Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perinatal hypoxic-ischemic (HI) brain damage continues to be a major clinical problem. We investigated the contribution of the MAP kinase c-Jun N-terminal kinase (JNK), to neonatal HI brain damage. JNK regulates several transcriptional (via AP-1 activation) and non-transcriptional processes involved in brain damage such as inflammation and cell death/survival. P7 rats were subjected to HI by unilateral carotid artery occlusion and hypoxia. HI-induced activation of cerebral AP-1 peaked at 3-6h post-HI. Intraperitoneal administration of the JNK-inhibitor TAT-JBD immediately after HI prevented AP-1 activation. TAT-JBD treatment within 3h after HI reduced early neuronal damage by approximately 30%. JNK/AP-1 inhibition did not reduce HI-induced cytokine/chemokine expression. Analysis of indicators of apoptotic cell death revealed that TAT-JBD markedly reduced the HI-induced increase in active caspase 3. However, the upstream mediators of apoptosis: active caspase 8, cleaved Bid, mitochondrial cytochrome c release and caspase 9 cleavage were not reduced after TAT-JBD. TAT-JBD inhibited the HI-induced increase in Smac/DIABLO, an inhibitor of IAPs that prevent activation of caspase 3. TAT-JBD treatment also reduced cleavage of alpha-fodrin, indicating that calpain-mediated brain damage was reduced. Neuroprotection by TAT-JBD treatment was long-lasting as gray- and white matter damage was diminished by approximately 50% at 14 weeks post-HI concomitantly with marked improvement of sensorimotor behavior and cognitive functioning. In conclusion, JNK inhibition by TAT-JBD treatment reduced neonatal HI brain damage with a therapeutic window of 3h and long-lasting anatomical and behavioral improvements. We propose that inhibition of mitochondrial Smac/DIABLO release and calpain activation contribute to neuroprotection by TAT-JBD.
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PMID:Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury. 1976 83

Neuronal cell death caused by glutamate excitotoxicity is prevalent in various neurological disorders and has been associated with the transcriptional activation of activator protein-1 (AP-1). In this study, we tested 19 recently isolated AP-1 inhibitory peptides, fused to the cell penetrating peptide TAT, for their efficacy in preventing cell death in cortical neuronal cultures following glutamate excitotoxicity. Five peptides (PYC19D-TAT, PYC35D-TAT, PYC36D-TAT, PYC38D-TAT, PYC41D-TAT) displayed neuroprotective activity in concentration responses in both l- and retro-inverso d-isoforms with increasing levels of neuroprotection peaking at 83%. Interestingly, the D-TAT peptide displayed a neuroprotective effect increasing neuronal survival to 25%. Using an AP-1 luciferase reporter assay, we confirmed that the AP-1 inhibitory peptides reduce AP-1 transcriptional activation, and that c-Jun and c-Fos mRNA following glutamate exposure is reduced. In addition, following glutamate exposure the AP-1 inhibitory peptides decreased calpain-mediated alpha-fodrin cleavage, but not neuronal calcium influx. Finally, as neuronal death following glutamate excitotoxicity was transcriptionally independent (actinomycin D insensitive), our data indicate that activation of AP-1 proteins can induce cell death via non-transcriptional pathways. Thus, these peptides have potential application as therapeutics directly or for the rational design of small molecule inhibitors in both apoptotic and necrotic neuronal death associated with AP-1 activation.
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PMID:AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures. 1987 34