Neuroprotective Benefits Research Articles

Coffee and Alzheimer's Disease: Reviewing the Neuroprotective Effects of Bioactive Compounds

Alzheimer's disease (AD) is a common neurodegenerative disorder primarily managed with symptomatic treatments. Coffee, a popular beverage, contains bioactive compounds like caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol, which may offer neuroprotective benefits. These compounds could potentially address AD-related pathologies such as amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and inflammation. This review explores the neuroprotective potential of coffee's bioactive components in AD. Aim of the Study This study aims to review research on the neuroprotective effects of coffee and its bioactive compounds in Alzheimer's disease. It seeks to understand how these compounds may mitigate AD-related pathologies and their potential in preventive and therapeutic applications. The study also identifies knowledge gaps and suggests future research directions. Material and Methods We reviewed literature from PubMed, Google Scholar and other scientific sources using keywords: Alzheimer's disease, coffee, neuroprotective, caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol. Conclusions Emerging evidence indicates that coffee's bioactive compounds may offer neuroprotective benefits against Alzheimer's disease. Compounds such as caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol show potential in mitigating key AD pathologies. However, the current evidence is preliminary, and more research is needed to fully understand their cognitive benefits and mechanisms. Investigating these properties is particularly relevant given the aging global population and the age-related nature of AD.

Anesthetics in pathological cerebrovascular conditions.

The increasing prevalence of pathological cerebrovascular conditions, including stroke, hypertensive encephalopathy, and chronic disorders, underscores the importance of anesthetic considerations for affected patients. Preserving cerebral oxygenation and blood flow during anesthesia is paramount to prevent neurological deterioration. Furthermore, protecting vulnerable neurons from damage is crucial for optimal outcomes. Recent research suggests that anesthetic agents may provide a potentially therapeutic approach for managing pathological cerebrovascular conditions. Anesthetics target neural mechanisms underlying cerebrovascular dysfunction, thereby modulating neuroinflammation, protecting neurons against ischemic injury, and improving cerebral hemodynamics. However, optimal strategies regarding mechanisms, dosage, and indications remain uncertain. This review aims to clarify the physiological effects, mechanisms of action, and reported neuroprotective benefits of anesthetics in patients with various pathological cerebrovascular conditions. Investigating anesthetic effects in cerebrovascular disease holds promise for developing novel therapeutic strategies.

Glycogen synthase kinase 3 (GSK3) inhibition: a potential therapeutic strategy for Alzheimer's disease.

Alzheimer's disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued. According to estimates from the World Health Organization (WHO), 18 million individuals worldwide suffer from AD. Major initiatives to identify risk factors, enhance care giving, and conduct basic research to delay the beginning of AD were started by the USA, France, Germany, France, and various other nations. Widely recognized as a key player in the development and subsequent progression of AD pathogenesis, glycogen synthase kinase-3 (GSK-3) controls a number of crucial targets associated with neuronal degeneration. GSK-3 inhibition has been linked to reduced tau hyperphosphorylation, β-amyloid formation, and neuroprotective benefits in Alzheimer's disease. Lithium, the very first inhibitor ofGSK-3βthat was used therapeutically,has been successfully used for many years with remarkable results. A great variety of structurally varied strong GSK-3β blockers have been identified in recent years. The purpose of this thorough review is to cover the biological and structural elements of glycogen synthase kinase, as well as the medicinal chemistry aspects of GSK inhibitors that have been produced in recent years.

Low body mass index patients have worse outcomes after mechanical thrombectomy

BackgroundThere is evidence that frailty is an independent predictor of worse outcomes after stroke. Similarly, although obesity is associated with a higher risk for stroke, there are multiple reports describing...

Vanillin and Its Derivatives: A Critical Review of Their Anti-Inflammatory, Anti-Infective, Wound-Healing, Neuroprotective, and Anti-Cancer Health-Promoting Benefits

Inflammation and thrombosis are implicated in several non-communicable chronic disorders, including cardiovascular diseases, diabetes, renal and neurodegenerative disorders, skin diseases, and especially in cancer. Natural bioactives and especially phytochemicals like phenolic compounds have been proposed to reduce the inflammatory burden with several health benefits against these disorders. Vanillin is a phenolic compound found in the seeds of various species of vanilla plants. It has been known since ancient times for its aromatic and soothing properties; however, recent outcomes have outlined several other pleiotropic actions for this phenolic bioactive compound. Within this article, the potent anti-inflammatory activities of vanillin and its derivatives are thoroughly reviewed, with emphasis on their anti-cancer, anti-infective, wound-healing, and neuroprotective health-promoting properties. The mechanisms of their action(s), along with recent outcomes from in vitro and in vivo studies and clinical trials, on the benefits of these vanillin-based phenolic bioactives against each of these disorders, and especially against specific types of cancer, are also outlined. Limitations and future perspectives of their use solely as bioactive ingredients, as ingredients in several functional products—such as functional foods, supplements, nutraceuticals, or even cosmetics and drugs—and even as adjuvant therapies are also discussed.

