Neuropathic pain (NP) continues to be a significant clinical issue because the existing treatment modalities have very low efficacy and tolerability. An increasing body of mechanistic and translational data is identifying the endocannabinoid system (ECS) as a key regulator of nociceptive transmission, neuroinflammation, and maladaptive synaptic plasticity. This review critically synthesizes preclinical actions, pharmacological variety, and clinical trial evidence supporting cannabinoid-based interventions to NP, alongside identifying translational challenges, safety concerns, and emerging precision- medicine strategies. The approach adopted was a narrative review approach. To identify the relevant literature, published within the last two decades, PubMed, Scopus, Web of Science, Google Scholar were searched using the keywords that are related to cannabinoids, endocannabinoid system, neuropathic pain, phytocannabinoids, and clinical trials. Relevance was used to select preclinical, mechanistic, and clinical studies. The article is written in the form of a narrative review and is not organized in the system of a systematic review. The preclinical evidence demonstrates that cannabinoids regulate NP by acting through CB1- and CB2-mediated, inhibitory effects on the release of neurotransmitters, central sensitization, neuroinflammation and regulation of transient receptor potential (TRP) channels. Phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as synthetic cannabinoids, are effective in various experimental NP models. Clinical trials report variable but clinically significant decreases in the intensity of pain, sleep disturbance, and allodynia; although results vary depending on formulation, dose, route of administration, and heterogeneity of patients. Safety data show dose-related adverse effects, such as dizziness, cognitive impairment, and psychoactive effects, with CBD showing a relatively positive tolerability profile. Although there is a high level of mechanistic support, the translation to consistent clinical benefit is still limited due to pharmacokinetic variability, variation in the ratio of THC:CBD, and patient-specific factors. Other issues are standardization of formulations, safety testing in the long term, and variability in regulations. The varied actions of cannabinoids on NP pathophysiology, through CB1/CB2 agonism, neuroinflammation suppression, and TRP modulation, are strongly supported by preclinical evidence, but are hampered by pharmacokinetic variability, inconsistent THC: CBD ratios and inconsistent patient response. CBD has a good tolerability despite the challenges such as regulatory barriers and lack of long-term safety evidence, which highlights the potential of CBD in precision tactics. To enhance the reliability of treatments, our findings demonstrate that the same delivery mechanisms and tailor-made dosages are needed. Cannabinoids are a promising but emerging treatment option of neuropathic pain. Despite the strong preclinical evidence, the clinical outcomes are still heterogeneous. The future research should focus on optimizing cannabinoid-based therapies compositions, designing better delivery systems, and conducting a long-term safety evaluation to fully realize the translational potential of cannabinoid-based therapies in the management of NPs.
Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.
Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment. The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes. Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress. To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents. This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.
The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease.
Cardiospermum halicacabum, commonly known as balloon vine or love in a puff, is a medicinal plant recognized for its diverse phytoactive compounds. This plant contains various bioactive constituents, including alkaloids like cardiospermin, flavonoids such as quercetin, and triterpenoids, which contribute to its therapeutic properties. This scoping review presents current literature on the neuroprotective, anti-inflammatory, and antioxidant potentials of Cardiospermum halicacabum, along with preclinical findings, patent reports, and commercially accessible formulations and nanoformulations. This scoping review was conducted in accordance with the PRISMA-ScR guidelines. A comprehensive search of Web of Science, PubMed, Embase, Medline, Google Scholar, and Google Patents was conducted (2008-2024) using keywords such as Cardiospermum halicacabum, balloon vine, antioxidant, anti-inflammatory, and neuroprotective. Only English-language, peer-reviewed articles, patents, and commercially available formulations were included. Studies unrelated to the plant's neuroprotective, anti-inflammatory, or antioxidant mechanisms were excluded. Screening, data extraction, and critical appraisal were performed independently by three reviewers. Studies suggest that Cardiospermum halicacabum exhibits significant neuroprotective effects, potentially due to its antioxidant activity, which protects neuronal cells from oxidative stressinduced damage. The plant's anti-inflammatory properties are well-documented, indicating efficacy in reducing inflammation through mechanisms that modulate cytokine production and inhibit inflammatory pathways. Its antioxidant constituents scavenge free radicals, preventing oxidative damage to cells and tissues that extends its potential applications in managing oxidative stressrelated disorders. The findings highlight the promising therapeutic potential of Cardiospermum halicacabum in neuroprotection, anti-inflammatory responses, and oxidative stress management. While preclinical studies support its efficacy, further research, including clinical trials, is required to confirm its pharmacological benefits and optimize its therapeutic applications. The development of nanoformulations suggests an advanced approach to enhancing bioavailability and targeted drug delivery. Cardiospermum halicacabum shows promise as a multifaceted therapeutic agent, particularly in neurological and inflammatory conditions. Due to its antioxidant, anti-inflammatory, and neuroprotective properties, Cardiospermum halicacabum can be considered a potential neuroprotective agent. While preclinical data are encouraging, further clinical trials are necessary to validate its efficacy and safety for human use. Medicinal potential.
