Neuroprotective Potential Research Articles

Neuroprotective effects of biogenic silver nanoparticles in Parkinson's disease: In vitro and in vivo study

The study aimed to develop immunomodulatory silver nanoparticles (CHT-PCT/AgNPs) using a green chemistry approach with Umbilicaria esculenta (U.E.) extract to protect neurons from Parkinson's disease. The synthesized CHT-PCT/AgNPs measured 88.2 ± 33.7 nm in size, with a zeta potential of approximately 24.5 ± 1.9 mV. In vitro assays demonstrated that the green-synthesized nanoparticles exhibited greater biocompatibility and antioxidant properties compared to chemically synthesized AgNPs. The MTT assay indicated that CHT-PCT/AgNPs were cytocompatible up to 50 μg/mL, but higher concentrations resulted in significant toxicity. The DPPH assay revealed dose-dependent antioxidant activity, although it was lower than that of ascorbic acid. In animal studies of MPTP-induced Parkinsonism, the count of tyrosine hydroxylase (TH)-positive cells varied across groups, with healthy controls showing 145.3 ± 11.0 cells compared to the negative control group with only 21.6 ± 4.1. Additionally, the number of DRD1-positive cells also reflected a similar trend. These findings suggest that CHT-PCT/AgNPs may serve as a potential neuroprotective agent to mitigate Parkinson's disease.

Biochemical investigation and in silico analysis of the therapeutic efficacy of Ipriflavone through Tet-1 Surface-Modified-PLGA nanoparticles in Streptozotocin-Induced Alzheimer’s like Disease: Reduced oxidative damage and etiological Descriptors

Ipriflavone (IPRI), an isoflavone derivative, is clinically used to prevent postmenopausal bone loss in addition to its antioxidant and cognitive benefits. However, its poor aqueous solubility retained its bioavailability. New strategies have been developed to improve the bioavailability and solubility of neurological medications to enhance their potency and limit adverse effects. This study aimed to prepare targeted IPRI-poly-lactic-co-glycolic acid (PLGA) nanoparticles coupled with Tet-1 peptide to increase the therapeutic potency of IPRI in a rat model of Alzheimer’s disease (AD). Streptozotocin (STZ) exacerbates Alzheimer-related alterations by promoting central insulin resistance resulted from defective signaling pathways related to neuroinflammation and neurotoxicity. Bilateral intracerebroventricular (icv) injection of STZ was used to introduce the AD model. Icv-STZ injection significantly affected brain insulin, oxidative stress, inflammatory, and apoptotic indicators and caused behavioral abnormalities. STZ promoted the formation of amyloid β42 (Aβ42) by increasing BACE1 and reducing ADAM10 and ADAM17 expression levels. STZ also triggered the accumulation of neurofibrillary tangles and synaptic dysfunction, which are crucial for neurological impairments. Icv-STZ injection showed evident degenerative changes in the pyramidal cell layer and significantly reduced the count of viable cells in both CA1 and prefrontal cortex, indicating increased neuronal cell death. IPRI successfully ameliorated cognitive dysfunction by improving the phosphorylated forms of cAMP-response element-binding protein (pCREB) and extracellular signal-regulated kinase 1/2 (pERK1/2) related to synaptic plasticity. Targeted IPRI nanoparticles exceeded free IPRI potential in reducing oxidative stress, acetylcholinesterase/monoamine oxidase activities, Tau phosphorylation, and Aβ42 levels revealing less degenerative changes and increased viable neuron counts. IPRI-targeted nanoparticles improved the neuroprotective potential of free IPRI, making this strategy applicable to treat many neurodegenerative diseases. Finally, the in silico study predicted its ability to cross the BBB and to bind various protein targets in the brain.

Neuroprotective potential of paddy rice: Advancing nutritional and therapeutic strategies for brain health

Paddy rice has gained attention beyond its role as a staple food, now recognized for its neuroprotective properties due to its rich phytochemical content. Compounds like tocotrienols, gamma-oryzanol, and phenolic acids in paddy rice exhibit antioxidant, anti-inflammatory, and neuroregenerative properties. These compounds help reduce oxidative stress, manage neuroinflammation, balance neurotransmitter function, and promote neurogenesis, supporting overall brain health and potentially delaying neurodegenerative processes. Components like gamma-oryzanol and ferulic acid show promise in decreasing neuroinflammation and enhancing dopaminergic function, suggesting therapeutic potential for conditions like Parkinson's and Alzheimer's. Research indicates paddy rice bioactives can improve cognitive function and neural resilience, underscoring their therapeutic value for neurological disorders. Further studies are required to validate these findings in clinical settings, explore optimal dosages, and enhance bioavailability. This review summarizes recent research, highlighting the promising effects of paddy rice-derived nutraceuticals and emphasizing the importance of bridging lab discoveries with practical medical applications through comprehensive research efforts.

