Neurological Disorders Research Articles

Repositioning Canagliflozin for Mitigation of Aluminium Chloride-Induced Alzheimer’s Disease: Involvement of TXNIP/NLRP3 Inflammasome Axis, Mitochondrial Dysfunction, and SIRT1/HMGB1 Signalling

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the world. Due to failure of the traditional drugs to produce a complete cure for AD, the search for new safe and effective lines of therapy has attracted the attention of ongoing research. Canagliflozin is an anti-diabetic agent with proven efficacy in the treatment of neurological disorders in which mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy play a pathophysiological role. Elucidation of the potential effects of different doses of canagliflozin on AD induced by aluminium chloride in rats and exploration of the molecular mechanisms that may contribute to these effects were the primary objectives of the current study. Materials and Methods: In a rat model of AD, the effect of three different doses of canagliflozin on the behavioural, biochemical, and histopathological alterations induced by aluminium chloride was assessed. Results: Canagliflozin administered to aluminium chloride-treated animals induced dose-dependent normalisation in the behavioural tests, augmentation of the antioxidant defence mechanisms, inhibition of TXNIP/NLRP3 inflammasome signalling, modulation of the SIRT1/HMGB1 axis, interference with the pro-inflammatory and the pro-apoptotic mechanisms, and restoration of the mitochondrial functions and autophagy in the hippocampal tissues to approximately baseline values. In addition, canagliflozin exhibited an interesting dose-dependent ability to repress aluminium chloride-induced histopathological changes in the brain. Conclusions: The effects of canagliflozin on oxidative stress, mitochondrial functions, inflammatory pathways, and autophagy signals may open new gates towards the mitigation of the pathologic features of AD.

Aminoacyl-tRNA synthetase defects in neurological diseases.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes to support protein synthesis in all organisms. Recent studies, empowered by advancements in genome sequencing, have uncovered an increasing number of disease-causing mutations in aaRSs. Monoallelic aaRS mutations typically lead to dominant peripheral neuropathies such as Charcot-Marie-Tooth (CMT) disease, whereas biallelic aaRS mutations often impair the central nervous system (CNS) and cause neurodevelopmental disorders. Here, we review recent progress in the disease onsets, molecular basis, and potential therapies for diseases caused by aaRS mutations, with a focus on biallelic mutations in cytoplasmic aaRSs.

"Brain Biopsy Revolution: Unveiling the Core Syringe Technique with Clinical Insights"

BackgroundObtaining a definitive pathological diagnosis from brain tissue sampling was challenging due to the small, non-representative sample. This study introduced a novel syringe technique for brain biopsy aimed at enhancing diagnostic accuracy by obtaining core tissue samples that better represent the targeted tissue. MethodsThe ten patients with atypical brain lesions underwent the syringe biopsy. After meticulous preoperative planning with neuronavigation, a minimally invasive approach was used: a 3 cm skin incision and a 14 mm burr hole were created. A modified 3-cc syringe was used to create negative pressure and cannulate the brain tissue. The desired sample size (24 cm³) was obtained by controlling the syringe depth and withdrawal. Medical records were reviewed to assess sample analysis results and any complications. ResultsThe syringe technique successfully yielded adequate tissue samples in 9 out of 10 patients. In one case, the desired tissue could not be retrieved and required a microsurgical approach for removal. In all ten cases, a correct diagnosis was made without significant complications. ConclusionThe preliminary findings suggest that the syringe technique is both safe and effective for obtaining substantial volumes of brain tissue, facilitating accurate pathological evaluation in cases of complex neurological disorders.