The Gut-Brain Axis (GBA) has a complex role in chronic neuroinflammation, which is increasingly connected to neurodegenerative diseases (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). Through neuronal, endocrine, and immunological pathways, the GBA enables twoway communication between the gastrointestinal tract and the central nervous system. According to recent research, the pathophysiology of neuroinflammatory responses in NDDs may be significantly influenced by gut dysbiosis, increased intestinal permeability, and modified microbial metabolites, such as Short-Chain Fatty Acids (SCFAs) and polyphenols. This study summarizes preclinical and clinical data supporting several anti- inflammatory approaches targeting GBA. Probiotics and fecal microbiota transplantation are two examples of microbiota-based treatments that have demonstrated promise in reducing neuroinflammatory responses and enhancing cognitive performance. Mediterranean and polyphenol-rich diets are among the dietary therapies that show promise in modifying the composition of microorganisms, lowering pro-inflammatory signaling, and enhancing neuroprotection. Through microbiota regulation, pharmacological substances such as curcumin, resveratrol, and SCFA mimetics also have anti-neuroinflammatory benefits. However, a number of translational challenges still exist, including limitations in animal models, a lack of standardized therapies, and inter-individual microbiome heterogeneity. In order to provide precise, GBA-targeted therapies, future views place a strong emphasis on integrating multi-omics, artificial intelligence, and personalized medicine. This study highlights a new therapeutic approach to treating neurodegeneration by examining the translational potential of anti- inflammatory therapies targeting GBA. It also emphasizes the necessity of strong clinical studies to confirm these findings.
Neurodegenerative disorders, including Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by progressive neuronal loss driven by damage or apoptosis. Although their precise etiologies remain unclear, neuronal degeneration is a common pathological hallmark. This review compiles and critically evaluates studies investigating the potential of isoquinoline derivatives to mitigate neurodegeneration. Particular attention is given to their inhibitory effects on key enzymes implicated in these disorders and structural modifications aimed at improving potency and reducing toxicity. Experimental findings demonstrate that isoquinoline derivatives exhibit significant inhibitory activity against several neurodegeneration-related enzymes. These compounds show promise in attenuating disease progression in preclinical models, supporting their potential as therapeutic leads. Isoquinoline derivatives display multitarget properties, and structural optimization has enhanced their efficacy and safety profiles. Their multifunctional nature could offer advantages over current single-target therapies by improving efficacy and reducing adverse effects. Isoquinoline derivatives represent promising scaffolds for developing novel therapeutics targeting neurodegenerative disorders. However, most data are limited to in vitro and earlystage preclinical studies. Comprehensive mechanistic investigations, standardized in vivo evaluations, and early-phase clinical trials are required to establish their pharmacokinetics, blood-brain barrier permeability, safety, and therapeutic potential.
Weaning is a critical developmental stage that can trigger intestinal inflammation through disruption of microbial homeostasis, immune responses, and epithelial barrier integrity. While numerous studies have explored gene expression changes during weaning in animals, no comparable analyses have been conducted in humans. Given the close physiological and genetic similarity between pigs and humans, piglet data were employed to investigate the molecular mechanisms underlying weaning-induced intestinal inflammation and its potential links to neurological pathways. A curated set of 117 differentially expressed genes related to gut inflammation was collected from bibliographic sources. Protein-protein interaction network analysis was performed using NetworkAnalyst and Cytoscape, followed by hub gene selection and functional enrichment using KOBAS, ClusterProfiler, and StringApp. Among the identified hub genes, SOD1, CAT, TNF, CXCR4, TLR2, and TGFB1 play key roles in oxidative stress, immune response, glial regulation, and neuroinflammatory signaling. Enrichment analysis revealed significant associations with pathways such as Amyotrophic Lateral Sclerosis, TGF-β signaling, Folate and Vitamin B12 metabolism, and Inflammatory Bowel Disease, as well as biological processes like gliogenesis, hypoxia response, and cytokine signaling. These findings suggest that intestinal inflammation during weaning may have systemic implications, highlighting shared molecular pathways relevant to neuroinflammatory-related processes. This study provides new insight into the genetic and molecular landscape of weaning-induced inflammation and its broader systemic effects. The identified shared molecular pathways may provide a foundation for future experimental studies investigating the broader biological implications of early-life intestinal inflammation.
Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification. A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs. ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies. Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers. Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.
Multiple sclerosis (MS) is a progressive, immune-mediated condition characterized by the destruction of myelin, the protective insulation surrounding nerve fibers. This ongoing assault triggers a cascade of damage, including persistent inflammatory responses, loss of myelinproducing oligodendrocytes, axonal degradation, and cumulative neurological impairment. While motor and sensory difficulties are hallmark features, patients frequently contend with less visible but equally debilitating symptoms such as cognitive dysfunction, profound fatigue, affective disorders, nerve pain, and autonomic instability. These often-overlooked manifestations critically impact well-being and functional capacity. The pathophysiology of MS is increasingly understood as a network of overlapping cellular and molecular dysfunctions. Alongside irregularities in the endocannabinoid signaling network, key contributors include aberrant immune communication, persistently activated microglia, impaired mitochondrial energy production, and dysregulated activity of enzymes like PDE7, MAGL, ROCK, and PADs. These interconnected pathways collectively drive disease initiation and advancement. This analysis synthesizes established information on current FDA-approved treatments for MS and examines promising novel small-molecule compounds aimed at specific disease-relevant targets. A significant focus is placed on medicinal chemistry advancements, particularly the design and optimization of heterocyclic compounds. Scaffolds incorporating quinolines, pyrimidines, indoles, and related nitrogen-containing structures demonstrate considerable potential for conferring immunomodulation, reducing inflammation, and protecting neural tissue. By evaluating structure-activity relationships, binding mechanisms, and strategic drug design, this review offers an integrated perspective to inform the creation of new, targeted therapies for MS.
The search for effective treatments for neurodegenerative diseases, particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts for 60-80% of dementia cases globally, affecting approximately about 50 million people. Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting significant attention from regulatory agencies, such as the US FDA. This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's disease (AD) treatment using a novel network pharmacology approach. Specifically, it explored the interaction of dolutegravir with key molecular targets involved in AD pathology, predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic candidate. This study employed a network pharmacology framework to evaluate dolutegravir, an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its possible therapeutic mechanisms. A network pharmacology approach was used to predict the drug targets of dolutegravir. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein- protein interaction (PPI) network analysis was conducted to assess key interactions and molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the predicted targets. PPI network analysis revealed that dolutegravir interacted with several key targets, including BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8, CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol). The findings indicated that dolutegravir holds significant potential in modulating key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's established pharmacological profile, offers a promising route for accelerated therapeutic development in AD.
This study aims to investigate the antidepressant properties of Hispidulin, a flavonoid present in Scutellaria barbata D. Don. The selection of Hispidulin stems from its notable inhibitory activity against Xanthine Oxidase (XO), a parameter in the pathophysiology of depression. Mice were subjected to a rigorous evaluation using a murine model of Chronic Unpredictable Mild Stress (CUMS) to induce depression for 21 days and antidepressant properties were rigorously assessed using the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Imipramine and fluoxetine were used as standard drugs. Additionally, neurochemical analyses were conducted to quantify serotonin (5-HT), norepinephrine (NE), and dopamine (DA) levels in the cortex, hippocampus, and hypothalamus. Further mechanistic insights were sought through the estimation of monoamine oxidase (MAO) activity and assessment of antioxidant enzyme levels in the brain. Plasma nitrite and corticosterone levels were also measured to delineate the underlying mechanism of action. Hispidulin demonstrated significant antidepressant effects, as evidenced by reduced immobility time in TST and FST and increased exploratory behavior in OFT. Neurochemical analysis revealed restoration of 5-HT, NE, and DA levels in key brain regions. Furthermore, Hispidulin modulated MAO activity and enhanced antioxidant enzyme levels in the brain. Plasma nitrite levels were elevated, indicating enhanced nitric oxide synthesis, while corticosterone levels were reduced. Our findings indicate that Hispidulin exerts potent antidepressant effects, potentially mediated through its influence on monoaminergic neurotransmitters, MAO activity, and antioxidant defenses. These results provide valuable mechanistic insights into the antidepressant action of Hispidulin, supporting its potential therapeutic application in depressive disorders.
