استكشف المجموعة الواسعة من العناوين المتاحة.

Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0–2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0–1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.

As the leading causes of human disability and mortality, neurological diseases affect millions of people worldwide and are on the rise. Although the general roles of several signaling pathways in the pathogenesis of neurodegenerative disorders have so far been identified, the exact pathophysiology of neuronal disorders and their effective treatments have not yet been precisely elucidated. This requires multi-target treatments, which should simultaneously attenuate neuronal inflammation, oxidative stress, and apoptosis. In this regard, astaxanthin (AST) has gained growing interest as a multi-target pharmacological agent against neurological disorders including Parkinson's disease (PD), Alzheimer's disease (AD), brain and spinal cord injuries, neuropathic pain (NP), aging, depression, and autism. The present review highlights the neuroprotective effects of AST mainly based on its anti-inflammatory, antioxidative, and anti-apoptotic properties that underlies its pharmacological mechanisms of action to tackle neurodegeneration. The need to develop novel AST delivery systems, including nanoformulations, targeted therapy, and beyond, is also considered.

Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)2 (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.

As an endogenous neuroprotectant agent, adenosine is extensively distributed and is particularly abundant in the central nervous system (CNS). Under physiological conditions, the concentration of adenosine is low intra‐ and extracellularly, but increases significantly in response to stress. The majority of adenosine functions are receptor‐mediated, and primarily include the A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Adenosine is currently widely used in the treatment of diseases of the CNS and the cardiovascular systems, and the mechanisms are related to the disease types, disease locations, and the adenosine receptors distribution in the CNS. For example, the main infarction sites of cerebral ischemia are cortex and striatum, which have high levels of A1 and A2A receptors. Cerebral ischemia is manifested with A1R decrease and A2AR increase, as well as reduction in the A1R‐mediated inhibitory processes and enhancement of the A2AR‐mediated excitatory process. Adenosine receptor dysfunction is also involved in the pathology of Alzheimer's disease (AD), depression, and epilepsy. Thus, the adenosine receptor balance theory is important for brain disease treatment. The concentration of adenosine can be increased by endogenous or exogenous pathways due to its short half‐life and high inactivation properties. Therefore, we will discuss the function of adenosine and its receptors, adenosine formation, and metabolism, and its role for the treatment of CNS diseases (such as cerebral ischemia, AD, depression, Parkinson's disease, epilepsy, and sleep disorders). This article will provide a scientific basis for the development of novel adenosine derivatives through adenosine structure modification, which will lead to experimental applications.

Nowadays, the worldwide interest is growing to use medicinal plants and their active constituents to develop new potent medicines with fewer side effects. Precise dietary compounds have prospective beneficial applications for various neurodegenerative ailments. Rosmarinic acid is a polyphenol and is detectable most primarily in many Lamiaceae families, for instance, Rosmarinus officinalis also called rosemary. This review prepared a broad and updated literature review on rosmarinic acid elucidating its biological activities on some nervous system disorders. Rosmarinic acid has significant antinociceptive, neuroprotective, and neuroregenerative effects. In this regard, we classified and discussed our findings in different nervous system disorders including Alzheimer’s disease, epilepsy, depression, Huntington’s disease, familial amyotrophic lateral sclerosis, Parkinson’s disease, cerebral ischemia/reperfusion injury, spinal cord injury, stress, anxiety, and pain.

Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection.

As our global population ages, the treatment of neurodegenerative diseases is critical to our society. In recent years, researchers have begun to study the role of biologically active chemicals from plants and herbs to gain new inspiration and develop new therapeutic drugs. Ginseng ( C.A. Mey.) is a famous Chinese herbal medicine with a variety of pharmacological activities. It has been used to treat various diseases since ancient times. Extensive research over the years has shown that ginseng has potential as a neuroprotective drug, and its neuroprotective effects can be used to treat and prevent neurological damage or pathologically related diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, depression symptoms, and strokes). Moreover, evidence for the medicinal and health benefits of ginsenoside, its main active ingredient, in the prevention of neurodegenerative diseases is increasing, and current clinical results have not reported any serious adverse reactions to ginseng. Therefore, we briefly review the recent research and development on the beneficial effects and mechanisms of ginseng and its main active ingredient, ginsenoside, in the prevention and treatment of neurodegenerative diseases, hoping to provide some ideas for the discovery and identification of ginseng neuroprotection.

In this randomized trial involving patients with acute stroke, prehospital administration of magnesium sulfate by paramedics within 2 hours after the onset of stroke symptoms (within 1 hour for 74% of patients) did not improve neurologic outcomes. Stroke is the second leading cause of death and a leading cause of adult disability worldwide. Unfortunately, currently available therapies for acute ischemic stroke, which are all reperfusion-based, are only moderately effective. 1 , 2 Treatment with tissue plasminogen activator (t-PA), the only pharmacologic treatment approved by a regulatory agency for the treatment of acute ischemic stroke, results in early reperfusion in less than half of treated patients, can be started only after neuroimaging has ruled out intracerebral hemorrhage, and is used in only 2 to 7% of patients with acute ischemic stroke in the United States. 1 Mechanical thrombectomy devices improve patient . . .