Neuroprotective Potential of Tanshinone-IIA in Mitigating Propionic Acidinduced Experimental Autism-like Behavioral and Neurochemical Alterations: Insights into c-JNK and p38MAPK Pathways.

Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK. In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma. Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan- IIA's molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections. Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.

Enriching the Mediterranean diet could nourish the brain more effectively

The increasing prevalence of neurodegenerative disorders represents a challenge to the global health of all nations and populations, particularly with increasing longevity. Urgent prevention strategies are therefore needed, and one opportunity may be to explore the relationship between dietary patterns and brain health which has emerged as a promising strategy. Numerous studies indicate that dietary choices have a significant impact on cognitive function, memory and the risks of neurological disorders, recognizing the dynamic role of diet in maintaining cognitive abilities. One of the most studied dietary styles, the Mediterranean diet, characterized by healthy, plant-based foods fats and moderate consumption of animal products, has demonstrated its neuroprotective potential. Rich in antioxidants, vitamins and polyphenols, this diet shows consistent associations with cardiovascular health and cognitive function. Some less talked about foods, such as seaweed, blackcurrants, Lion’s Mane mushroom and chia seeds, are emerging as potential brain health boosters. These and other new foods could enrich the Western diet making it capable of effectively preventing neurological disorders. Despite promising scientific data, difficulties persist in understanding the complex relationship between nutrition and brain health. Individual variability, long-term dietary adherence, comorbidities, and the need for rigorous clinical evidence pose obstacles. In this review, we would like to focus our attention on the future of brain-diets, which should involve accessible, personalized and evidence-based interventions, providing hope against the challenges posed by neurodegenerative diseases. In fact, as research progresses, more and more attention are being placed to brain health, promising a harmonious and resilient cognitive landscape for individuals and society.

Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations.

Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H2O2 (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6min for 15 days. The drug was administered daily 30min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H2O2-induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders.

Antioxidant and neuroprotective potential of extracts from Hass avocado peel obtained through a biorefinery process: A sustainable strategy for the valorization of agro-food waste

This study presents a novel three-step biorefinery approach for extracting bioactive compounds from Hass avocado (Persea americana, Mill.) epicarp. By sequentially using supercritical CO2, CO2-expanded ethanol, and subcritical water, we efficiently recovered a diverse range of extracts with distinct phytochemical profiles and potent biological activities. Our innovative extraction strategy outperformed conventional methods, demonstrating the potential of biorefinery for sustainable valorization of agricultural byproducts. Medium and high extracts exhibited strong antioxidant and anticholinesterase activity. For example, the CO2-expanded ethanol extracts demonstrated an ABTS radical cation scavenging capacity of 3.01 ± 0.06 mmol Trolox equivalents/g and an SC50 value of 53.4 ± 1.2 μg/mL for anticholinesterase activity. These findings highlight the feasibility of integrating biorefinery processes into circular economy initiatives to create high-value bioproducts while minimizing waste.

Neuroprotective Role of Ranolazine: ESR1 and NMDA Receptor Agonist in Traumatic Brain Injury in Drosophila melanogaster, In Silico and In Vivo Correlation

Abstract Objective In this study, a high-impact trauma (HIT) device was used for inducing moderate traumatic brain injury (TBI) in Drosophila melanogaster. Mechanical injuries in flies caused by rapid acceleration and assertion produce symptoms characteristics of TBI in humans. Materials and Methods Docking studies were carried out to check the binding affinity of the drug toward the receptors. Various oxidative stress parameters, catalase level, glutathione level, superoxide dismutase (SOD) level, malondialdehyde (MDA), and nitric oxide levels, were measured. The mortality index and neuroprotective potential were carried out in TBI in D. melanogaster models. Results In the current study, there was an increase in oxidative stress following TBI as evidenced by a significant decrease in the catalase, glutathione, and SOD levels and increase in the level of MDA and nitric oxide after 24 hours. Antioxidant enzymes, catalase and glutathione peroxidase, have a dominant role in TBI. Docking studies were carried out on estrogen receptor 1 (pdb: 1TVO and 1UOM) and NDMA receptor (pdb: 3QEL) as agonist showing the binding affinity of the drug toward the receptors. In comparison to the vehicle-treated group, there was a dose-dependent significant increase in the SOD level and percentage climbing along with a decrease in the MDA level and total protein content. The mortality index was also observed at three concentrations of ranolazine (1, 2, and 4 mg/mL) in D. melanogaster homogenate. These findings suggest that ranolazine has a good neuroprotective potential in the treatment of TBI in the D. melanogaster model. Conclusion Present study concluded the scientific evaluation of neuroprotective potential of ranolazine in the treatment of TBI in the D. melanogaster model.

