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

Abstract

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 p38α and not the p38β isoform is an important contributor to stressor-induced proinflammatory cytokine upregulation and glia-dependent neurotoxicity. However, the contribution of neuronal p38α and p38β isoforms in responses to neurotoxic agents is less well understood. In the current study, we used cortical neurons from wild-type or p38β knockout mice, and wild-type neurons treated with two highly selective inhibitors of p38α 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 p38β knockout neurons was not significantly different. In contrast, selective inhibition of neuronal p38α was neuroprotective. Our results show that neuronal p38β is not required for neurotoxicity induced by multiple toxic insults, but that p38α in the neuron contributes quantitatively to the neuronal dysfunction responses. These data are consistent with our previous findings of the critical importance of microglia p38α compared to p38β, and continue to support selective targeting of the p38α isoform as a potential therapeutic strategy.

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

“…77,78 However, the roles of the other p38 isoforms in neuronal cells have yet to be elucidated. Whereas other studies have found that the p38a isoform leads to neuronal death, 76 the present data demonstrated that an increased level of phosphorylated p38c (and/or p38d) enhanced the survival of primary RGCs. Interestingly, Ferrari et al 79 recently identified a similar phenomenon showing that the survival effects of p38c are opposite to those of p38a in vascular endothelial cells.…”

“…73 Using cells within the CNS, several studies have demonstrated that the p38 MAPKa isoform is a relatively more important contributor to stressor-induced proinflammatory cytokine production and neurotoxicity compared with the p38b isoform. [74][75][76] Several studies have reported that SB203580, a typical inhibitor of p38 MAPKa and p38 MAPKb, rescues RGCs from NMDA and optic nerve injury, suggesting the involvement of p38 MAPKa and p38 MAPKb in RGC survival. 77,78 However, the roles of the other p38 isoforms in neuronal cells have yet to be elucidated.…”

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

“…Among four isoforms of p38 (p38a, b, g, and d), p38a is ubiquitously and significantly expressed in most cell types (reviewed by Cuadrado and Nebreda, 2010) and in human brains (Wang et al, 1997). p38a is particularly responsive to stressful stimuli (Han et al, 1994) including stress associated with glutamate (Sun et al, 2003;Xing et al, 2015) and EW (Jung et al, 2011). Thus, we focused on p38a among the four isoforms and used 1 mM of SB203580 since it is a selective p38a/b inhibitor at a dose of 1-5 mM (Mihara et al, 2008).…”

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

“…In attempting to dissect the role of p38 MAPK in AD, it is essential to distin-guish between p38␣ and p38␤ MAPK enzymes, as they have different functions (26). To investigate the pathogenic function of neuronal p38␣ MAPK, we used Cre-Lox or knockdown techniques to ablate p38␣ MAPK specifically in neurons and examined the effect on BACE1 degradation in this study.…”