Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Neuroprotective potential of traditional Ayurvedic Kadha:age-related neurological disorders:a comprehensive literature review

Despite modern medicine’s advancements,age-related neurological diseases like Alzheimer’s disease and Parkinson’s disease remain challenging due to high costs,side effects,and limited accessibility.Ayurveda,a traditional Indian medicine system,offers Kadha tea as a potential herbal option.This review explores Kadha’s components(basil(Ocimum basilicum L.),black pepper(Piper nigrum L.),Cinnamon(Cinnamomum verum J.Presl),ginger(Zingiber officinale Roscoe),and raisin(Vitis vinifera L.))and their interaction with various neurological disorders.Studies suggest Kadha exhibits anti-inflammatory,antioxidant,and antiviral properties,potentially impacting Alzheimer’s disease,Parkinson’s disease,neurotoxicity,neuroinflammation,and brain trauma.By focusing on specific disease mechanisms and Kadha’s intergrade effects,this review aims to elucidate its potential role in managing age-related neurological disorders.

Augmentation of transforming growth factor-βsignaling for the treatment of neurological disorders

Members of the transforming growth factor-β(TGF-β)superfamily perform a wide range of essential functions during development and in adulthood,as well as in response to injury and inflammation(Luo,2022).In the adult central nervous system,TGF-βs and their receptors are widely expressed in all of the major neuronal,glial,and vascular cell types.Members of the TGF-βsuperfamily are pivotal responders to pathological insults to the brain.Dysfunction of TGF-βsignaling contributes to pathogenesis of neurological disorders.Manipulation of TGF-βsignaling pathway alters pathological and functional outcomes in models of neurological diseases(Luo,2022).Therefore,the TGF-βsignaling pathway has emerged as a potential therapeutic target against neurological diseases.

Past,present,and future of deep transcranial magnetic stimulation:A review in psychiatric and neurological disorders

Deep transcranial magnetic stimulation(DTMS)is a new non-invasive neuromodulation technique based on repetitive transcranial magnetic stimulation technology.The new H-coil has significant advantages in the treatment and mechanism research of psychiatric and neurological disorders.This is due to its deep stimulation site and wide range of action.This paper reviews the clinical progress of DTMS in psychiatric and neurological disorders such as Parkinson’s disease,Alzheimer’s disease,post-stroke motor dysfunction,aphasia,and other neurological disorders,as well as anxiety,depression,and schizophrenia.

Repurposing niclosamide for the treatment of neurological disorders

Neurological disorders are still one of the major causes of death,and the vast need to find efficacious therapy is nowadays an essential goal of the scientific community.For Parkinson's disease(PD),amyotrophic lateral sclerosis(ALS),spinal cord injury,and intracerebral hemorrhage.

Drug utilization evaluation of medications used in the management of neurological disorders

Background and object:The burden of neurological disorders in India is expected to increase due to the rapid demographic and epidemiological transition,with irrational drug use,which is also a global concern.Thus,drug utilization evaluation is designed to ensure appropriate medicine use within the healthcare settings.The aim of the study was to assess the rate and pattern of drug utilization in the management of neurological disorders.Materials and methods:A hospital-based cross-sectional drug utilization evaluation study on neurological drugs was carried out at the Department of Neurology over a span of six months.All legible prescriptions consisting neurological medications irrespective of patient's gender,aged≥18 years were included for the study.The World Health Organization(WHO)core drug use indicators were used to assess the drug prescribing and utilization patterns.Results:A total of 310 prescriptions were reviewed,where male predominance was found to be 56.45%.Out of 310 prescriptions,drugs belonging to 26 neurological classes were prescribed for the management of various neurological disorders.The majority of patients were diagnosed with epilepsy and the most prescribed drugs per patient were phenytoin(14.8%)and valproic acid(6.45%).By following the WHO core drug prescribing indicators,65.47%of drugs prescribed from the India National List of Essential Medicines,2022,followed by 29.83%of drugs prescribed in generic name and 10.86%of prescriptions including injections.Conclusion:The study findings showed that the prescribing pattern in the Department of Neurology was in accordance with the WHO core prescribing indicators.But,the extent of polypharmacy prescriptions was very high.Therefore,interventions are very necessary to promote rational drug prescribing patterns and thus clinical pharmacists can contribute to assess and review the drug utilization pattern to optimize the drug therapy and improvement in patient safety.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Gait analysis in swine,sheep,and goats after neurologic injury:a literature review