A randomized clinical trial evaluating Hydralazine’s efficacy in early-stage Alzheimer’s disease: The EHSAN Study

Alzheimer’s Disease (AD), a neurodegenerative disorder escalating worldwide, remains incurable with existing interventions merely mitigating symptoms. Hydralazine, an antihypertensive agent, has displayed neuroprotective potential in AD animal models via amplification of mitochondrial functionality and stimulation of stress management and repair pathways. Nevertheless, its effectiveness and tolerability in human AD cohorts are yet to be confirmed. This study protocol describes the design of an ongoing, single-center, randomized, triple-blind, placebo-controlled trial to assess hydralazine’s effects on cognitive function in mild to moderate -stage AD patients. We will enroll 424 patients aged 50 and older, meeting NINCDS-ADRDA criteria for probable AD with Mini-Mental State Examination scores from 12–26. They’ll be randomly assigned to receive either hydralazine HCL (25 mg, thrice daily) or a placebo for 12 months. The primary outcome is the Alzheimer’s Disease Assessment Scale change from baseline to 12 months. Secondary outcomes include various measures using Lawton instrumental activities of daily living scale, neuropsychiatry inventory, and caregiver activity survey. This trial will explore the potential benefits and risks of hydralazine in mild to moderate AD treatment. It’s the first trial examining hydralazine’s impact on mild to moderate -stage AD in human and is registered at the Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552AQ, registered 13/04/2021). Ethics approval was granted by the Research Ethics Committee of the National Institute for Medical Research Development (IR.NIMAD.REC.1398.424), following the SPIRIT Statement guidelines. Findings will be disseminated via peer-reviewed publications and conferences. This inaugural human clinical trial evaluates hydralazine’s impact on patients in the mild to moderate AD. Executed with a randomized, triple-blind, placebo-controlled methodology, this study incorporates a significant sample size and an extended monitoring duration. Multiple parameters, including cognitive capabilities, will be assessed. Potential limitations include the inherent homogeneity of the AD cohort, the lack of biomarker assays, and the unpredictable progression of the disease. Notably, the study might not elucidate the protracted effects of hydralazine beyond a 12-month period. Another limitation of our clinical trial is that patients were diagnosed with Alzheimer’s disease based solely on clinical evaluation and MRI findings, without the inclusion of specific biomarkers, which may impact the accuracy and specificity of the diagnosis. Trial registration: Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552, registered 13/04/2021).

Unleashing the power of golden berry leaves to counteract cyclophosphamide's toll with antioxidant, anti-inflammatory, anti-apoptotic, and neurotransmitter boosting effects