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders.

For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times. The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson's disease, epilepsy, Alzheimer's disease, and other Neurological disorders. Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2. While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively. As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

Preventive effects of transcranial photobiomodulation on epileptogenesis in a kainic acid-induced rat epilepsy model

ObjectiveTemporal lobe epilepsy affects nearly 50 million people worldwide and is a major burden to families and society. A significant portion of patients are living in developing countries with limited access to therapeutic resources. This highlights the urgent need to develop more readily available, noninvasive treatments for seizure control. This research explored the effectiveness of transcranial photobiomodulation (tPBM), a non-invasive method utilizing photon-tissue interactions, for preventing epileptogenesis and controlling seizures. MethodsIn a kainic acid (KA)-induced rat model of epilepsy, two different wavelengths of tPBM, 808 nm and 940 nm, were applied separately in two groups of animals (KA + 808 and KA + 940). The ability of tPBM for seizure control was evaluated by comparing the occurrence rate of interictal epileptiform discharges (IED) and behavioral seizures among three groups: KA, KA + 808, KA + 940. Prevention of epileptogenesis was assessed by comparing the occurrence rate of high frequency oscillations (HFOs), especially fast ripple (FR) rate, among the three groups. Nissl staining and immunostaining for the apoptosis marker-caspase-3, were used as indications of neuroprotection. ResultsThe KA + 808 group and the KA + 940 group showed significantly lower FR and IED rates compared to the KA group. Weekly FR rates started to drop during the first week of tPBM treatment. The KA + 808 and KA + 940 groups also displayed milder seizure behaviors and less neuronal loss in hippocampal areas compared to KA rats without tPBM treatment. Similarly, lower caspase-3 levels in the KA + 808 and KA + 940 compared with the KA group suggested effectiveness of tPBM in reducing cell death. SignificancetPBM of 808 nm/940 nm showed effectiveness in suppressing epileptogenesis and ictogenesis in the KA-induced rat epilepsy model. This effectiveness of tPBM can be linked to the neuroprotection benefits of photon-tissue interactions. Further studies are warranted to elucidate the fundamental mechanism of tPBM protection, determine optimal treatment parameters and validate its effectiveness in other epilepsy models.

Silica Nanoparticles from Melon Seed Husk Abrogated Binary Metal(loid) Mediated Cerebellar Dysfunction by Attenuation of Oxido-inflammatory Response and Upregulation of Neurotrophic Factors in Male Albino Rats.

Silica nanoparticles (SiNPs) have been touted for their role in the management of non-communicable diseases. Their neuroprotective benefits against heavy metal-induced neurotoxicity remain largely unexplored. This is a comparative evaluation of the oxido-inflammatory and neurotrophic effects of Ni, Al, and Ni/Al mixture on the cerebellum of male albino rats with or without treatment with SiNPs generated from melon seed husk. The study complied with the ARRIVE guidelines for reporting in vivo experiments. A total of 91, 7-9 week-old weight-matched male Sprague rats (to avoid sex bias) were randomly divided into 13 different dosing groups where Group 1 served as the control. Other groups received 0.2mg/kg Ni, 1mg/kg Al, and 0.2mg/kg Ni + 1mg/kg Al mixture with or without different doses of SiNP for 90 days. Rotarod performance was carried out. Oxidative stress markers, Ni, Al, Ca, Fe, Mg, neurotrophic factors, amyloid beta (Aβ-42), cyclooxygenase-2 (COX-2), and acetylcholinesterase (AChE) were determined in the cerebellum. SiNPs from melon seed husk caused a significant decrease in Aβ-42 level and activities of AChE and COX-2 and a significant increase in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mediated by Ni, Al, and Ni/Al mixture exposure in rats. Neurotoxicity of the Ni/Al mixture is via heightened neuronal lipoperoxidative damage, decreased Mg, and increased Fe, and co-administration of SiNPs from melon seed husk with the Ni/Al mixture attenuated some of these biochemical changes in the cerebellum.

