JNK is activated but does not mediate hippocampal neuronal apoptosis in experimental neonatal pneumococcal meningitis

Sury, Matthias D.; Agarinis, Claudia; Widmer, Hans-Rudolf; Leib, Stephen L.; Christen, Stephan (2008). JNK is activated but does not mediate hippocampal neuronal apoptosis in experimental neonatal pneumococcal meningitis. Neurobiology of disease, 32(1), pp. 142-150. Amsterdam: Elsevier 10.1016/J.nbd.2008.07.006

Text 1-s2.0-S0969996108001563-main.pdf__tid=82eb19aa-24e5-11e5-a1e2-00000aacb360&acdnat=1436300566_5e08efac72d38afdda7ae093187ce209 - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (1MB)

Pneumococcal meningitis is associated with caspase 3-dependent apoptosis of recently post-mitotic immature neurons in the dentate gyrus of the hippocampus. The death of these cells is implicated in the learning and memory deficits in patients surviving the disease. The stress-activated protein kinase c-Jun N-terminal kinase (JNK) has been shown to be an important mediator of caspase 3-dependent neuronal apoptosis. However, whether JNK is involved in hippocampal apoptosis caused by pneumococcal meningitis has so far not been investigated. Here we show in a neonatal rat model of pneumococcal meningitis that JNK3 but not JNK1 or JNK2 is activated in the hippocampus during the acute phase of infection. At the cellular level, JNK3 activation was accompanied in the dentate gyrus by markedly increased phosphorylation of its major downstream target c-Jun in early immature (Hu-positive) neurons, but not in migrating (doublecortin-positive) neurons, the cells that do undergo apoptosis. These findings suggested that JNK may not be involved in pneumococcal meningitis-induced hippocampal apoptosis. Indeed, although intracerebroventricular administration of D-JNKI-1 or AS601245 (two highly specific JNK inhibitors) inhibited c-Jun phosphorylation and protein expression in the hippocampus, hippocampal apoptosis was unaffected. Collectively, these results demonstrate that JNK does not mediate hippocampal apoptosis in pneumococcal meningitis, and that JNK may be involved in processes unrelated to apoptosis in this disease.

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