Medical research on neurologic ailments requires representative animal models to validate treatments before they are translated to human clinical trials.Rodents are the predominant animal model used in neurological research despite limited anatomic and physiologic similarities to humans.As a result,functional testing designed to assess locomotor recovery after neurologic impairment is well established in rodent models.Comparatively,large r,more clinically relevant models have not been as well studied.To achieve similar locomotor testing standardization in larger animals,the models must be accessible to a wide array of researchers.Non-human primates are the most relevant animal model fo r translational research,however ethical and financial barriers limit their accessibility.This review focuses on swine,sheep,and goats as large animal alternatives for transitional studies between rodents and non-human primates.The objective of this review is to compare motor testing and data collection methods used in swine,sheep,and goats to encourage testing standardization in these larger animal models.The PubMed database was analyzed by searching combinations of swine,sheep,and goats,neurologic injuries,and functional assessments.Findings were categorized by animal model,data collection method,and assessment design.Swine and sheep were used in the majority of the studies,while only two studies were found using goats.The functional assessments included open pen analysis,treadmill walking,and guided free walking.Data collection methods included subjective behavioral rating scales and objective tools such as pressure-sensitive mats and image-based analysis software.Overall,swine and sheep were well-suited for a variety of assessment designs,with treadmill walking and guided free walking offering the most consistency across multiple trials.Data collection methods varied,but image-based gait analysis software provided the most robust analysis.Future studies should be conducted to standardize functional testing methods after neurologic impairment in large animals.

Spectrum of Neurological Disorders Related to Autoimmune Diseases in Brazzaville, Congo

Background: Autoimmune diseases, which are among the leading causes of morbidity and mortality in the world, are pathologies caused by a dysfunction of the immune system. They can affect the central nervous system, the peripheral nervous system or both nervous systems. Objectives: To describe the epidemiological, clinical, paraclinical, therapeutic and evolutive aspects of neurological disorders related to autoimmune diseases. Methods: This was a prospective cohort study. It was carried out from 1 January 2015 to 31 December 2019 (5 years). It focused on patients aged 15 years and above, who were hospitalized or followed as ambulatory patients for neurological disorders related to autoimmune diseases in the neurology department of the university teaching hospital in Brazzaville. Results: Among the 41 patients who fulfilled inclusion criteria, there were 29 (70.73%) women and 12 (29.27%) men. The average age of patients was 38.3 ± 13.8 years. An increase in the frequency of neurological disorders related to autoimmune diseases was observed every year. The main neurological disorders were neuromyelitis optica spectrum disorders (n = 14;34.15%), acute polyradiculoneuropathies (n = 13;31.71%), chronic polyradiculoneuropathies (n = 4;9.75%) and acute disseminated encephalomyelitis (n = 3;7.31%). The treatments administered, which consisted of corticosteroids and immunosuppressive drugs, had significantly improved the vital prognosis and functional status of patients (p = 0.025). Conclusion: In our study population, neurological disorders related to autoimmune diseases are rare. The neurological clinico-pathological entities diagnosed are similar to those reported in the literature. The therapeutic approaches used improve the quality of life of patients.

Impact of gut–brain interaction in emerging neurological disorders

The central nervous system(CNS)is a reservoir of immune privilege.Specialized immune glial cells are responsible for maintenance and defense against foreign invaders.The blood–brain barrier(BBB)prevents detrimental pathogens and potentially overreactive immune cells from entering the periphery.When the double-edged neuroinflammatory response is overloaded,it no longer has the protective function of promoting neuroregeneration.Notably,microbiota and its derivatives may emerge as pathogen-associated molecular patterns of brain pathology,causing microbiome–gut–brain axis dysregulation from the bottom-up.When dysbiosis of the gastrointestinal flora leads to subsequent alterations in BBB permeability,peripheral immune cells are recruited to the brain.This results in amplification of neuroinflammatory circuits in the brain,which eventually leads to specific neurological disorders.Aggressive treatment strategies for gastrointestinal disorders may protect against specific immune responses to gastrointestinal disorders,which can lead to potential protective effects in the CNS.Accordingly,this study investigated the mutual effects of microbiota and the gut–brain axis,which may provide targeting strategies for future disease treatment.

Urinary Sphincter Disorders of Neurological Origin: Prognostic Aspects in the Neurology Department of the Ignace Deen National Hospital

Introduction: Complications of Urinary sphincter disorders of neurological origin can be life threatening. The objective of this study was to describe the prognosis of urinary sphincter disorders during neurological conditions. Methods: This was a six-month analytical study conducted at the neurological unit of the Hôpital national Ignace Deen. Including patients with urinary sphincter disorders following a neurological condition;Chi-square, Fischer, and Student’s t-tests were used for variables with a p value less than 0.10 and then included in a logistic model with a significance level set at 0.05 and a 95% confidence interval. Results: We collected 1081 patients among whom, 324 presented, that is to say a frequency of 30%, which concerned subjects aged 57.3 ± 16.4 years with a slight female predominance 50.3%. Urinary incontinence (80.6%) was associated with complications such as urinary tract infection with a high proportion of cerebral damage (92.3%). HIV infection (P = 0.015), bedsores (P = 0.049), and inhalation pneumonia (P = 0.001) were the main poor prognostic factors. Conclusion: Urinary sphincter disorders are elements of poor prognosis, both vital and functional, concerning elderly subjects with a predominance of urinary incontinence. HIV infection, bedsores, pneumopathy are poor prognostic factors.