L-Theanine Ameliorates Obesity-Related Complications Induced by High-Fat Diet in Mice: Insights from Transcriptomics and Metabolomics.

Obesity is a major public health concern globally. Plant-based ingredients have been proposed as alternative treatments for obesity. L-Theanine (THE), a unique nutraceutical component of tea, is known for its neuroprotective and cognitive benefits. However, there are few reports on THE's effects and mechanisms in improving obesity and its complications. In this study, the alleviating effects and potential mechanisms of THE on obesity-related complications (ORCs) induced by a high-fat diet(HFD) in mice were explored by performing biochemical, hepatic transcriptomics, and plasma metabolomics analyses. The results indicated THE (900 mg/kg of body weight) was effective in mitigating ORCs by decreasing body weight gain and fat deposition, improving glycolipid metabolism disorders, inflammation dysregulation, and alleviating fatty liver formation due to long-term HFD. The hepatic transcriptomics data suggested that THE intervention suppresses the lipid metabolism and inflammation pathways in HFD-fed mice, thereby inhibiting hepatic steatosis and inflammation. Moreover, plasma metabolomics analysis revealed that THE exhibited positive effects on the homeostasis of plasma metabolite balance, such as phosphatidylcholine (PC(14:0/18:1)), phosphatidylethanolamine (Lyso-PE(14:0)), phosphatidic acid (PA(16:0e/18:0)), stigmasterol, and deoxycholic acid glycine conjugate. These metabolites were strongly correlated with ORC-related indicators. Our results indicated that THE, as a functional food additive, possesses potential for ORC alleviation. However, the exact molecular mechanism of how THE alleviates ORCs needs to be investigated in the future.

Unveiling the Neuroprotective Potential of Date Palm (Phoenix dactylifera): A Systematic Review.

Background: Neurodegenerative diseases primarily afflict the elderly and are characterized by a progressive loss of neurons. Oxidative stress is intricately linked to the advancement of these conditions. This study focuses on Phoenix dactylifera (P. dactylifera; Family: Arecaceae), commonly known as "Ajwa," a globally cultivated herbal plant renowned for its potent antioxidant properties and reported neuroprotective effects in pharmacological studies. Method: This comprehensive systematic review delves into the antioxidant properties of plant extracts and their phytochemical components, with a particular emphasis on P. dactylifera and its potential neuroprotective benefits. Preferred reporting items for systemic reviews and meta-analysis (PRISMA) were employed to review the articles. Results: The study includes 269 articles published in the literature and 17 were selected after qualitative analysis. The growing body of research underscores the critical role of polyphenolic compounds found in P. dactylifera, which significantly contribute to its neuroprotective effects through antioxidant mechanisms. Despite emerging insights into the antioxidant actions of P. dactylifera, further investigation is essential to fully elucidate the specific pathways through which it confers neuroprotection. Conclusions: Like many other plant-based supplements, P. dactylifera's antioxidant effects are likely mediated by synergistic interactions among its diverse bioactive compounds, rather than by any single constituent alone. Therefore, additional preclinical and clinical studies are necessary to explore P. dactylifera's therapeutic potential comprehensively, especially in terms of its targeted antioxidant activities aimed at mitigating neurodegenerative processes. Such research holds promise for advancing our understanding and potentially harnessing the therapeutic benefits of P. dactylifera in neuroprotection.

The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

Targeted Temperature Management for Out-of-Hospital Cardiac Arrest Survivors.

Targeted temperature management (TTM), specifically therapeutic hypothermia, has been proposed to provide neuroprotective and mortality benefits for out-of-hospital cardiac arrest (OHCA) survivors. This proposition was based on small-scale trials from the early 2000s, leading to its incorporation into various international guidelines. The proposed neuroprotective mechanisms include reducing cerebral metabolic rate, stabilizing the blood-brain barrier, reducing the release of excitatory neurotransmitters, and suppressing apoptotic pathways. However, these early trials have been criticized for their high risk of bias and lack of standardized protocols. Recent evidence from more rigorously controlled randomized trials indicates no significant association between hypothermia and improved neurological outcomes or survival rates. This review explores the latest clinical evidence on TTM for OHCA patients, discussing the pathophysiology, evaluating the effectiveness of hypothermia through various clinical trials, and providing recommendations for future research and clinical practice.

Dietary Choline Intake Is Beneficial for Cognitive Function and Delays Cognitive Decline: A 22-Year Large-Scale Prospective Cohort Study from China Health and Nutrition Survey.