Ethnopharmacological relevanceGolden berries (Physalis peruviana) are esteemed for their healing properties and widespread use in traditional medicine, particularly for their neuroprotective benefits. Aim of the studyThis work aims to evaluate the neuroprotective effect of golden berry total leaf extract cultivated in Egypt (TLE) against cyclophosphamide (CP)-induced neurotoxicity and to identify the chemical composition of different organs of P. peruviana from both Egypt and USA. Material and methodsMetabolite profiling of TLE was conducted using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). In the animal model experiment, CP (100 mg/kg, i.p.) was administered once weekly for four weeks to induce neurocognitive dysfunction. Concurrently, TLE (500 mg/kg, orally) was administered twice weekly throughout the four weeks to evaluate its effectiveness in alleviating CP-induced neuronal deficits. Behavioral assessments, Morris water maze and passive avoidance tests, were conducted, followed by, histological evaluations of brain tissue samples. Additionally, biochemical analyses were performed on hippocampal tissue samples, examining the following markers, acetylcholinesterase activity (AChE), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) activity, nuclear factor kappa B (p-NF-κB p65) (Ser536), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), and Bax (Bcl-2-associated X) levels. ResultsTLE significantly preserved hippocampal neurons and improved cognitive performance in behavioral tests. TLE achieved these beneficial effects by suppressing AChE activity, diminishing the oxidative stress and restoring redox balance via inhibiting p-NFκB/IL-1β,/TNFα/IL-6 cascades. Leaf extract revealed the highest total phenolic content (TPC) (2.7 ± 6.41 mg GAE/g extract) and total flavonoid content (TFC) (0.37 ± 1.19 mg QE/g) and the strongest antioxidant effects in Ferric Reducing Antioxidant Power (FRAP) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC50 values of 21.13 ± 1.48 and 18.19 ± 1.29 μg/mL, respectively. UHPLC–QTOF-MS/MS analysis resulted in the tentative identification of 20 metabolites including phenolic acids, flavonoids, hydroxycinnamic acid amides, and alkyl resorcinols. ConclusionsFindings verify for the first time the neuroprotective potential of golden berry leaf, currently discarded as agricultural waste, and highlight its multifaceted mechanism of neuroprotection in CP-induced neurotoxicity, suggesting its suitability as a promising therapeutic agent for neurotoxicity management.

Oxysophocarpine Prevents the Glutamate-Induced Apoptosis of HT-22 Cells via the Nrf2/HO-1 Signaling Pathway.

Oxysophocarpine (OSC), a quinolizidine alkaloid, shows neuroprotective potential, though its mechanisms are unclear. The aim of the present study was to investigate the neuroprotective effects of OSC through the nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway using the HT-22 cell line. Assessments of cell viability were conducted utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Assessments of oxidative stress (OS) were conducted through the quantification of reactive oxygen species (ROS). The integrity of the mitochondrial membrane potential (MMP) was scrutinized using fluorescent probe technology. Apoptosis levels were quantified using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The trafficking of Nrf2 within the cell nucleus was examined through immunofluorescence analysis. Furthermore, Western blotting (WB) was applied to evaluate the expression levels of proteins implicated in apoptosis and the Nrf2/HO-1 pathway. To further probe the influence of OSC on the overexpression of antioxidant enzymes, cells were subjected to transfection with HO-1 siRNA. The results showed that OSC inhibited glutamate-induced OS, as evidenced by reduced cell viability and ROS levels. Furthermore, the apoptotic condition induced by glutamate in HT-22 cells was significantly reduced following OSC treatment. More interestingly, the Nrf2/HO-1 signaling pathway was upregulated following OSC treatment. These results suggest that OSC can exert neuroprotective effects by regulating the Nrf2/HO-1 pathway to inhibit neuronal cell apoptosis, potentially aiding in the treatment of neurodegenerative diseases.

Berberine-loaded iron oxide nanoparticles alleviate cuprizone-induced astrocytic reactivity in a rat model of multiple sclerosis.

Berberine (BBN) is a naturally occurring alkaloid as a secondary metabolite in many plants and exhibits several benefits including neuroprotective activities. However, data on the neuromodulating potential of nanoformulated BBN are still lacking. In the present study, BBN loaded within iron oxide nanoparticles (BBN-IONP) were prepared and characterized by transmission electron microscopy FTIR, X-ray photoelectron spectroscopy particle-size distribution, zeta potential, and HPLC. The remyelinating neuroprotective potential of BBN-IONP relative to free BBN was evaluated against cuprizone (CPZ)-induced neurotoxicity (rats administered 0.2% CPZ powder (w/w) for five weeks). CPZ rats were treated with either free BBN or IONP-BBN (50 mg/kg/day, orally) for 14 days. Cognitive function was estimated using Y-maze. Biochemically, total antioxidant capacity lipid peroxides and reduced glutathione in the brain tissue, as well as, serum interferon-gamma levels were estimated. Moreover, the genetic expression contents of myelin basic protein Matrix metallopeptidase-9 Tumor necrosis factor-α (TNF-α), and S100β were measured. The histopathological patterns and immunohistochemical assessment of Glial Fibrillary Acidic Protein in both cerebral cortex and hippocampus CA1 regions were investigated. CPZ-rats treated with either free BBN or IONP-BBN demonstrated memory restoring, anti-oxidative, anti-inflammatory, anti-astrocytic, and remyelinating activities. Comparing free BBN with IONP-BBN revealed that the latter altered the neuromodulating activities of BBN, showing superior neuroprotective activities of IONP-BBN relative to BBN. In conclusion, both forms of BBN possess neuroprotective potential. However, the use of IONPs for brain delivery and the safety of these nano-based forms need further investigation.