Epilepsy is a common and frequently devastating disorder affecting millions of people. According to a recent survey, 1-2% of the Indian population suffers from major mental disorders and 5% suffers from minor mental disorders. Epilepsy is among those mental disorders that affect 30 million people worldwide. Currently, the treatment of epilepsy involves agents which modulate sodium-ion channels, enhance GABAergic transmission, and agents with multiple modes of action. Various classes of synthetic drugs are used to treat epilepsy, but these drugs are often challenged due to their unwanted side effects. Medicinal plants have been a part of human society which combating diseases from the dawn of civilization. The plant Cyanthillium cinereum (L.) H. Rob. is mainly found in the Himalayas from Kashmir to Nepal at an altitude of 8000 m. Decoction of this plant is traditionally used as an anti-cancer, anti-malarial, anti-epileptic, and in neurosis and skin diseases. The present study investigated the anti-epileptic activity of Cyanthillium cinereum leaves against pentylenetetrazole (PTZ)-induced epileptic model in mice. Plant extracts were prepared using solvents in increasing polarity viz., petroleum ether, chloroform, ethanol, and water, using a Soxhlet apparatus. The bio-active extract was characterized using FTIR and GC techniques. In vivo antioxidants like GSH and SOD level, oxidative stress markers- MDA and hemoglobin and platelet count were also estimated in the animal brain. Amongst all extracts tested, only ethanol extract of Cyanthillium cinereum significantly (p<0.05) inhibited generalized tonic-clonic seizures in PTZ-induced epilepsy in mice in a dose (100 or 200 mg/kg., p.o.) dependent manner. The dose of 200 mg/kg of extract exhibited the most significant effect. It is also found that treatment with ethanol extract on PTZ-induced epilepsy in mice significantly (p<0.05) reduces the duration of convulsion and delays the onset of clonic convulsion. The present findings suggest that the high amounts of phenols and flavonoids in the ethanol extract could be responsible for the anti-epileptic effect. Moreover, the ethanol extract also restored GSH, SOD and hemoglobin and platelet level and decreased oxidative marker- MDA content in the mice brain.
One percent of persons over 65 years of age suffer from Parkinson's disease, a neurological ailment marked by dopaminergic neurons in the nigrostriatal pathway gradually dying and being depleted in the striatum. Parkin and PINK1 gene mutations, which are essential for mitophagy and impair mitochondrial function, are the cause of it. Parkinson's disease is linked to a number of motor and impairment disorders, including bradykinesia, rigid muscles, tremor at rest, and imbalance. Numerous signaling pathways, including α-synuclein aggregation, lead to age-related decline in proteolytic defense systems. Parkinson's disease etiology involves oxidative stress, ferroptosis, mitochondrial failure, and neuroinflammation. Parkinson's disease is significantly influenced by neuroinflammation, which is a result of both innate and adaptive immune responses. The purpose of studying mechanisms and phytomolecules is to assist researchers in creating therapies for Parkinson's disease. Phytomolecules, like curcumin, β- amyrin, berberine, capsaicin, and gentisic acid, exert neuroprotective properties by reducing ROS levels, lessening α-synuclein-induced toxicity, and shielding the cells from apoptosis. In conclusion, the studies presented here provide valuable insights into the potential of various medications for Parkinson's disease treatment. By understanding the mechanisms behind these treatments, researchers can develop more effective treatments for PD.
Major Depressive Disorder (MDD) is a psychiatric disorder that has a tight connection to stressful experiences, decreased levels of endogenous antioxidants and enhanced levels of oxidative stress. We drafted this research to define the results of combining agmatine and melatonin on stress-induced depression in mice. Experimental groups included the non-stressed group treated with vehicle (ethanol at a concentration of 0.0005%), stressed vehicle (ethanol at a concentration of 0.0005%)-treated group, group treated with fluoxetine (10 mg/kg/day), group treated with melatonin (10 mg/kg/day), group treated with agmatine (1 mg/kg/day), group receiving a combination of melatonin (10 mg/kg/day) and agmatine (1 mg/kg/day). The animals were subjected to restraint stress for two hours daily for a duration of one week, concurrently with the daily oral administration of agents through drinking water. Open field test and forced swimming test were operated on the 8th day. The oxidative stress markers were measured in the mice hippocampus. Stress led to the elevation of immobility time. The combination group showed a significant effect in comparison to the agmatine and melatonin groups. The combination of melatonin and agmatine was successful in the elevation of hippocampus catalase activity; and this effect was comparable in the fluoxetine group. We observed enhancement of superoxide dismutase activity in treatment groups and reduction in malondialdehyde levels in melatonin, agmatine and combination groups. A combination of agmatine and melatonin improves stress-induced depression more effectively than each alone, which may result from suppressing oxidative stress.
