechanisms leading to movement morbidity remain largely unknown for many aquatic invertebrates. In this study, we analyzed the effects that rotenone poisoning exerts on the activity of dopamine (DA) and acetylcholine (ACh) synthesis enzymes in the central nervous system (CNS) of Asian shore crab, Hemigrapsus sanguineus (de Haan, 1835), and elucidated the association of its locomotor behavior with Parkinson's-like symptoms. An immunocytochemistry analysis showed a reduction in tyrosine hydroxylase (TH) in the median brain and the ventral nerve cord (VNC), which correlated with the subsequent decrease in the locomotor activity of shore crabs. We also observed a variation in cholinergic neurons' activity, mostly in the ventral regions of the VNC. Moreover, the rotenone-treated crabs showed signs of damage to ChAT-lir neurons in the VNC. These data suggest that chronic treatment with low doses of rotenone decreases the DA level in the VNC and the ACh level in the brain and leads to progressive and irreversible reductions in the crab's locomotor activity, life span, and changes in behavior.

CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice.

Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.

IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system.

The central nervous system (CNS) includes anatomically distinct macrophage populations including parenchyma microglia and CNS-associated macrophages (CAMs) localized at the interfaces like meninges and perivascular space, which play specialized roles for the maintenance of the CNS homeostasis with the help of precisely controlled gene expressions. However, the transcriptional machinery that determines their cell-type specific states of microglia and CAMs remains poorly understood. Here we show, by myeloid cell-specific deletion of transcription factors, IRF8 and MAFB, that both adult microglia and CAMs utilize IRF8 to maintain their core gene signatures, although the genes altered by IRF8 deletion are different in the two macrophage populations. By contrast, MAFB deficiency robustly affected the gene expression profile of adult microglia, whereas CAMs are almost independent of MAFB. Our data suggest that distinct transcriptional machineries regulate different macrophages in the CNS.

Exploring the safety of lycorine in the central nervous system and its impact on pain-like behaviors in mice.

Alkaloid analgesics have been associated with adverse effects on the central nervous system (CNS). Therefore, it is crucial to characterize the effects of alkaloid analgesics. Plants rich in lycorine, an alkaloid, have shown promise as analgesics. However, the exploration of their CNS side effects, and analgesic effectiveness remains incomplete. The aim of the present study was to investigate the CNS safety profiles of lycorine and its potential analgesic efficacy. Lycorine (3, 10, and 30 mg/kg, intraperitoneal) did not affect motor coordination, and doses of 3 and 10 mg/kg of lycorine did not lead to any impairment in spontaneous locomotor activity. However, the highest dose (30 mg/kg) demonstrated a significant impairment in rearing behavior and an increase in immobility. The safety doses were subsequently used to assess the analgesic efficacy of lycorine in a mouse model of inflammatory pain. Lycorine (1, 3, and 10 mg/kg, intraperitoneal) demonstrated a dose-dependent reduction in pain-like behaviors in formalin-induced mice. In the in vitro study, lycorine regulated immune cells, suggesting its involvement as a cellular mechanism underlying the suppression of pain-like behaviors observed in the formalin model. Overall, our findings delineate the CNS safety range of lycorine in mice and suggest its potential use as an analgesic.

Pharmacokinetic Modeling of the Effect of Tariquidar on Ondansetron Disposition into the Central Nervous System.

PURPOSE: Serotonin (5-HT3) receptor antagonists are promising agents for treatment of neuropathic pain. However, insufficient drug exposure at the central nervous system (CNS) might result in lack of efficacy. The goal of this study was to evaluate the impact of administration of a Pgp inhibitor (tariquidar) on ondansetron exposure in the brain, spinal cord, and cerebrospinal fluid in a wild-type rat model. METHODS: Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data. RESULTS: The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination. CONCLUSIONS: The study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies.

Indirect neurogenesis in space and time.

During central nervous system (CNS) development, neural progenitor cells (NPCs) generate neurons and glia in two different ways. In direct neurogenesis, daughter cells differentiate directly into neurons or glia, whereas in indirect neurogenesis, neurons or glia are generated after one or more daughter cell divisions. Intriguingly, indirect neurogenesis is not stochastically deployed and plays instructive roles during CNS development: increased generation of cells from specific lineages; increased generation of early or late-born cell types within a lineage; and increased cell diversification. Increased indirect neurogenesis might contribute to the anterior CNS expansion evident throughout the Bilateria and help to modify brain-region size without requiring increased NPC numbers or extended neurogenesis. Increased indirect neurogenesis could be an evolutionary driver of the gyrencephalic (that is, folded) cortex that emerged during mammalian evolution and might even have increased during hominid evolution. Thus, selection of indirect versus direct neurogenesis provides a powerful developmental and evolutionary instrument that drives not only the evolution of CNS complexity but also brain expansion and modulation of brain-region size, and thereby the evolution of increasingly advanced cognitive abilities. This Review describes indirect neurogenesis in several model species and humans, and highlights some of the molecular genetic mechanisms that control this important process.

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity.