Unlocking the Potential of Oxymatrine: A Comprehensive Review of Its Neuroprotective Mechanisms and Therapeutic Prospects in Neurological Disorders.

Sophora flavescens, the source of oxymatrine, is gaining popularity due to its potential in neuroprotection and treatment of various neurological conditions like epilepsy, depression, Parkinson's, Alzheimer's and multiple sclerosis. Its natural occurrence and promising preliminary research highlight its ability to reduce nerve cell damage and inflammation, attributed to its antiapoptotic, antioxidant and anti-inflammatory properties. However, challenges like solubility, potential adverse effects and limited bioavailability hinder its full therapeutic utilization. Current strategies, including formulation optimization and innovative drug delivery systems, aim to enhance its efficacy and safety. Despite its potential, further research is necessary to overcome these obstacles and maximize its clinical effectiveness. Conclusively, oxymatrine demonstrates distinct neuroprotective properties, offering unique advantages over other agents currently being studied or used in clinical practice for neurological disorders. nevertheless, additional study is necessary to surmount current obstacles and maximize its effectiveness for clinical settings. This study provides a comprehensive overview of oxymatrine's neuroprotective mechanisms and therapeutic potential while emphasizing the need for continued investigation and development for practical clinical application.

Unraveling neuroprotection with Kv1.3 potassium channel blockade by a scorpion venom peptide

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide’s potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12’s, offering insights into its pharmacological utility. The peptide’s impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions.

An increase of lysosomes through EGF-triggered endocytosis attenuated zinc-mediated lysosomal membrane permeabilization and neuronal cell death

In the context of acute brain injuries, where zinc neurotoxicity and oxidative stress are acknowledged contributors to neuronal damage, we investigated the pivotal role of lysosomes as a potential protective mechanism. Our research commenced with an exploration of epidermal growth factor (EGF) and its impact on lysosomal dynamics, particularly its neuroprotective potential against zinc-induced cytotoxicity. Using primary mouse cerebrocortical cultures, we observed the rapid induction of EGFR endocytosis triggered by EGF, resulting in a transient increase in lysosomal vesicles. Furthermore, EGF stimulated lysosomal biogenesis, evident through elevated expression of lysosomal-associated membrane protein 1 (LAMP-1) and the induction and activation of prominent lysosomal proteases, particularly cathepsin B (CTSB). This process of EGFR endocytosis was found to promote lysosomal augmentation, thus conferring protection against zinc-induced lysosomal membrane permeabilization (LMP) and subsequent neuronal death. Notably, the neuroprotective effects and lysosomal enhancement induced by EGF were almost completely reversed by the inhibition of clathrin-mediated and caveolin-mediated endocytosis pathways, along with the disruption of retrograde trafficking. Furthermore, tyrosine kinase inhibition of EGFR nullified EGFR endocytosis, resulting in the abrogation of EGF-induced lysosomal upregulation and neuroprotection. An intriguing aspect of our study is the successful replication of EGF’s neuroprotective effects through the overexpression of LAMP-1, which significantly reduced zinc-induced LMP and cell death, demonstrated in both primary mouse cerebrocortical neuronal cultures and human embryonic kidney (HEK) cells. Our research extended beyond zinc-induced neurotoxicity, as we observed EGF’s protective effects against other oxidative stressors linked to intracellular zinc release, including hydrogen peroxide (H2O2) and 1-methyl-4-phenylpyridinium ion (MPP+). Collectively, our findings unveil the intricate interplay between EGF-triggered EGFR endocytosis, lysosomal upregulation, an increase in the regulatory capacity for zinc homeostasis, and the subsequent alleviation of zinc-induced neurotoxicity. These results present promising avenues for therapeutic interventions to enhance neuroprotection by targeting lysosomal augmentation.