Pattern of Neurological Disorders among Children Presenting at the Neurology Unit of Tertiary Hospital in Awka

Background: Many children in Nigeria suffer from detrimental, debilitating and lifelong neurologic disorders, many of which are highly preventable using simple, cost-effective interventions. Objective: To examine the pattern of neurological disorders among children presenting at the neurology unit of Chukwuemeka Odumegwu Ojukwu University Teaching Hospital Amaku, Awka, Nigeria. Methods: A retrospective review of the hospital records of children who presented at the Paediatric Neurology Unit between 1st March 2020 and 31st March 2022 was carried out. Data were abstracted using a proforma and analyzed using SPSS Version 21. Results: A total of 138 children aged 0 to 15 years were seen in the unit during the period under review. 115 (83.35%) of these children were diagnosed with chronic neurological disorders. Those with chronic neurological disorders had a male:female ratio of 1.9:1, and the majority (65%) of them were below 5 years of age. The most common presenting complaints were delayed milestones (43.4%), seizures (23.8%), and speech disorders (17.2%). The most typical diagnosis was cerebral palsy (CP) (34.7%), seizure disorder (29.8%) and attention deficit hyperactivity disorder (8.9%). Perinatal asphyxia (47.7%), neonatal jaundice (17.0%) and central nervous system infections (CNS) infections (12.5%) were identified as the major risk factors responsible for these neurologic disorders. Conclusion: Cerebral palsy and seizure disorders constitute the major neurological disorders among children seen in our institution. Efforts should be intensified at reducing the incidence and impact of perinatal asphyxia, neonatal jaundice and CNS infections, identified as the major culprits, to curb the menace of these debilitating lifelong neurologic sequelae.

Distinct molecular profiles of skull bone marrow in health and neurological disorders

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positronemission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.

Stem cells:a promising candidate to treat neurological disorders

Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous system.Therefore,based on the regenerative capacity of stem cells,transplantation therapies of various stem cells have been tested in basic research and preclinical trials,and some have shown great prospects.This manuscript overviews the cellular and molecular characteristics of embryonic stem cells,induced pluripotent stem cells,neural stem cells,retinal stem/progenitor cells,mesenchymal stem/stromal cells,and their derivatives in vivo and in vitro as sources for regenerative therapy.These cells have all been considered as candidates to treat several major neurological disorders and diseases,owing to their self-renewal capacity,multi-directional differentiation,neurotrophic properties,and immune modulation effects.We also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease,and age-related macular degeneration,as well as traumatic brain injury and glioblastoma.In spite of a few unsuccessful cases,risks of tumorigenicity,and ethical concerns,most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system disease.In summary,these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological disorders.Thus,stem cells are a promising candidate for the treatment of nervous system diseases.

Tongue dysfunction in neurological and neuromuscular disorders: A narrative literature review

Evaluation of oral function is useful for tracking longitudinal changes in swallowing function. Using videofluoroscopic(VF) images, we can evaluate swallowing function, but it is extremely difficult to quantitatively evaluate the oral phase. Recently, several studies have tried to quantitatively assess tongue function by analyzing tongue movement on VF images, to measure tongue thickness by ultrasonography, and to measure tongue pressure as surrogate for tongue strength. In this review article,the current state of quantitative assessments of tongue function for identification and management of dysphagia in patients with neuromuscular and other neurological disorders(NNMD) has been outlined. Disturbed bolus transport in patients with NNMD has been quantitatively measured on VF images by analyzing tongue base movement and bolus transport from the mouth to the pharynx. Enlarged tongue in Duchenne muscular dystrophy patients were observed by measuring the transverse width of the tongue on ultrasound. Tongue pressures that were measured using a handheld probe in NNMD patients were less than half of those in healthy subjects. More studies are needed to develop guidelines what types of tongue dysfunction give an indication of adjusting diet and introducing tube feeding to NNMD patients.

Studying neurological disorders using induced pluripotent stem cells and optogenetics

Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.

The biological clock: future of neurological disorders therapy

Dear editors, The seminal, discoveries by Jeffrey Connor Hall, Michael Rosbash and Michael Warren Young have earned the Nobel Prize in Physiology and Medicine 2017 for revealing a crucial physiological mechanism explaining biological clock, with important implications for human health and diseases. The work explains the interplay between the biological clock, the transcriptional feedback loop, and neuroscience, where they identified genes and proteins that work together both in humans and other animals. This article describes the link between biological clock disruption and consequent neurodegeneration and also highlights the significance of biological clock modulators for possible clinical interventions in neurological disorders.