Current Neuropharmacology最新文献

{"title":"Olanzapine Induces Adipogenesis and Glucose Uptake by Activating Glycolysis and Synergizing with the PI3K-AKT Pathway.","authors":"Shen Li, Yun Fu, Wanyao Wang, Jiali Qiu, Yepei Huang, Xuemin Li, Ke Yang, Xiawen Yu, Yanyan Ma, Yuan Zhang, Miaomiao Zhang, Jie Li, Wei-Dong Li","doi":"10.2174/1570159X22666240815120547","DOIUrl":"https://doi.org/10.2174/1570159X22666240815120547","url":null,"abstract":"<p><strong>Background: </strong>Administration of olanzapine (OLA) is closely associated with obesity and glycolipid abnormalities in patients with schizophrenia (SCZ), although the exact molecular mecha- nisms remain elusive.</p><p><strong>Objective: </strong>We conducted comprehensive animal and molecular experiments to elucidate the mecha- nisms underlying OLA-induced weight gain.</p><p><strong>Methods: </strong>We investigated the mechanisms of OLA-induced adipogenesis and lipid storage by em- ploying a real-time ATP production rate assay, glucose uptake test, and reactive oxygen species (ROS) detection in 3T3-L1 cells and AMSCs. Rodent models were treated with OLA using various interven- tion durations, dietary patterns (normal diets/western diets), and drug doses. We assessed body weight, epididymal and liver fat levels, and metabolic markers in both male and female mice.</p><p><strong>Results: </strong>OLA accelerates adipogenesis by directly activating glycolysis and its downstream PI3K sig- naling pathway in differentiated adipocytes. OLA promotes glucose uptake in differentiated 3T3-L1 preadipocytes. In mouse models with normal glycolipid metabolism, OLA administration failed to in- crease food intake and weight gain despite elevated GAPDH expression, a marker related to glycolysis and PI3K-AKT. This supports the notion that glycolysis plays a significant role in OLA-induced met- abolic dysfunction.</p><p><strong>Conclusion: </strong>OLA induces glycolysis and activates the downstream PI3K-AKT signaling pathway, thereby promoting adipogenesis.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiRNA Dysregulation in Brain Injury: An In Silico Study to Clarify the Role of a MiRNA Set.","authors":"Francesco Sessa, Cristoforo Pomara, Flavia Schembari, Massimiliano Esposito, Emanuele Capasso, Mauro Pesaresi, Eduardo Osuna, Efehan Ulas, Christian Zammit, Monica Salerno","doi":"10.2174/1570159X22666240808124427","DOIUrl":"10.2174/1570159X22666240808124427","url":null,"abstract":"<p><strong>Background: </strong>The identification of specific circulating miRNAs has been proposed as a valuable tool for elucidating the pathophysiology of brain damage or injury and predicting patient outcomes.</p><p><strong>Objective: </strong>This study aims to apply several bioinformatic tools in order to clarify miRNA interactions with potential genes involved in brain injury, emphasizing the need of using a computational approach to determine the most likely correlations between miRNAs and target genes. Specifically, this study centers on elucidating the roles of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a.</p><p><strong>Methods: </strong>After a careful evaluation of different software available (analyzing the strengths and limitations), we applied three tools, one to perform an analysis of the validated targets (miRTarBase), and two to evaluate functional annotations (miRBase and TAM 2.0).</p><p><strong>Results: </strong>Research findings indicate elevated levels of miR-135a and miR-34b in patients with traumatic brain injury (TBI) within the first day post-injury, while miR-200c and miR-34c were found to be upregulated after 7 days. Moreover, miR-451a and miR-135a were found overexpressed in the serum, while miRNAs 34b, 34c, and 200c, had lower serum levels at baseline post brain injury.</p><p><strong>Conclusion: </strong>This study emphasizes the use of computational methods in determining the most likely relationships between miRNAs and target genes by investigating several bioinformatic techniques to elucidate miRNA interactions with potential genes. Specifically, this study focuses on the functions of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a, providing an up-to-date overview and suggesting future research directions for identifying theranomiRNAs related to brain injury, both at the tissue and serum levels.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Causality between Gut Microbiota Dysbiosis and Poisoning by Narcotics and Psychodysleptics: A Mendelian Randomization Analysis.","authors":"Ning Wang, Zhenbo Su","doi":"10.2174/1570159X22999240729092453","DOIUrl":"10.2174/1570159X22999240729092453","url":null,"abstract":"<p><strong>Background: </strong>This study investigates the connection between gut microbiota and poisoning caused by narcotics and psychodysleptics, using Mendelian randomization (MR) to explore possible causal relationships.