Phytochemicals in Parkinson's Disease: a Pathway to Neuroprotection and Personalized Medicine.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the progressive loss of dopaminergic neurons in the substantia nigra. While current treatments primarily manage symptoms, there is increasing interest in alternative approaches, particularly the use of phytochemicals from medicinal plants. These natural compounds have demonstrated promising neuroprotective potential in preclinical studies by targeting key pathological mechanisms such as oxidative stress, neuroinflammation, and protein aggregation. However, the clinical translation of these phytochemicals is limited due to a lack of robust clinical trials evaluating their safety, efficacy, and pharmacokinetics. This review provides a comprehensive overview of the neuroprotective potential of phytochemicals in PD management, examining the mechanisms underlying PD pathogenesis and emphasizing neuroprotection. It explores the historical and current research on medicinal plants like Mucuna pruriens, Curcuma longa, and Ginkgo biloba, and discusses the challenges in clinical translation, including ethical and practical considerations and the integration with conventional therapies. It further underscores the need for future research to elucidate mechanisms of action, optimize drug delivery, and conduct rigorous clinical trials to establish the safety and efficacy of phytochemicals, aiming to shape future neuroprotective strategies and develop more effective, personalized treatments for PD.

Neuroprotective Effects of Ethanol Extract Polyscias guilfoylei (EEPG) Against Glutamate Induced Neurotoxicity in HT22 Cells.

Oxidative stress induced by glutamate is a significant contributor to neuronal cell damage and can lead to neurodegenerative diseases such as Alzheimer's, Huntington's, and ischemic brain injury. At the cellular level, oxidative stress increases Ca2+ ion influx and reactive oxygen species (ROS), which activate the MAPK signaling pathway. Additionally, the generation of ROS causes mitochondrial dysfunction, triggering apoptosis by promoting the translocation of AIF to the nucleus from the mitochondria. The neuroprotective potential of Polyscias guilfoylei has not yet been reported. Therefore, in this study, the ethanol extract of Polyscias guilfoylei (EEPG) was examined for its protective effect against oxidative cell damage caused by glutamate in neuronal cells. EEPG treatment increased the viability of HT22 cells exposed to high concentrations of glutamate. Cellular Ca2+ ion influx and ROS generation decreased with EEPG treatment in glutamate-treated HT22 cells. EEPG treatment inhibited MAPK activation and AIF nuclear translocation. In an in vivo study, EEPG attenuated brain cell death in an ischemic brain injury rat model. This study demonstrates the potential therapeutic effects of Polyscias guilfoylei in the treatment of ischemic brain injury.

In silico and in vivo evaluations of fisetin and fisetin-loaded nanosuspension on monoamine oxidase inhibition in Aβ(25–35) induced dementia in mice model

BackgroundAmyloid beta (Aβ) plaques on the extracellular matrix and intracellular neurofibrillary tangles comprise the key indicative pathology of Alzheimer's disease (AD). Fisetin, an antioxidant bioactive compound having pharmacotherapeutic effects is applied by traditional Chinese medicine (TCM) such as Toxicodendron vernicifum (Chinese lacquer tree), Cotinus coggygria Scop, Gan Shuang granulates and formula of Acacia catechu-Scutellariae Radix. Nevertheless, fisetin has constraints such as low oral bioavailability, insignificant aqueous solubility and high hepatic metabolisms. ObjectiveThis investigation aimed to envisage the effects of fisetin and its optimised nanoformulation on Aβ(25–35) desirous neurotoxicity in mice through deciphering inhibitory actions against monoamine oxidase A and B (MAO-A and B) enzymes following molecular docking. MethodsMolecular docking with MAO-A and B enzymes were accomplished by AMDock's integrated AutoDock Tools (ADT) scripts. For in vivo studies, fisetin nanosuspension was prepared by nanoprecipitation method and evaluated for standard characterization. 10 and 20 mg/kg of fisetin and 10 mg/kg of fisetin nanosuspension were given once daily to mice for 21 days. On the 15th day, the mice were challenged with Aβ(25–35) by intracerebroventricular injection (ICV) and behavioural tests (open field and elevated plus maze) were performed on the 20th day. Biochemical and histology were examined in brain tissues. ResultsFisetin docked to the catalytic positions of MAO-A and B, unveiling good binding scores and molecular interactions with amino acid residues for inhibition activities. Fisetin nanosuspension has average particle size (225.4 ± 2.95 nm) with low polydispersity index (0.19) and standard zeta potential (-19.13 ± 1.17 mV). Findings showed that fisetin increased locomotor activity and reduced anxiety-like behaviour. Fisetin and its nanosuspension significantly reduced the concentration of MAO-A (P < 0.01) and MAO-B enzymes suggesting a potential neuroprotection effect in Aβ peptide-induced amnesia in mice. ConclusionFisetin with optimized bioavailability, effectively exhibits neuroprotection through molecular interactions of MAO enzymes. Further investigations affidavits the neuroprotection through bidirectional pathways related to biogenic amines and their deamination on Aβ stress conditions.