Applications and Developments of Gene Therapy Drug Delivery Systems for Neurological Disorders

AbstractNeurological diseases (NDs) such as Alzheimer's disease, Parkinson's disease, ischemic strokes, spinal cord injuries, and other similar conditions that continue to pose a substantial health and economic burden on a global scale. It is crucial to tackle the difficulties provided by current medications due to the adverse effects and its immunological reactions to develop improved treatments for neurodegenerative illnesses. Gene therapy is currently being extensively used in preclinical and clinical studies for various diseases because of its ability to enhance the delivery and effectiveness of treatments. Various gene delivery techniques, including messenger RNA, small interfering RNA, antisense oligonucleotides, microRNA, CRISPR/Cas9 system, and plasmid DNA, have been created to address these difficulties. The goal of this study is to provide a clear overview of the pathophysiological underpinnings of NDs illnesses while also illuminating recent developments in gene delivery vector technologies. It goes over the main classifications of these vectors, their individual benefits and drawbacks, and their specific applications in the delivery of gene therapy.

Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice

CD3(+) CD4(−) CD8(−) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulate complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.

Insights into the Therapeutic and Pharmacological Properties of Resveratrol as a Nutraceutical Antioxidant Polyphenol in Health Promotion and Disease Prevention.

Resveratrol (3, 5, 4'-trihydroxystilbene) is a polyphenolic derivative with herbal origin. It has attracted considerable attention in recent decades. Many studies have revealed the benefits of Resveratrol over several human disease models, including heart and neurological diseases, nephroprotective, immune regulation, antidiabetic, anti-obesity, age-related diseases, antiviral, and anticancer in experimental and clinical conditions. Recently, the antioxidant and anti-inflammatory activities of Resveratrol have been observed, and it has been shown that Resveratrol reduces inflammatory biomarkers, such as tissue degradation factor, cyclooxygenase 2, nitric oxide synthase, and interleukins. All of these activities appear to be dependent on its structural properties, such as the number and position of the hydroxyl group, which regulates oxidative stress, cell death, and inflammation. Resveratrol is well tolerated and safe even at higher pharmacological doses and desirably affects cardiovascular, neurological, and diabetic diseases. Consequently, it is plausible that Resveratrol can be regarded as a beneficial nutritional additive and a complementary drug, particularly for therapeutic applications. The present review provides an overview of currently available investigations on preventive and therapeutic characteristics and the main molecular mechanisms of Resveratrol and its potent derivatives in various diseases. Thus, this review would enhance knowledge and information about Resveratrol and encourage researchers worldwide to consider it as a pharmaceutical drug to struggle with future health crises against different human disorders.

Integrating early life stress in neurological disease: advancing preventive neurology

BackgroundIn 2021, an estimated 43% of the world’s population had been diagnosed with a neurological disorder. Early life stress (ELS) is now a well-established risk factor for later-life neurological disorders....

Neuroprotection and mechanisms of ginsenosides in nervous system diseases: Progress and perspectives.

Ginsenosides are the primary component discernible from ginseng, including Rb1, Rb2, Rd, Rg1, Rg2, and compound K, and so forth. They have been shown to have multiple pharmacological activities. In recent years, more and more studies have been devoted to the neuroprotection of various ginsenosides against neurological diseases and their potential mechanisms. This paper comprehensively summarizes and reviews the neuroprotective effects of various ginsenosides on neurological diseases, especially acute and chronic neurodegenerative diseases, and their mechanisms, as well as their potential therapeutic applications to promote neuroprotection in disease prevention, treatment, and prognosis. Briefly, ginsenosides exert effective neuroprotective effects on neurological conditions, including stroke, Alzheimer's disease, Parkinson's disease, and brain/spinal cord injuries through a variety of molecular mechanisms, including anti-inflammatory, antioxidant, and anti-apoptotic. Among them, some signaling pathways play important roles in related processes, such as PI3K/Akt, TLR4/NF-κB, ROS/TXNIP/NLRP3, HO-1/Nrf2, Wnt/β-catenin, and Ca2+ pathway. In conclusion, the present study reviews the research progress on the neuroprotective effects of ginsenosides in the last decade, with the aim of furnishing essential theoretical underpinning and effective references for further research and exploration of the multiple medicinal values of Chinese herbal medicines and their small molecule compounds, including ginseng and panax ginseng. Because there is less evidence in the existing clinical studies, future research should be focused on clinical trials in order to truly reflect the clinical value of various ginsenosides for the benefit of patients.