</p><p><strong>Methods: </strong>The study employed the MR analysis, leveraging genetic variants as instrumental variables to facilitate robust causal inference. Data for gut microbiota was extracted from the MiBioGen study, integrating genome-wide genotyping data with 16S fecal microbiota profiles. Outcome metrics were based on the Finngen study. Genetic instruments were meticulously extracted based on stringent criteria, and harmonized with SNP outcomes associated with \"Poisoning by narcotics and psychodysleptics [hallucinogens]\". The inverse-variance weighted (IVW) method was utilized for MR analysis, supplemented by sensitivity analyses including MR-Egger Regression, Weighted Median Approach, and Leave-One-Out Cross-Validation.</p><p><strong>Results: </strong>Among various microbial groups, nine showed significant statistical links. Specifically, Class Negativicutes (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) and Order Selenomonadales (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) were notably associated. These findings were consistent across different sensitivity analyses.</p><p><strong>Conclusion: </strong>The relationship between gut microbiota and the adverse effects of narcotics and psychodysleptics is an emerging area of research. Our MR study identifies certain microbes that might influence the body's response to these substances. These insights could help in predicting and treating the effects of narcotics and psychodysleptics in the future.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ghrelin, Neuroinflammation, Oxidative Stress, and Mood Disorders: What Are the Connections?","authors":"Jessica Mingardi, Ramona Meanti, Caterina Paoli, Carlo Cifani, Antonio Torsello, Maurizio Popoli, Laura Musazzi","doi":"10.2174/1570159X22999240722095039","DOIUrl":"10.2174/1570159X22999240722095039","url":null,"abstract":"<p><p>Ghrelin is a gut peptide hormone associated with feeding behavior and energy homeostasis. Acylated ghrelin binds to the growth hormone secretagogue receptor 1a subtype (GHS-R1a) in the hippocampus, leading to GH release from the anterior pituitary. However, in recent years, ghrelin and its receptor have also been implicated in other processes, including the regulation of cardiomyocyte function, muscle trophism, and bone metabolism. Moreover, GHS-R1a is distributed throughout the brain and is expressed in brain areas that regulate the stress response and emotional behavior. Consistently, a growing body of evidence supports the role of ghrelin in regulating stress response and mood. Stress has consistently been shown to increase ghrelin levels, and despite some inconsistencies, both human and rodent studies suggested antidepressant effects of ghrelin. Nevertheless, the precise mechanism by which ghrelin influences stress response and mood remains largely unknown. Intriguingly, ghrelin and GHS-R1a were consistently reported to exert anti-inflammatory, antioxidant, and neurotrophic effects both in vivo and in vitro, although this has never been directly assessed in relation to psychopathology. In the present review we will discuss available literature linking ghrelin with the stress response and depressive-like behavior in animal models as well as evidence describing the interplay between ghrelin and neuroinflammation/oxidative stress. Although further studies are required to understand the mechanisms involved in the action of ghrelin on mood, we hypothesize that the antiinflammatory and anti-oxidative properties of ghrelin may give a key contribution.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.","authors":"Miriam Ciani, Giovanna Rigillo, Cristina Benatti, Luca Pani, Johanna M C Blom, Nicoletta Brunello, Fabio Tascedda, Silvia Alboni","doi":"10.2174/1570159X22666240705143649","DOIUrl":"10.2174/1570159X22666240705143649","url":null,"abstract":"<p><strong>Background: </strong>Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge.</p><p><strong>Methods: </strong>The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD.</p><p><strong>Results: </strong>Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway.</p><p><strong>Conclusion: </strong>Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.</p>.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Induced Pluripotent Stem Cells in the Treatment of Stroke","authors":"Yasaman Mahdizadeh Darban, Hamid Askari, Maryam Ghasemi-Kasman, Hanie Yavarpour-Bal, Amirabbas Dehpanah, Parnia Gholizade, Nasrin Nosratiyan","doi":"10.2174/1570159x22666240603084558","DOIUrl":"https://doi.org/10.2174/1570159x22666240603084558","url":null,"abstract":"Stroke is a neurological disorder with high disability and mortality rates. Almost 80% of stroke cases are ischemic stroke, and the remaining are hemorrhagic stroke. The only approved treatment for ischemic stroke is thrombolysis and/or thrombectomy. However, these treatments cannot sufficiently relieve the disease outcome, and many patients remain disabled even after effective thrombolysis. Therefore, rehabilitative therapies are necessary to induce remodeling in the brain. Currently, stem cell transplantation, especially via the use of induced pluripotent stem cells (iPSCs), is considered a promising alternative therapy for stimulating neurogenesis and brain remodeling. iPSCs are generated from somatic cells by specific transcription factors. The biological functions of iPSCs are similar to those of embryonic stem cells (ESCs), including immunomodulation, reduced cerebral blood flow, cerebral edema, and autophagy. Although iPSC therapy plays a promising role in both