Journal of neurology & neurophysiology最新文献

The approval of new therapies to treat neurodegenerative disease conditions by the Food and Drug administration (FDA) has been hindered by many failed clinical trials, which were based upon "significant" efficacy in preclinical or translational studies. Additional problems during drug development related to significant adverse events and unforeseen toxicity have also hampered drug development. Recent reviews of preclinical data suggests that many studies have over-estimated efficacy due to poor or inadequate study design, exclusion of important data (negative or neutral) and lack of study randomization and blinding. This article describes in detail a set of recommendations to improve the quality of science being conducted in laboratories worldwide, with the goal of documenting in the peer-reviewed literature, including Journal of Neurology and Neurophysiology, the scientific basis for the continued development of specific strategies to treat neurodegenerative diseases such as Stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Spinal cord injury, and Amyotrophic lateral sclerosis. The minimum recommendations for effective translational research include the need for model justification, study group randomization and blinding, power analysis calculations, appropriate statistical analysis of all data sets, and a conflict of interest statement by investigators. It will also be beneficial to demonstrate reproducible efficacy in multiple species and in studies done by independent laboratories.

Despite considerable research that has contributed to a better understanding of the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed. The only effective treatment for ischemic stroke is rapid recanalization of an occluded vessel by dissolving the clot with tissue plasminogen activator (tPA). However, stroke adversely affects vascular function as well that can cause secondary brain injury and limit treatment that depends on a patent vasculature. In middle cerebral arteries (MCA), ischemia/reperfusion (I/R) cause loss of myogenic tone, vascular paralysis, and endothelial dysfunction that can lead to loss of autoregulation. In contrast, brain parenchymal arterioles retain considerable tone during I/R that likely contributes to expansion of the infarct into the penumbra. Microvascular dysregulation also occurs during ischemic stroke that causes edema and hemorrhage, exacerbating the primary insult. Ischemic injury of vasculature is progressive with longer duration of I/R. Early postischemic reperfusion has beneficial effects on stroke outcome but can impair vascular function and exacerbate ischemic injury after longer durations of I/R. This review focuses on current knowledge on the effects of I/R on the structure and function of different vascular segments in the brain and highlight some of the more promising targets for vascular protection.

Hemorrhagic stroke which is a form of stroke that affects 20% of all stroke patients is a devastating condition for which new treatments must be developed. Current treatment methods are quite insufficient to reduce long term morbidity and high mortality rate, up to 50%, associated with bleeding into critical brain structures, into ventricular spaces and within the subarachnoid space. During the last 10-15 years, significant advances in the understanding of important mechanisms that contribute to cell death and clinical deficits have been made. The most important observations revolve around a key set of basic mechanisms that are altered in brain bleeding models, including activation of membrane metalloproteinases, oxidative stress and both inflammatory and coagulation pathways. Moreover, it is now becoming apparent that brain hemorrhage can activate the ischemic stroke cascade in neurons, glial cells and the vascular compartment. The activation of multiple pathways allows comes the opportunity to intervene pharmacologically using monotherapy or combination therapy. Ultimately, combination therapy or pleiotropic compounds with multi-target activities should prove to be more efficacious than any single therapy alone. This article provides a comprehensive look at possible targets for small molecule intervention as well as some new approaches that result in metabolic down-regulation or inhibition of multiple pathways simultaneously.