Harnessing Brain Plasticity: The Therapeutic Power of Repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) in Neurotransmitter Modulation, Receptor Dynamics, and Neuroimaging for Neurological Innovations

Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer’s disease, stroke, Parkinson’s disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients’ care.

A Recent Advance on Phytochemicals, Nutraceutical and Pharmacological Activities of Buckwheat.

Buckwheat, a member of the Fagopyrum genus in the Polygonaceae family, is an ancient pseudocereal with noteworthy nutraceutical properties that have been relatively less explored. This crop holds great promise for the future due to its gluten-free protein, wellbalanced amino acid profile, and the presence of bioactive flavonoids that promote good health. With its gluten-free nature and a combination of beneficial nutritional components, buckwheat shows significant potential for a variety of health benefits. The objective of the present review aims to explore various nutritional and pharmacological properties of buckwheat. With the help of various search engines such as, Pubmed, Google and Semantic Scholar, research and review papers were carefully investigated and summarized in a comprehensive review. A fascinating spectrum of nutritional and pharmacological activities of common buckwheat and Tartary buckwheat were explored such as antidiabetic, anti-inflammatory, neurological disorders, antiobesity, anticancer, cardiovascular agents and many more. This review provides a concise overview of the current understanding of the chemical composition of both common buckwheat and Tartary buckwheat and the captivating spectrum of pharmacological activity and also underscoring their immense potential for future advancements.

A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins.

Interplays Between Matrix Metalloproteinases and Neurotropic Viruses: An Overview.

Matrix metalloproteinases (MMPs) are a diverse group of proteases involved in various physiological and pathological processes through modulation of extracellular matrix (ECM) components, cytokines, and growth factors. In the central nervous system (CNS), MMPs play a major role in CNS development, plasticity, repair, and reorganisation contributing to learning, memory, and neuroimmune response to injury. MMPs are also linked to various neurological disorders such as Alzheimer's disease, Parkinson's disease, cerebral aneurysm, stroke, epilepsy, multiple sclerosis, and brain cancer suggesting these proteases as key regulatory factors in the nervous system. Moreover, MMPs have been involved in the pathogenesis of neurotropic viral infections via dysregulation of various cellular processes, which may highlight these factors as potential targets for the treatment and control of neurological complications associated with viral pathogens. This review provides an overview of the roles of MMPs in various physiological processes of the CNS and their interactions with neurotropic viral pathogens.

Prof. G Srinivasa Acharya: A guiding light and a skilled practitioner

Abstract This article aims to shed light on the substantial contributions made by renowned visionary Dr. G. Srinivas Acharya in the field of Ayurveda. Dr. Acharya’s journey has been characterized by dedication, hard work, and a relentless pursuit of knowledge. With a strong grounding in Ayurvedic principles, he has been instrumental in bridging the gap between ancient wisdom and modern science. Dr. Acharya’s expertise in treating a wide range of diseases is truly remarkable. From autoimmune disorders to cancer, diabetes, hypertension, arthritis, skin conditions, neurological disorders, stress management, rejuvenation therapies, and more, he has made a lasting impact on the lives of countless patients. His expertise in employing Rasayana Chikitsa for the treatment of challenging cases has been particularly noteworthy. Beyond his clinical practice, his tireless efforts in promoting Ayurveda at international forums and establishing collaborations with leading universities and institutions have played a significant role in raising awareness about this ancient medical system. By sharing his knowledge and inspiring others, he has contributed to the growth and recognition of Ayurveda on a global scale. His dedication to the field of Ayurveda, coupled with his innovative approach and expertise in treatment, has earned him a place of prominence among the visionaries who have dedicated themselves to this ancient science.