hemorrhagic and ischemic stroke, its application is associated with certain limitations. Tumor formation, immune rejection, stem cell survival, and migration are some concerns associated with stem cell therapy. Therefore, cell-free therapy as an alternative method can overcome these limitations. This study reviews the therapeutic application of iPSCs in stroke models and the underlying mechanisms and constraints of these cells. Moreover, cell-free therapy using exosomes, apoptotic bodies, and microvesicles as alternative treatments is discussed.","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum MicroRNAs as Predictors of Diagnosis and Drug-resistance in Temporal Lobe Epilepsy: A Preliminary Study","authors":"Gloria Bertoli, Francesco Fortunato, Claudia Cava, Ida Manna, Francesca Gallivanone, Angelo Labate, Antonella Panio, Danilo Porro, Antonio Gambardella","doi":"10.2174/1570159x22666240516145823","DOIUrl":"https://doi.org/10.2174/1570159x22666240516145823","url":null,"abstract":"Objective: Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy, and the current clinical diagnosis is based on EEG, clinical neurological history and neuroimaging findings. Methods: So far, there are no blood-based molecular biomarkers of TLE to support clinical diagnosis, despite the pathogenic mechanisms underlying TLE involving defects in the regulation of gene expression. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression. Results: Recent studies show the feasibility of detecting miRNAs in body fluids; circulating miRNAs have emerged as potential clinical biomarkers in epilepsy, although the TLE miRNA profile needs to be addressed. Here, we analysed the diagnostic potential of 8 circulating miRNAs in sera of 52 TLE patients and 40 age- and sex-matched donor controls by RT-qPCR analyses. Conclusion: We found that miR-34a-5p, -106b-5p, -130a-3p, -146a-5p, and -19a-3p are differently expressed in TLE compared to control subjects, suggesting a diagnostic role. Furthermore, we found that miR-34a-5p, -106b-5p, -146a-5p and miR-451a could become prognostic biomarkers, being differentially expressed between drug-resistant and drug-responsive TLE subjects. Therefore, serum miRNAs are diagnostic and drug-resistance predictive molecules of TLE.","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":"43 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring Brain Pathways Involved in Diabetes-Associated Neurocognitive Disorders: The Potential of Dipeptidyl Peptidase 4 Inhibitors as a Therapeutic Strategy.","authors":"Iwona Piątkowska-Chmiel, Monika Gawrońska-Grzywacz, Kamil Pawłowski, Jarosław Dudka, Brygida Ślaska, Angelika Tkaczyk-Wlizło, Krzysztof Kowal, Mariola Herbet","doi":"10.2174/1570159X22666240517094428","DOIUrl":"https://doi.org/10.2174/1570159X22666240517094428","url":null,"abstract":"<p><p>Diabetes, a widespread chronic metabolic disease, is projected to affect 783 million people globally by 2045. Recent studies emphasize the neuroprotective potential of dipeptidyl peptidase 4 (DPP4i) inhibitors, pointing toward a promising avenue for intervention in addressing cognitive challenges associated with diabetes. Due to limited data on the effect of DPP4i on brain pathways involved in diabetes-related neurocognitive disorders, the decision was made to conduct this study to fill existing knowledge gaps on this topic. The primary aim of our study was to evaluate the potential of DPP4 inhibitors (DPP4i) in preventing cognitive decline in mice with type 2 diabetes (T2D), placing special emphasis on gaining insight into the complex molecular mechanisms underlying this action. We examined drug efficacy in modulating neurotrophic factors, calcium levels, and the expression of key genes (HIF1α, APP, Arc) crucial for neural plasticity. Conducting cognitive assessments with the hole board and passive avoidance tests, we discerned a remarkable influence of short-term gliptin usage on the limiting progress of cognitive dysfunction in diabetic mice. The administration of DPP4 inhibitors led to heightened neurotrophin levels, increased HIF1α in the prefrontal cortex, and a significant elevation in Arc mRNA levels. Our findings reveal that DPP4 inhibitors effectively limit the progression of diabetes-related cognitive disorders. This breakthrough discovery not only opens new research avenues but also constitutes a potential starting point for creating innovative strategies for the treatment of central nervous system disorders focused on improving cognitive abilities.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications.","authors":"Yu Tao, Yufang Sun, Xinghong Jiang, Jin Tao, Yuan Zhang","doi":"10.2174/1570159X22666240528161117","DOIUrl":"10.2174/1570159X22666240528161117","url":null,"abstract":"<p><p>Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.","authors":"Valentina Tedeschi, Silvia Sapienza, Raffaella Ciancio, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo","doi":"10.2174/1570159X22666240517101846","DOIUrl":"https://doi.org/10.2174/1570159X22666240517101846","url":null,"abstract":"<p><p>Besides controlling several organellar functions, lysosomal channels also guide the catabolic \"self-eating\" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}