The pharmacophoric approach relies on the theory of possessing ubiquitous chemical functionalities, and carrying a uniform spatial conformation that provides a route to enhanced potency on the same target receptor. JNK3, also known as c-Jun N-terminal kinase 3, is a protein kinase that plays a crucial role in various cellular processes, particularly in the central nervous system (CNS). In this study, a kernel-based partial least square (KPLS)- based Two-dimensional Quantitative structural activity relationship (2D QSAR) model to predict pharmacophores responsible for c-Jun-N-terminal kinase 3 (JNK3) inhibition. A library of small molecule JNK3 inhibitors was created from the literature, and a predictive model was built using Canvas 2.6. The analysis revealed key structural determinants of activity. Compounds with high pIC50 values (>6) showed numerous favorable contributions, particularly secondary benzamide nitrogen and methylene groups. Steric effects were more influential than inductive effects, with bulkier groups like t-butyl reducing activity. Positive contributions were observed with OH, OCH3, and -F substituents, while unfavorable effects were linked to tertiary nitrogen, methyl, and primary amino groups. Substituted sulphonamides and benzotriazole moieties enhanced activity unless modified with amino or carbonyl groups. Favorable contributions were noted for terminal heterocyclic rings like pyrimidinyl acetonitrile, whereas phenyl substitutions and certain piperazine configurations were detrimental. Hydrogen in the urea moiety and avoiding bulky substitutions were crucial for activity. These insights guide the design of potent JNK3 inhibitors. The present study highlights the significant impact of substituents on molecular activity, with steric effects, particularly on the phenyl ring, playing a dominant role. Favorable contributions are linked to substitutions like hydroxyl, methoxy, and fluorine, while bulky and meta substitutions reduce activity. Functional groups like unsubstituted sulfonamide or free hydrogen in urea are crucial for activity. Insights into steric, electronic, and positional factors, combined with analysis of JNK3 inhibitors, will guide the design of more selective molecules.
Major depressive disorder represents a complicated mental disorder characterized by persistent feelings of unhappiness and loss of interest. More evidence suggests a high potential correlation between vitamin D deficiency and depression. However, the underlying mechanisms and the therapeutic potential of vitamin D supplementation are still not properly understood. The purpose of this research is to evaluate the effect of vitamin D supplementation on depressive behaviors using a rat model of depression and explore the potential mechanisms involved. Depression is a prevalent mental health disorder that significantly impacts the quality of life of individuals. Despite the availability of various treatment options, many patients still experience suboptimal outcomes, highlighting the need for further exploration of novel therapeutic approaches. In recent years, the importance of vitamin D in mental health, particularly in depression, has gained considerable attention. In this project, we propose to utilize an animal model of depressed rats to evaluate the effect of vitamin D supplementation on depressive behaviors. We employed a range of well-established behavioral tests to assess changes in depressive-like behaviors following vitamin D supplementation. Additionally, histopathological examinations of the hippocampal region, known to be involved in mood regulation, were performed to assess structural alterations and cellular changes associated with depression and vitamin D supplementation. The findings demonstrate the therapeutic potential of vitamin D supplementation by improving neuronal reorganization and proliferation in the hippocampus, suggesting an interest in investigating other mechanisms of interaction. The findings of this research will provide valuable insight into the therapeutic potential of vitamin D in depression and shed light on the underlying mechanisms involved.