CB1 Receptors In NG2 CELLS MEDIATE CANNABINOID-EVOKED FUNCTIONAL MYELIN REGENERATION

Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB1-deficient mice. Overall, this study identifies CB1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.

Associations between post-traumatic stress disorder and neurological disorders: A genetic correlation and Mendelian randomization study

Associations between post-traumatic stress disorder and neurological disorders: A genetic correlation and Mendelian randomization study

Decoupling Between Brain Activity and Cerebrospinal Fluid Movement in Neurological Disorders.

Recent research has identified a link between the global mean signal of resting-state functional MRI (fMRI) and macro-scale cerebrospinal fluid movement, indicating the potential link between this resting-state dynamic and brain waste clearance. Consistent with this notion, the strength of this coupling has been associated with multiple neurodegenerative disease pathologies, especially the build-up of toxic proteins. This article aimed to review the latest advancements in this research area, emphasizing studies on spontaneous global brain activity that is tightly linked to the global mean resting-state fMRI signal, and aimed to discuss potential mechanisms through which this activity and associated physiological modulations might affect brain waste clearance. The available evidence supports the presence of a highly organized global brain activity that is linked to arousal and memory systems. This global brain dynamic, along with its associated physiological modulations, has the potential to influence brain waste clearance through multiple pathways through multiple pathways. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Optimized primary dorsal root ganglion cell culture protocol for reliable K+ current patch-clamp recordings

DRG primary neuron cultures, derived from rodents, closely mimic properties of sensory neurons in vivo and are highly useful for studying pain and neurological disorders. These cultures are pivotal in patch clamp electrophysiology for sensory neuron properties analysis. A detailed, replicable protocol in scientific research ensures experiment accuracy and reproducibility. This paper provides comprehensive details for replicating the protocol and achieving consistent results in primary DRG cell culture as used for patch clamp recordings. We outlined a comprehensive protocol for establishing primary DRG cell culture, optimized for improved gigaseal formation in whole-cell patch-clamp recordings. Additionally, we conducted a simulation study focused on recording macroscopic K+ channels. The findings established an optimized novel protocol that works reliably for whole-cell patch clamp recordings and data analysis using primary DRG cells prepared as described in this publication. The details for the protocol in the literature are dispersed across various publications, making it challenging to find a comprehensive summary in one source. This study confirms, for the first time, the efficacy of using fewer protocol steps, which reduces stress and variability in obtaining suitable cells for patch clamp recordings compared to existing methods in the literature. Given the challenges posed by the dissociation process of primary DRG cells and the importance of comprehensive method documentation in the literature, the protocol presented provides improved and consistent applications of primary DRG cell culture in patch clamp recordings

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA generates transcript isoforms by utilizing various polyadenylation sites (PASs) from the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

Employing Convolutional Neural Networks And Explainable Artificial intelligence for the Detection of Seizures from Electroencephalogram Signal

A seizure is a rapid, uncontrolled burst of electrical activity in the brain. Epilepsy is a neurological disorder caused by repeated seizures. Effective management requires early detection. This research aims to create a convolutional neural network (CNN) and explainable artificial intelligence (XAI) integrated system for epileptic seizure detection, using techniques such as Shapley additive explanation (SHAP) for better interpretability. The relevant data is acquired from a variety of electroencephalogram (EEG) dataset to facilitate the development of the model. To identify the EEG data, the proposed system combines deep learning models with feature extraction technique. Model visualization and XAI approaches like feature importance analysis from SHAP values offer clear insights into the model's decision-making process. Evaluation criteria like specificity and accuracy are used to assess the models' performance. This framework's objective is to create simple seizure detection systems that assist early epilepsy patient identification and individualized treatment plans. This research aims in opening the door to improved patient care and treatment by developing the field of epilepsy seizure detection.