Ischemia, cerebral neurodegeneration

Due to the numerous possible reactions and related biological consequences, inappropriate overproduction of NO can cause a series of disease states such as a variety of neurodegeneration diseases including inflammation, rheumatic disease, septic shock, diabetes melhtus, and cerebral ischemia. Therefore development of isoform-specific NOS inhibitors to regulate NO synthesis has been an active research area. 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

At this time, however, we are not aware of any compounds selected primarily by their neuroprotection activity on rodent models that have established clinical efficacy for dementias or related neurodegenerative diseases. This may be partially explained by their priority development for stroke, and clinicians have found it is difficult or unlikely to slow the ischemia in patients if they are not treated aggressively within 3 h of the initial ischemic event. The speed of neurodegeneration in stroke (cerebral ischemia) makes it a much more difficult target for drug intervention than neurodegeneration from slower pathologies such as Alzheimer s, Parkinson s, and malfunctions in neurotransmitters. 

Martin, L. J., Al-Abdulla, N. A., Brambrink, A. M., Kirsch, J. R., Sieber, F. E., and Portera-Cailliau, C. (1998). Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation A perspective on the contributions of apoptosis and necrosis. Brain Res. Bull. 46, 281-309. 

Increased activity of GSK-3/3 has been reported during neuronal degeneration (Beurel and Jope, 2006) and it has been associated with the promotion of the intrinsic mitochondrial pathway of apoptosis (Brazil and Hemmings, 2001). Pharmacological inhibition of GSK-3/3 reduces neuronal cell death caused by cerebral ischemia (Kelly et al., 2004), suggesting that prevention of GSK-3/3 activation may represent a potential approach to minimize neurodegeneration in the retina. 

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