Abstract
Mild hypothermia and its key product, cold‐inducible protein RBM3, possess robust neuroprotective effects against various neurotoxins. However, we previously showed that mild hypothermia fails to attenuate the neurotoxicity from MPP+, one of typical neurotoxins related to the increasing risk of Parkinson disease (PD). To better understand the role of mild hypothermia and RBM3 in PD progression, another known PD‐related neurotoxin, rotenone (ROT) was utilized in this study. Using immunoblotting, cell viability assays and TUNEL staining, we revealed that mild hypothermia (32°C) significantly reduced the apoptosis induced by ROT in human neuroblastoma SH‐SY5Y cells, when compared to normothermia (37°C). Meanwhile, the overexpression of RBM3 in SH‐SY5Y cells mimicked the neuroprotective effects of mild hypothermia on ROT‐induced cytotoxicity. Upon ROT stimulation, MAPK signalling like p38, JNK and ERK, and AMPK and GSK‐3β signalling were activated. When RBM3 was overexpressed, only the activation of p38, JNK and ERK signalling was inhibited, leaving AMPK and GSK‐3β signalling unaffected. Similarly, mild hypothermia also inhibited the activation of MAPKs induced by ROT. Lastly, it was demonstrated that the MAPK (especially p38 and ERK) inhibition by their individual inhibitors significantly decreased the neurotoxicity of ROT in SH‐SY5Y cells. In conclusion, these data demonstrate that RBM3 mediates mild hypothermia‐related neuroprotection against ROT by inhibiting the MAPK signalling of p38, JNK and ERK.
Highlights
Parkinson's disease (PD) is a complex multifactorial disorder that is primarily characterized by the loss of nigral dopaminergic neurons.[1,2,3] the aetiology and pathogenesis of PD are poorly understood, environmental exposure‐induced mitochondrial dysfunction is frequently observed in the substantia nigra and cortex in PD.[4]
We previously showed that the overexpression of RBM3 protects dopaminergic neuroblastoma cells SH‐SY5Y from the apoptosis induced by nitric oxide (NO), ultra‐violet (UV) irradiation and an overdose of retinoic acid (RA), whereas RBM3 knockdown revokes the neuroprotective effects of mild hypothermia in SH‐SY5Y cells.[20,21,22]
ROT‐treated cells exposed to hypothermia showed a markedly reduced expression of apoptosis‐related protein, cleaved poly (ADP‐ribose) polymerase (PARP), compared to the control cells exposed to normothermia (P = 0.0075; Figure 1B,C)
Summary
Parkinson's disease (PD) is a complex multifactorial disorder that is primarily characterized by the loss of nigral dopaminergic neurons.[1,2,3] the aetiology and pathogenesis of PD are poorly understood, environmental exposure‐induced mitochondrial dysfunction is frequently observed in the substantia nigra and cortex in PD.[4]. In primary neurons and cortical organotypic slice cultures, mild hypothermia markedly increased RBM3 expression and rescued neuronal cells from forced apoptosis.[17,18,19] In Alzheimer‐type and prion‐infected mouse models, RBM3 was identified as a crucial mediator of hypothermia‐induced neuroprotection,[13] revealing that RBM3 induction/overexpression may provide protection in cases of acute brain injury and in neurodegenerative diseases. We tested if the inhibition of MAPK signalling pathways could rescue ROT‐induced apoptosis
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