as-601245 and Reperfusion-Injury

The article reviews the literature regarding the role of c-Jun-N-terminal kinases (JNK) and its inhibitors in brain damage in the settings of ischemia and reperfusion injury. The implication of JNK in signaling mechanisms involved in ischemia-reperfusion-induced cerebral injury are discussed. Described effects associated with JNK inhibition using synthetic and natural substances in experimental models of ischemic and reperfusion injury of the brain. Results of experimental studies demonstrated that JNK represent promising therapeutic targets for brain protection against ischemic stroke. However, multiple physiologic functions of various JNK family members do not allow for the systemic use of non-specific JNK inhibitors for therapeutic purposes. The authors conclude that the continuous search for selective inhibitors of JNK3 remains an important task.

Topics: Acetonitriles; Animals; Anthracenes; Benzothiazoles; Brain; Brain Ischemia; Gene Expression Regulation; Ginsenosides; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 10; Neuroprotective Agents; Oximes; Plant Extracts; Protein Kinase Inhibitors; Quinoxalines; Reperfusion Injury; Signal Transduction

c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to a number of extracellular stimuli, including inflammatory cytokines, UV irradiation and ischaemia. A large body of evidence supports a role for JNK signalling in stress-induced apoptosis. It has been hypothesized that JNK may contribute to the apoptotic response by regulating the intrinsic cell death pathway involving the mitochondria. Here, we examined the role of the JNK signalling pathway in hippocampal CA1 apoptotic neurones following transient ischaemia in gerbils. We showed early activation of death receptor-dependent apoptosis (caspase-8 activation 2 days after ischaemia) and a biphasic activation of caspase-3 and caspase-9 after ischaemia. Activation of the mitochondrial pathway, as measured by cytochrome c release, appeared as a late event (5-7 days after ischaemia). AS601245, a novel JNK inhibitor, antagonized activation of both pathways and significantly protected CA1 neurones from cell death. Our results suggest a key role of JNK in the control of death receptor and mitochondrial-dependent apoptosis after transient ischaemia.

Topics: Acetonitriles; Analysis of Variance; Animals; Apoptosis; Benzothiazoles; Caspases; Cytochromes c; Enzyme Activation; Gerbillinae; Hippocampus; In Situ Nick-End Labeling; Ischemic Attack, Transient; JNK Mitogen-Activated Protein Kinases; Male; Mitochondria; Neurons; Reperfusion Injury; Thiazoles; Time Factors