Pre-clinical studies have discovered the neuroprotective function and the benefit for cognitive function of choline. However, it remains unclear whether these benefits observed in animal studies also work in humans. The aims of this study are to examine the effects of dietary choline intake on cognitive function and cognitive decline during ageing in middle-aged and elderly Chinese. We included 1887 subjects aged 55~79 years with 6696 observations from the China Health and Nutrition Survey cohort study. The subjects were followed up for 6 to 21 years, with an average of 12.2 years. A dietary survey was conducted over 3 consecutive days with a 24 h recall, using household weight-recording methods. Based on the China Food Composition, data from USDA, and published literature, the dietary choline intake was calculated as the sum of free choline, phosphocholine, phosphatidylcholine, sphingomyelin, and glycerophosphocholine. Cognitive function was assessed using a subset of the Telephone Interview for Cognitive Status-modified (TICS-m) items. In order to eliminate the different weight of scores in each domain, the scores were converted by dividing by the maximum score in each domain, which ranged from 0 to 3 points. Higher cognitive scores represented better cognition. We used two-level mixed effect models to estimate the effects of dietary choline intake on cognitive score and cognitive decline rate in males and females, respectively. The average dietary choline intake was 161.1 mg/d for the baseline. After adjusting for confounders, the dietary choline intake was significantly associated with higher cognitive score in both males and females. The cognitive score in the highest quartile group of dietary choline was 0.085 for males and 0.077 for females-higher than those in the lowest quartile group (p < 0.01 for males, p < 0.05 for females). For every 10-year increase in age, the cognitive score decreased by 0.266 for males and 0.283 for females. The cognitive score decline rate of the third quartile group of dietary choline was 0.125/10 years lower than that of the lowest quartile group in females (p < 0.05). Dietary choline intake not only improves cognitive function, but also postpones cognitive decline during the aging process. The findings of this study highlight the neuroprotective benefit of choline in the middle-aged and elderly Chinese population, especially among females.

Comparative Neuroprotective Potential of Nanoformulated and Free Resveratrol Against Cuprizone-Induced Demyelination in Rats.

Demyelination is a frequent yet crippling neurological disease associated with multiple sclerosis (MS). The cuprizone (CZ) model, which causes demyelination through oxidative stress and neuroinflammation, is a popular tool used by researchers to examine this process. The polyphenol resveratrol (RESV) has become a promising neuroprotective agent in seeking for efficient therapies. In a rat model given CZ, we created and examined iron oxide nanoparticles (IONPs) loaded with RESV (IONP-RESV) to see how effective they were as a therapeutic agent against free RESV. According to molecular mechanisms, exposure to CZ resulted in a marked downregulation of myelin proteolipid protein (PLP) expression and an overexpression of the inflammatory markers tumor necrosis factor-α (TNF-α) and S100β, which are indicators of demyelination and neuroinflammation. It is remarkable that these CZ-induced alterations could be reversed by therapy with either RESV or IONP-RESV. Interestingly, IONP-RESV showed even stronger anti-inflammatory activity, as shown by a more noticeable downregulation of TNF-α and S100β expression. These results were confirmed by histopathological examination of the cerebral cortices. Our findings support the better neuroprotective benefits of RESV-loaded IONPs over free RESV in reducing demyelination and neuroinflammation brought on by CZ. Owing to their pro-remyelinating, anti-inflammatory, and antioxidant properties, RESV-loaded IONPs show promise as a neurotherapeutic intervention in the future for neurological diseases such as multiple sclerosis.

Targeting calcium dependant/cAMP/PKA/CREB pathway and GABAergic transmission by drotaverine and hesperidin for amelioration of tardive dyskinesia

Antipsychotics, commonly used for anxiety and psychosis, are linked to severe side effects like fatal ventricular arrhythmias, sudden cardiac death, and movement disorders, limiting their therapeutic use. This research aimed to explore novel mechanisms to treat psychotic anxiety while minimizing these risks. Drotaverine activates the cAMP/PKA/CREB pathway, while Hesperidin inhibits dopaminergic hyperactivity. Using a reserpine-induced orofacial dyskinesia model, which mimics tardive dyskinesia linked to oxidative stress, reserpine (1 mg/kg, s.c) was administered for three days. Rats were pre-treated with drotaverine (8 mg/kg, p.o) and hesperidin (50 mg/kg, p.o) for five days. Statistical analysis via one-way ANOVA and Dunnett’s test showed that reserpine significantly increased vacuous chewing movements (VCMs), tongue protrusions (TPs), and reduced locomotion and exploration. Pre-treatment with drotaverine and hesperidin reduced VCMs and TPs. Reserpine-treated rats had lower catalase and higher lipid peroxidation (LPO) levels, indicators of oxidative stress, which were reversed by the drugs. Additionally, drotaverine improved cognition by modulating the cAMP/PKA/CREB pathway, and Hesperidin offered neuroprotection through GABAergic transmission. Both drugs, alone or in combination, demonstrate potential as alternative therapies for psychotic anxiety with neuroprotective benefits.

MicroRNA-based engineered mesenchymal stem cell extracellular vesicles to treat visual deficits after blast-induced trauma

Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 108 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased “b” wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications.

Ameliorative effects of gallic acid on tebuconazole–induced adverse effects in the cerebellum of adult albino rats: histopathological and immunohistochemical evidence

ABSTRACT Tebuconazole (TEB) is a common triazole sterol demethylation inhibitor fungicide utilized to manage a variety of diseases in crops like cereals, fruits, and vegetables. The aim of this work was to assess the effects of TEB on the structure of the cerebellum in adult albino rats and possible protective impact of co-administration of Gallic acid (GA). Four groups of forty adult male albino rats were randomly selected, and the rats in group I received corn oil through daily gavage for 4 weeks. Group II received GA dissolved in the normal saline at a dose of 100 mg/kg through daily gavage for 4 weeks, group III administered with TEB dissolved in corn oil at its acceptable daily intake dose (0.02 mg/kg body weight) through daily gavage for 4 weeks, group IV rats received both TEB and GA. For light microscopic, ultrastructural, and immunohistochemical investigations, cerebellar specimens were prepared. TEB exposure led to neuronal damage in the form of degenerated Purkinje cells with vacuolated cytoplasm, areas of lost Purkinje cells, the basket cells appeared vacuolated with degenerated neuropil, the granule cells clumped with congested areas between them, dilated cerebellar islands, weak positive bcl2 immunoreactions in the Purkinje cells, and numerous GFAP-positive astrocytes. GA mitigated TEB-mediated histological changes in the cerebellar cortex. We concluded that TEB caused Purkinje neurons in the rat cerebellar cortex to degenerate and undergo apoptosis. GA had a neuroprotective benefit against TEB toxicity in the rat cerebellar cortex.

Oxidative Stress in Cerebral Ischemia/Reperfusion Injury

Oxidative stress in cerebral ischemia/reperfusion injury (CIRI) involves reactive oxygen and nitrogen species (ROS and RNS). Despite efficient antioxidant pathways in the brain, hypoxia triggers the production of oxygen free radicals and downregulates ATP, which leads to oxidative stress. Sources of free radicals during CIRI include Ca&lt;sup&gt;2+&lt;/sup&gt;-dependent enzymes, phospholipid degradation and mitochondrial enlargement. Upon reperfusion, the abrupt increase of oxygen triggers a massive radical production via enzymes like xantin oxidase (XO), phospholipase A2 (PLA2) and oxide synthases (OS). These enzymes play an essential role in neuronal damage by excitotoxicity, lipoperoxidation, nitrosylation, inflammation and programmed cell death (PCD). Endothelial nitric oxide synthase (eNOS) decreases as compared to neuronal nitric oxide synthase (nNOS). This is associated with neuronal damage, endothelial inflammation, apoptosis and oxidative stress. Strategies promoting activation of eNOS while inhibiting nNOS could offer neuroprotective benefits in CIRI. Understanding and targeting these pathways could mitigate brain damage in ischemia/reperfusion events. Clinically, tissue plasminogen activator (t-PA) has been shown to restore cerebral blood flow. However, serious side effects have been described, including hemorrhagic transformation. Different treatments are currently under investigation to avoid I/R injury. Baicalin has been reported as a potential agent that could improve t-PA adverse effects, which have to do with peroxynitrite synthesis and matrix metalloproteinase (MMP) expression. In this review, CIRI and interventions in oxidative stress are addressed. Special attention is paid to efficient antioxidant mechanisms in the brain and the production of free radicals, especially nNOS-derived nitric oxide (NO). The primary purpose is to describe accessible radical pathways with the activity of Ca&lt;sup&gt;2+&lt;/sup&gt;-dependent oxidative enzymes, leading to membrane phospholipids and mitochondrial breakdown. &lt;strong&gt;Key&lt;/strong&gt;&lt;strong&gt;w&lt;/strong&gt;&lt;strong&gt;ords&lt;/strong&gt;Oxidative stress; cerebral ischemia/reperfusion; nitric oxide; reactive oxygen species; nitric oxide synthase

The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex® - A Cannabis-derived Spray.

Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.