Inhibition of Neuronal p38α, but not p38β MAPK, Provides Neuroprotection Against Three Different Neurotoxic Insults

The p38 mitogen-activated protein kinase (MAPK) pathway plays a key role in pathological glial activation and neuroinflammatory responses. Our previous studies demonstrated that microglial p38 alpha and not the p38 beta isoform is an important contributor to stressor-induced proinflammatory cytokine upregulation and glia-dependent neurotoxicity. However, the contribution of neuronal p38 alpha and p38 beta isoforms in responses to neurotoxic agents is less well understood. In the current study, we used cortical neurons from wild-type or p38 beta knockout mice, and wild-type neurons treated with two highly selective inhibitors of p38 alpha MAPK. Neurons were treated with one of three neurotoxic insults (L-glutamate, sodium nitroprusside, and oxygen-glucose deprivation), and neurotoxicity was assessed. All three stimuli led to neuronal death and neurite degeneration, and the degree of neurotoxicity induced in wild-type and p38 beta knockout neurons was not significantly different. In contrast, selective inhibition of neuronal p38 alpha was neuroprotective. Our results show that neuronal p38 beta is not required for neurotoxicity induced by multiple toxic insults, but that p38 alpha in the neuron contributes quantitatively to the neuronal dysfunction responses. These data are consistent with our previous findings of the critical importance of microglia p38 alpha compared to p38 beta, and continue to support selective targeting of the p38 alpha isoform as a potential therapeutic strategy.