<p> Introduction: Mental problems are associated with early neonatal and in utero exposure to maternal stress. With established negative impacts on mental health and cognitive function, road traffic noise (RTN) has emerged as a ubiquitous environmental stressor. In this work, we have examined the effects of maternal exposure to RTN on the development of neurogenesis and spatial memory in the hippocampus (HC) of offspring and investigated possible strategies for mitigating these effects. </p><p> Method: During the prenatal maturation stage, female Sprague Dawley (SD) rats that were determined to be pregnant were exposed chronically to 100 dB SPL (sound pressure level) RTN for six hours per day. The Morris water maze and elevated plus maze tests were used to evaluate the neurobehavioral performances of the offspring. The oxidative stress and neurogenesis in the HC were evaluated using 2% 2,3,5-triphenyl tetrazolium chloride staining, HC histopathology, and biochemical methods (SOD: superoxide dismutase, GSH: glutathione, CAT: catalase, as well as TBARS: thiobarbituric acid reactive substance, MPO: myeloperoxidase, and AChE: acetylcholinesterase), respectively. Additionally, we looked at the potential therapeutic benefits of melatonin, edaravone, and an enriched environment. </p><p> Result: The results of our investigation showed that maternal exposure to 100 dB SPL RTN considerably reduced the offspring's spatial memory and caused distress. The biochemical estimation of HC tissue supernatant revealed a considerable increase in MPO, AChE, and TBARS levels and a marked reduction in SOD, CAT, and GSH levels. However, there were notable protective effects against these unfavorable outcomes due to the administration of melatonin and edaravone, as well as from being exposed to an enriched environment. </p><p> Discussion: In our study, prenatal exposure to 100 dB SPL RTN caused oxidative stress, which caused neurodegeneration, as well as decreased spatial memory and induced anxiety, being consistent with previous findings. In particular, compared to offspring of the 100 dB SPL RTNexposed group, offspring of the maternally treated EDV and MLT combination groups showed superior spatial memory function, reduced anxiety, and increased neurogenesis. </p><p> Conclusion: The findings of our study have offered promising pathways for public health policies and urban planning concerns, as well as useful insights into the development of tailored therapies to safeguard against the cognitive and neurological repercussions of maternal RTN exposure.
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by various neurobehavioral impairments. This study aims to review the preventive and therapeutic effects of Resveratrol (RSV) against ASD during various stages of life, specifically focusing on its influence on behavioral and neurodevelopmental biochemical mechanisms. On December 6, 2024, a comprehensive electronic search was conducted across several high-coverage databases, including Web of Science, Scopus, PubMed/MEDLINE, Embase, and the Cochrane Library. The most important data were extracted and reviewed after screening the publications based on our inclusion and exclusion criteria. RSV alleviates autistic-like social behaviors by promoting social interaction and mitigating repetitive behaviors, anxiety, and symptoms resembling depression. RSV influences chemokine receptor expression, diminishes pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ), and regulates mitochondrial function by reducing nitrosative stress and thiobarbituric acid reactive substances (TBARS) levels, while also increasing antioxidant markers like glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) in the brain. Additionally, it enhances neuronal organization, increases the proportions of interneurons (SOM+, PV+, CB+), and restores the integrity of the hippocampus. Moreover, RSV modulates epigenetic pathways, such as estrogen receptorbeta (ERβ) activation and sirtuin 1 (Sirt1) expression, counteracts learning, memory, and locomotor activity deficits, and normalizes cortical oscillations. It also potentially modulated gutbrain- axis dysregulation and neurotransmitters. RSV has shown promising effects on ASD, primarily through its influence on behavioral, neuromolecular, and neurodevelopmental mechanisms.
In stroke, reperfusion of blood to the cerebral ischemic area following sustained ischemia further exacerbates tissue damage, identified as cerebral ischemia and reperfusion (I/R) insult. Ischemic post-conditioning (IPoC) appears to offer benefits against I/R injury. The cascade of androgen receptors (ARs) has a vital role in cerebral stroke; however, its neurodefensive function in IPoC is unclear. This investigation aimed to explore the involvement of ARs in IPoC in cerebral I/R insult in rats. Global cerebral ischemia/reperfusion (GCI/R) insult in experimental animals was provoked by 10 minutes of obstruction of the bilateral carotid arteries after reperfusion for 24 hours. IPoC was carried out by providing a triad of I/R insults with a gap of 10 minutes of GCI after 24 hours of reperfusion. Lateral push, inclined beam, rota rod, hanging wire, and Morris-water maze experimentations were conducted on animals to determine motor control and cognitive functions (learning and memory). Cerebral oxidative damage markers (raised lipid peroxidation and reduced glutathione levels), acetylcholinesterase (AChE) activity, inflammatory indicators (interleukin-6, interleukin-10, tumor necrosis factor-α, and myeloperoxidase), infarction, and histopathological alterations were also assessed. Animals with I/R exhibited reduced motor function and memory along with raised cerebral oxidative damage, AChE activity, inflammation, infarction, and histopathological alterations. IPoC after ischemic events recuperated the damaging outcomes of I/R insult. 60 minutes before cerebral ischemia, pretreatment with testosterone mimicked the neurodefensive outcomes of IPoC. However, neuroprotective outcomes developed by IPoC were diminished by flutamide (ARs antagonist) pretreatment. IPoC may offer neuroprotective outcomes in I/R insult by modulation of ARmediated pathway.