Nicotinamide and Nicotinoyl-Gamma-Aminobutyric Acid as Neuroprotective Agents Against Type 1 Diabetes-Induced Nervous System Impairments in Rats.

Diabetes is a multifunctional chronic disease that affects both the central and/or peripheral nervous systems. This study assessed whether nicotinamide (NAm) or conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) could be potential neuroprotective agents against type 1 diabetes (T1D)-induced nervous system impairments in rats. After six weeks of T1D, induced by streptozotocin, nonlinear male Wistar rats were treated for two weeks with NAm (100mg/kg, i. p.) or N-GABA (55mg/kg, i. p.). Expression levels of myelin basic protein (MBP) were analyzed by immunoblotting. Polyol pathway parameters of the sciatic nerves were assessed spectrophotometrically, and their structure was examined histologically. NAm had no effect on blood glucose or body weight in T1D, while N-GABA reduced glucose by 1.5-fold. N-GABA also increased MBP expression by 1.48-fold, enhancing neuronal myelination, while NAm showed no such effect. Activation of the polyol pathway was observed in the T1D sciatic nerves. Both compounds decreased sorbitol content and aldose reductase activity, thereby alleviating changes similar to primary degeneration in the sciatic nerves and preventing peripheral neuropathy development. These results demonstrate that NAm and, more notably, N-GABA may exert neuroprotective effects against T1D-induced nervous system impairments by increasing MBP expression levels, improving myelination processes in the brain, inhibiting the polyol pathway, and partially restoring morphometric parameters in the sciatic nerves. This suggests their potential therapeutic efficacy as promising agents for the prevention of T1D-induced nervous system alterations.

Molecular and Behavioral Neuroprotective Effects of Clavulanic Acid and Crocin in Haloperidol-Induced Tardive Dyskinesia in Rats.

Clavulanic acid (ClvA), a beta-lactamase inhibitor, is being explored for its significant neuroprotective potential. The effects of ClvA were assessed both individually and in combination with crocin (Cr), an antioxidant derived from saffron, in the context of tardive dyskinesia (TD). In rat haloperidol (Hp)-induced-TD (1mg/kg, i.p. 21days), the effects of ClvA (50, 100, 150mg/kg) and Cr (10, 20, 40mg/kg) were assessed via vacuous chewing movements (VCM) and tongue protrusion (TP). Striatal malondialdehyde (MDA) and glutathione (GSH) were measured spectrophotometrically. Based on the results, ClvA (100mg/kg) and Cr (10mg/kg) were determined with sub-effective doses. Glutamate transporter-subtype1 (GLT1), dopamine active transporter (DAT), vesicular monoamine transporter-type2 (VMAT2), Bax/Bcl2, cleaved Caspase3, phosphorylated AKT/AKT, IL1β, and TNFα levels were quantified using western blotting in sub-effective doses and their combination. The behavioral results of catalepsy and orofacial dyskinesia demonstrated model establishment. Hp decreased GLT1 (p < 0.05), DAT (p < 0.01), VMAT2 (p < 0.001), GSH and pAKT/AKT (p < 0.0001); increased TNFα (p < 0.05), IL1β, cleaved Caspase3 (p < 0.001); MDA and Bax/Bcl2 (p < 0.0001). ClvA 100mg/kg reversed the decreased GLT1 and VMAT2 (p < 0.01), alongside the increased MDA (p < 0.0001) and VCM (p < 0.05). It also increased AKT phosphorylation (p < 0.05). No effects were noted on DAT, GSH, Bax/Bcl2, or inflammatory factors. However, the combination with Cr at 10mg/kg influenced ClvA on DAT (p < 0.01) and resulted in a significant increase in GSH (p < 0.0001). Additionally, there was a marked decrease in TNFα (p < 0.0001) and IL1β (p < 0.001), enhancing its effects on reducing MDA and increasing pAKT/AKT (p < 0.0001). The combination adversely affected GLT1. ClvA protects against TD via GLT1 and VMAT2; combined with Cr, it enhances antioxidant effects, improves DAT, and requires dose optimization for GLT1 disruption.