Neuropharmacology
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The subventricular zone (SVZ) of the lateral ventricle contains neural stem and progenitor cells that generate neuroblasts, which migrate to the olfactory bulb where they differentiate into interneurons. Ischemic stroke induces neurogenesis in the SVZ and these cells migrate to the boundary of the ischemic lesion. This article reviews current data on cytokinetics, signaling pathways and vascular niche that are involved in processes of proliferation, differentiation, and migration of neural progenitor cells after stroke.
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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. ⋯ Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized.
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Experimental research into brain ischemia contributes substantially to the understanding of ischemic injury mechanisms but suffers from its limited relevance for clinical treatment strategies. One of the reasons is the use of experimental models and methods that do not or only partially replicate the pathophysiology of naturally occurring brain ischemia. ⋯ Particular emphasis is given to the pathophysiological particularities of the various ischemia models, the application of imaging methods for the reliable differentiation between infarct core, penumbra, benign oligemia and normal tissue, as well as to the final outcome of experimental interventions. Based on this analysis, recommendations are given to improve the translational power of brain ischemia-related experimental research.
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Review Comparative Study
Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans.
A number of previous reviews have very eloquently summarized pain models and endpoints in animals. Many of these reviews also discuss how animal models have enhanced our understanding of pain mechanisms and make forward-looking statements as to our proximity to the development of effective mechanism-based treatments. While a number of reports cite failures of animal pain models to predict efficacy in humans, few have actually analyzed where these models have been successful. ⋯ Key to prediction of clinical efficacy is a lack of side effects, which may incorrectly suggest efficacy in animals and an understanding of how pharmacokinetic parameters translate from animals to man. As such, this review focuses on a description of the pharmacokinetic-pharmacodynamic relationship for a number of pain treatments that are effective in both animals and humans. Finally we discuss where and why animal pain models have failed and summarize improvements to pain models that should expand and improve their predictive power.
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Substantial evidence suggests that all commonly abused drugs act upon the brain reward circuitry to ultimately increase extracellular concentrations of the neurotransmitter dopamine in the nucleus accumbens and other forebrain areas. Many drugs of abuse appear to increase dopamine levels by dramatically increase the firing and bursting rates of dopamine neurons located in the ventral mesencephalon. Recent clinical evidence in humans and behavioral evidence in animals indicate that cannabinoid receptor antagonists such as SR141716A (Rimonabant) can reduce the self-administration of, and craving for, several commonly addictive drugs. ⋯ We propose, on the basis of recent studies in our laboratory and others, that these antagonists may act by blocking the effects of endogenously released cannabinoid molecules (endocannabinoids) that are released in an activity- and calcium-dependent manner from mesencephalic dopamine neurons. It is hypothesized that, through the antagonism of cannabinoid CB1 receptors located on inhibitory and excitatory axon terminals targeting the midbrain dopamine neurons, the effects of the endocannabinoids are occluded. The data from these studies therefore suggest that the endocannabinoid system and the CB1 receptors located in the ventral mesencephalon may play an important role in regulating drug reward processes, and that this substrate is recruited whenever dopamine neuron activity is increased.