Central and peripheral nervous system (CNS/PNS) proteoglycans (PGs) have diverse functional roles, this study examined how these control cellular behavior and tissue function. The CNS/PNS extracellular matrix (ECM) is a dynamic, responsive, highly interactive, space-filling, cell supportive, stabilizing structure maintaining tissue compartments, ionic microenvironments, and microgradients that regulate neuronal activity and maintain the neuron in an optimal ionic microenvironment. The CNS/PNS contains a high glycosaminoglycan content (60% hyaluronan, HA) and a diverse range of stabilizing PGs. Immobilization of HA in brain tissues by HA interactive hyalectan PGs preserves tissue hydration and neuronal activity, a paucity of HA in brain tissues results in a pro-convulsant epileptic phenotype. Diverse CS, KS, and HSPGs stabilize the blood-brain barrier and neurovascular unit, provide smart gel neurotransmitter neuron vesicle storage and delivery, organize the neuromuscular junction basement membrane, and provide motor neuron synaptic plasticity, and photoreceptor and neuron synaptic functions. PG-HA networks maintain ionic fluxes and microgradients and tissue compartments that contribute to membrane polarization dynamics essential to neuronal activation and neurotransduction. Hyalectans form neuroprotective perineuronal nets contributing to synaptic plasticity, memory, and cognitive learning. Sialoglycoprotein associated with cones and rods (SPACRCAN), an HA binding CSPG, stabilizes the inter-photoreceptor ECM. HSPGs pikachurin and eyes shut stabilize the photoreceptor synapse aiding in phototransduction and neurotransduction with retinal bipolar neurons crucial to visual acuity. This is achieved through Laminin G motifs in pikachurin, eyes shut, and neurexins that interact with the dystroglycan-cytoskeleton-ECM-stabilizing synaptic interconnections, neuronal interactive specificity, and co-ordination of regulatory action potentials in neural networks.

Methadone directly impairs central nervous system cells in vitro.

Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population.

Neuroinflammation: From Molecular Basis to Therapy.

Neuroinflammatory conditions in the central nervous system (CNS) are implicated in the pathogenesis of several neuroimmune disorders such as acquired demyelinating syndromes, autoimmune encephalopathies, acute or chronic bacterial and viral CNS infections as well as multiple sclerosis (MS) [...].

Human NMO-IgG Induced Different Pathological and Immunological Changes in the CNS and Peripheral Tissues of Mice.

OBJECTIVES: The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS. METHODS: C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test. RESULTS: We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field. CONCLUSIONS: We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues.

Il34 rescues metronidazole-induced impairment of spinal cord regeneration in zebrafish central nervous system.

Metronidazole (MTZ), a commonly used anti-infective drug in clinical practice, has also been employed as a prodrug in cell-targeted ablation systems in scientific research, exhibiting significant application value. However, it has been demonstrated that MTZ can induce neurotoxic symptoms to some extent during its use, and there is currently a lack of effective means to circumvent its toxicity in both clinical and research settings, which limits its application. Therefore, exploring the specific mechanisms underlying MTZ-induced neurotoxic symptoms and elucidating countermeasures will enhance the practical value of MTZ. In this study, using a zebrafish spinal cord injury regeneration model, we confirmed that MTZ neurotoxicity leads to impaired axon regeneration in the central nervous system. By overexpressing il34 in the central nervous system of zebrafish, we eliminated the inhibitory effect of MTZ on axonal regeneration and demonstrated that the pro-regenerative effect against MTZ neurotoxicity is not caused by excessive macrophages/microglia chemoattracted by interleukin 34(Il34). Transcriptome sequencing analysis and GO enrichment analysis of differentially expressed genes between groups revealed that Il34 may counteract MTZ neurotoxicity and promote spinal cord injury repair through biological processes that enhance cellular adhesion and cell location. In summary, our work uncovers a possible cause of MTZ neurotoxicity and provides a new perspective for eliminating MTZ toxicity.

Central Nervous System Adverse Reactions to Amantadine Intoxication: A Case Report and Analysis of JADER.

BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor in the Drosophila central nervous system.

Numerous roles for the Alk receptor tyrosine kinase have been described in Drosophila, including functions in the central nervous system (CNS), however the molecular details are poorly understood. To gain mechanistic insight, we employed Targeted DamID (TaDa) transcriptional profiling to identify targets of Alk signaling in the larval CNS. TaDa was employed in larval CNS tissues, while genetically manipulating Alk signaling output. The resulting TaDa data were analyzed together with larval CNS scRNA-seq datasets performed under similar conditions, identifying a role for Alk in the transcriptional regulation of neuroendocrine gene expression. Further integration with bulk and scRNA-seq datasets from larval brains in which Alk signaling was manipulated identified a previously uncharacterized Drosophila neuropeptide precursor encoded by CG4577 as an Alk signaling transcriptional target. CG4577, which we named Sparkly (Spar), is expressed in a subset of Alk-positive neuroendocrine cells in the developing larval CNS, including circadian clock neurons. In agreement with our TaDa analysis, overexpression of the Drosophila Alk ligand Jeb resulted in increased levels of Spar protein in the larval CNS. We show that Spar protein is expressed in circadian (clock) neurons, and flies lacking Spar exhibit defects in sleep and circadian activity control. In summary, we report a novel activity regulating neuropeptide precursor gene that is regulated by Alk signaling in the Drosophila CNS.

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics.

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System.

Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl-, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets.