BACKGROUND: Pre-clinical data suggest sex differences in mechanisms of cerebral ischemic injury. This might result in differential outcomes of putative neuroprotectants by sex, though little systematic data is available to assess this.
METHODS: We performed a systematic review of multicenter randomized controlled trials published from January 1980-June 2022 enrolling >100 subjects and testing neuroprotectants in acute ischemic stroke (AIS). For each trial, reported treatment effect by sex was extracted. When published results by sex were not available, we contacted individual authors to attempt to retrieve these data.
RESULTS: We identified 59 publications reporting 64 trials that met inclusion criteria. Of these, data on treatment effect by sex were published for 14/64 trials. Unpublished data for an additional 5 trials were obtained from trial investigators (19/64, or 29.7%). Two trials (one testing uric acid and one dexborneol) reported treatment benefit in women but not men. Pooled analysis of six trials of tirilazad reported worse treatment outcomes in women and no effect in men. No clear difference was apparent in the other trials.
CONCLUSIONS: Most trials did not report treatment effect by sex. Of those that did, there was little evidence of systematic sex differences in treatment response.

Alzheimer\'s disease (AD) and Parkinson\'s diseases (PD) are the two most common progressive neurodegenerative diseases with limited knowledge on their cause and, presently, have no cure. There is an existence of multiple treatment methods that target only the symptoms temporarily and do not stop the progression or prevent the onset of disease. Neurodegeneration is primarily attributed to the natural process of aging and the deleterious effects of heightened oxidative stress within the brain, whether via direct or indirect mechanisms. Emerging evidence suggests that certain nutritional aspects play a crucial role in the prevention and management of neurodegenerative diseases. Lutein, a dietary carotenoid, has been studied for its antioxidant properties for more than a decade with several applications against age-related macular degeneration. It is high antioxidant potential and selective accumulation in the brain makes it a versatile compound for combatting various neurodegenerative diseases. In this review, the studies exhibiting neuroprotective properties of lutein against neurodegenerative conditions, more specifically AD and PD in various model systems as well as clinical observations have been reviewed. Accordingly, the concerns associated with lutein absorption and potential strategies to improve its bioavailability have been discussed.

The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer\'s disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study\'s goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer\'s disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer\'s disease and can be utilised alone or as an add-on therapy for the condition.

Prothrombotic and proinflammatory properties of neutrophil extracellular traps (NETs) contribute to brain damage after ischemic stroke. CD21 is a novel phthalide neuroprotectant against cerebral ischemia in rodents. This study investigated effects of CD21 on the platelet-NET-thrombin axis and ischemic brain injury and the underlying mechanism. CD21 exerteddose-dependent neuroprotectionin rats that were subjected to2 h middle cerebral artery occlusion,dose-dependentlyinhibited adenosine diphosphate-mediatedplatelet aggregationin rats, and dose-dependentlyexertedanti-thrombotic activityin rodents that received a collagen-epinephrine combination, ferric chloride, or an arteriovenous shunt. Equimolar CD21 doses exerted stronger efficacy than 3-N-butylphthalide (NBP, natural phthalide for the treatment of ischemic stroke). CD21 dose-dependently improved regional cerebral blood flow, neurobehavioral deficits, and infarct volume in mice that were subjected to photothrombotic stroke (PTS). CD21 (13.79 mg/kg, i.v.) significantly decreased NET components (plasma dsDNA concentrations; mRNA levels of elastase, myeloperoxidase, and neutrophil gelatinase-associated lipocalin and protein level of citrullinated histone H3 in ischemic brain tissues), mRNA and protein levels of peptidyl-arginine deiminase 4 (PDA4, NET formation enzyme), and mRNA levels of NET-related inflammatory mediators (interleukin-1β, interleukin-17A, matrix metalloproteinase 8, and matrix metalloproteinase 9) in ischemic brain tissues, despite no effect on mRNA levels of deoxyribonuclease I (NET elimination enzyme). Pretreatment with compound C (inhibitor of adenosine monophosphate-activated protein kinase [AMPK]) significantly reversed the inhibitory effects of CD21 on NETs, PDA4, and inflammatory mediators in PTS mice. These results suggest that CD21 might regulate the platelet-NET-thrombin axis and protect against ischemic brain injury partly through the induction of AMPK activation.

Acute ischemic stroke is an important cause of death and long-term disability worldwide. In this work, we have synthesized a series of derivatives with 3,5‑diaryl substituent triazole scaffolds. The derivatives showed favorable protective effective in SNP-induced oxidative stress model, of which compound 5 was the most active. In vivo experiments showed that compound 5 could ameliorate neurological deficits, attenuate infarction sizes, reduce malonaldehyde (MDA) level and increase superoxide dismutase (SOD) level in middle cerebral artery occlusion (MCAO) rats. Preliminary safety evaluation showed that compound 5 exhibited low acute toxicity in BALB/c mice (LD50 greater than 1000 mg/kg). Further investigation indicated that compound 5 was able to scavenge ROS, restore mitochondrial membrane potential and protect PC12 cells from SNP-induced apoptosis. Moreover, compound 5 could initiate transcription of antioxidant response element (ARE) and induced expressions of antioxidative enzymes. Collectively, compound 5 might have the potency of treating acute ischemic stroke.

In recent years, the medical field had significantly progressed to a greater extent which was evidenced with increased life expectancy and decreased mortality rate. Due to the growth of medical field, numerous communicable diseases are prevented and eradicated, whereas the non-communicable disease incidence has been increased globally. One such non-communicable disease which threatens the global population is stroke. Stroke tends to be the second leading cause of death and disability in older population. In lower- and middle-income countries, increased incidence rate of stroke was also evidenced in younger population which is alarming. Lifestyle changes, poor physical activity, stress, consumption of alcohol, oral contraception, and smoking tend to be the causative agents of stroke. Since thrombus formation is the major pathology of stroke, drugs were targeted to thrombolysis. Currently thrombolytic, antiplatelet, and anticoagulant therapies were given for the stroke patients. But the recovery rate of stroke patients with available drugs is very slow. Hence, it is a need of today to discover a drug with increased recovery rate and decreased or nil side effects. Phytochemicals are the best options to treat such non-communicable chronic diseases. Visnagin is one such compound which is used to regulate blood pressure, treat kidney stones, tumors of bile duct, renal colic, and whooping cough. It possesses anti-inflammatory, neuroprotective, and cardioprotective properties; it was also proven to treat epileptic seizures. In this study, the anti-ischemic effect of a furanochrome visnagin was assessed in in vivo rat model. Middle cerebral ischemic/reperfusion was induced in healthy male Sprague Dawley rats and treated with different concentrations of visnagin. The neuroprotective effect of visnagin against cerebral ischemia-induced rats was assessed by analyzing the neurological score, brain edema, infract volume, and Evans blue leakage. The anti-inflammatory property of visnagin was assessed by quantifying proinflammatory cytokines in serum and brain tissues of cerebral ischemia-induced rats. Prostaglandin E-2, COX-2, and NFκ-β were estimated to assess the anti-ischemic effect of visnagin. Histopathological analysis with H&E staining was performed to confirm the neuroprotective effect of visnagin against cerebral ischemia. Our results authentically confirm that visnagin has prevented the inflammation in brain region of cerebral ischemia-induced rats. The neurological scoring and the quantification of PGE-2, COX-2, and NFκ-β prove the anti-ischemic effect of visnagin. Furthermore, the histopathological analysis of hippocampal region provides evidence to the neuroprotective effect of visnagin against cerebral ischemia. Overall, our study confirms visnagin as a potent alternative drug to treat stroke.

Neurodegenerative diseases and various other chronic ailments have gradually transformed into public-health issues. Neurodegenerative disorders are a range of progressive neural abnormalities characterized by cellular dysfunctions, neuronal structure, and function loss. Among many chronic disorders, oxidative stress, inflammation, mitochondrial dysregulation, and cellular alterations in the human body are considered the most prevalent diagnostic symptoms. They have a profound impact on patients\' health and wellbeing. The disease\'s poor curability, high healthcare costs, and lethality are the principal reasons for approaching and exploring the conventional treatment\'s phytotherapeutic alternatives. Ginkgo biloba (Maidenhair tree) is a well-known and widely used herbal plant in the Ginkgoaceae family. Its phytochemical constituents, Flavonoids, and terpenes, have been identified as the primary ingredients of Ginkgo biloba leaf extracts. It has been widely used due to its therapeutic properties, including its neuroprotective, anti-dementia, antioxidant, anti-inflammatory, vasoactive, anti-psychotic, anti-neoplastic, and anti-platelet activity. In recent decades, plenty of Ginkgo-derived substances has been researched and elucidated to have significant therapeutic effects in numerous disease models. This review aims to provide a thorough understanding of the botanical basis for Ginkgo biloba, its usage as herbal medicine, and its pivotal role in functional foods. Additionally, the clinical significance of Ginkgo biloba, as observed in various research works and clinical investigations, is also emphasized, facilitating a better understanding of their molecular basis and application in many chronic diseases.

Adjunctive melatonin use in schizophrenia, as supported by a modicum of evidence, has multiple transcending chronobiotic actions, including fixing concurrent sleep problems to bona fide augmentative antipsychotic actions, mitigating the risk of tardive dyskinesias, curbing the drastic metabolic syndrome and ultimately providing neuroprotective actions. Its use is rather an art than science!

Ischemic stroke is a main cause of cognitive neurological deficits and disability worldwide due to a plethora of neuronal apoptosis. Unfortunately, numerous neuroprotectants for neurons have failed because of biological toxicity, severe side effects, and poor efficacy. Tetrahedral framework nucleic acids (tFNAs) possess excellent biocompatibility and various biological functions. Here, we tested the efficacy of a tFNA for providing neuroprotection against neuronal apoptosis in ischemic stroke. The tFNA prevented apoptosis of neurons (SHSY-5Y cells) caused by oxygen-glucose deprivation/reoxygenation through interfering with ischemia cascades (excitotoxicity and oxidative stress) in vitro. It effectively ameliorated the microenvironment of the ischemic hemisphere by upregulating expression of erythropoietin and inhibiting inflammation, which reversed neuronal loss, alleviated cell apoptosis, significantly shrank the infarction volume from 33.9% to 2.7%, and attenuated neurological deficits in transient middle cerebral artery occlusion (tMCAo) rat models in vivo. In addition, blocking the TLR2-MyD88-NF-κB signaling pathway is a potential mechanism of the neuroprotection by tFNA in ischemic stroke. These findings indicate that tFNA is a safe pleiotropic nanoneuroprotectant and a promising therapeutic strategy for ischemic stroke.

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2\'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson\'s disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.