Ischemia apoptosis

Apoptosis is programed cell death and differs from necrosis in that it results in minimal inflammation and release of genetic material. Although necrosis is the predominant process that follows acute ischemia, apoptosis is important after more minor injury, particularly within the ischemic penumbra. Apoptosis is executed by the production, activation and action of caspases, which are protein-cleaving enzymes that dismantle cytoskeleton proteins and enzymes responsible for cellular repair (Zhang et al. 2004). Neurons are particularly susceptible to caspase-mediated cell death after cerebral ischemia, as demonstrated by the reduction in infarct size by caspase inhibitors in experimental models. 

Occlusion of portal branches of the liver parenchyma to be resected redistributes the totality of its portal blood flow, and consequently all its hepatotrophic contents, towards the FRL. This is the basic rationale of the method that triggers off regenerative activity of the nonembolized portion of the liver. Moreover, PVE dilates the portal branches in the FRL, exposing liver vasculature to stretch stress which act as a trigger for IL-6 release from endothelial cells and contribute to the activation of regenerative cascade in the FRL [26]. Induction of heat shock protein in the nonembolized lobe is supposed to have similar effects [40]. PVE also acts through two potentially complementary pathways specifically related to embolization ischemia and inflammation. With most of the embolic agents, PVE induces a mild ischemia apoptosis or necrosis of some hepatocytes, and intercellular disjunction. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH. Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg 2005 18 335-350. 

Sato M, Bagchi D, Tosaki A and Das DK. 2001. Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. Free Radic Biol Med 31(6) 729-737. 

Hypoxia-ischemia may initiate apoptosis in parallel with excitotoxicity 565 Triggers of ischemic apoptosis may include decreased supply or sensitivity to neurotrophins, oxidative stress, exposure to inflammatory cytokines or damage to mitochondria 566... 

D1 (10,17S-docosatriene) from DHA using tandem liquid chromatography-photodiode array-electrospray ionization-tandem mass spectrometry (LC-PDA-ESI-MS-MS)-based lipidomic analysis have been documented in ischemic brain [4] and retinal pigment epithelium [5], This new lipid is called neuroprotectin D1 (1) because of its neuro-protectiveproperties in brain ischemia-reperfusion [4] and in oxidative stress-challenged retinal pigment epithelial cells [5] (2) because of its potent ability to inactivate proapoptotic signaling (see apoptosis, Ch. 35) [5] and (3) because it is the first identified neuroprotective mediator derived from DHA. 

Suzuki, K. et al. Overexpression of interleukin-1 receptor antagonist provides cardioprotec-tion against ischemia-reperfusion inj ury associated with reduction in apoptosis. Circulation 104,1308, 2001. 

Wu, B., Iwakiri, R.,Tsunada, S., Utsumi, H., Kojima, M., Fujise, T., Ootanij, A., Fujimoto, K., iNOS enhances rat intestinal apoptosis after ischemia-reperfusion, Free Radical Biol. Med. 33 (2002), p. 649-658... 

Sunderland T, Tariot PN, Newhouse PA. (1988). Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly neuropsychiatric populations. Brain Res. 472 4y. 371-89. Tachikawa E, Kudo K, Flarada K, Kashimoto T, Miyate Y, Kakizaki A, Takahashi E. (1999). Effects of ginseng saponins on responses induced by various receptor stimuli. EurJ Pharmacol 369(1) 23-32. Tagami M, Ikeda K, Yamagata K, Nara Y, Fujino FI, Kubota A, Numano F, Yamori Y. (1999). Vitamin E prevents apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats. Lab Invest. 79(5) 609-15. 

In addition to the function of the ASM in receptor-triggered and developmental apoptosis, the enzyme has a central function in the cellular response to environmental stress stimuli. This review will focus on the examples of ischemia, ultraviolet (UV) light exposure and, in particular, y-irradiation. 

Yu, Z. P., Nikolova-KarakasMan, M., Zhou, D., Cheng, G., Schuchman, E. H., and Mattson, M. p., 2000, Pivotal rale for acidic sphingomyehnase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J Mol Neuroscience 15 85-97. 

Molecular imaging may potentially address not only the pathophysiology of ischemia but also vascular inflammation causing rupture of atherosclerotic plaques before major ischemic events. Initial approaches have used imaging of "indium radiolabeled monocytes [150], upregulated metallo-proteinases [151], and imaging of apoptosis in atherosclerotic lesions [152]. However, none have evolved into clinically useful tests. 

These drugs have also been studied for possible use in other conditions. Clinical studies show distinct benefit in some patients with pulmonary arterial hypertension, and possible benefit in systemic hypertension, cystic fibrosis, and benign prostatic hyperplasia. Preclinical studies suggest that sildenafil may be useful in preventing apoptosis and cardiac remodeling after ischemia and reperfusion. 

The convincing evidence from the experimental work presented here supports the conclusion that EGb is effective for the treatment of dementia and cerebral insufficiency. To sum up the major characteristics of the pharmacological activities of EGb, particularly in the CNS, the following conclusions can be readied. EGb improves hypoxic tolerance and protects cerebral neurons against apoptosis-, edema- and ischemia-induced injury. In addition, EGb inhibits age-related impairment of cerebral neurotransmitters, inducting muscarinic receptors, and 2-... 

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