CART attenuates endoplasmic reticulum stress response induced by cerebral ischemia and reperfusion through upregulating BDNF synthesis and secretion

Abstract

Cocaine and amphetamine regulated transcript (CART), a neuropeptide, has shown strong neuroprotective effects against cerebral ischemia and reperfusion (I/R) injury in vivo and in vitro. Here, we report a new effect of CART on ER stress which is induced by cerebral I/R in a rat model of middle cerebral artery occlusion (MCAO) or by oxygen and glucose deprivation (OGD) in cultured cortical neurons, as well as a new functionality of BDNF in the neuroprotection by CART against the ER stress in cerebral I/R. The results showed that CART was effective in reducing the neuronal apoptosis and expression of ER stress markers (GRP78, CHOP and cleaved caspase12), and increasing the BDNF expression in I/R injury rat cortex both in vivo and in vitro. In addition, the effects of CART on ischemia-induced neuronal apoptosis and ER stress were suppressed by tyrosine receptor kinase B (TrkB) IgG, whereas the effects of CART on BDNF transcription, synthesis and secretion were abolished by CREB siRNA. This work suggests that CART is functional in inhibiting the cerebral I/R-induced ER stress and neuronal apoptosis by facilitating the transcription, synthesis and secretion of BDNF in a CREB-dependent way.

Keywords: BDNF; CART; CATT/EBP homologous protein; CHOP; CREB; Cerebral ischemia; ER; Endoplasmic reticulum stress; GRP78; I/R; MCAO; Neuron; OGD; TrkB; brain derived neurotrophic factor; cAMP-response element binding protein; cocaine and amphetamine regulated transcript; eIF2α; endoplasmic reticulum; eukaryotic initiation factor 2α; glucose regulated protein 78; ischemia and reperfusion; middle cerebral artery occlusion; oxygen and glucose deprivation; tyrosine receptor kinase B.