Mitochondrial mechanism of neuroprotection by CART

Abstract

We previously demonstrated that the neuropeptide cocaine-and amphetamine-regulated transcript (CART) is protective against focal cerebral ischemia in vivo and against neuronal cell death in culture induced by oxygen-glucose deprivation (OGD). The mechanism of neuroprotection by CART is unknown, in part due to lack of knowledge regarding its putative receptor. Using a yeast two-hybrid system with CART's carboxy-terminal to screen a mouse brain cDNA library, we uncovered a potential direct interaction between CART and subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB). We confirmed CART/SDHB binding using in vitro pull-down assay, and tested the effects of CART peptide on SDH activity, Complex II (CII) activity and ATP production in primary cultured cortical neurons under basal conditions and after OGD. At concentrations between 0.2 and 4 nM, CART significantly increased SDH function, CII activity and ATP generation in purified mitochondria and intact neurons under baseline conditions. Furthermore, pretreatment with CART enhanced mitochondrial mechanisms of neuronal survival and prevented the decline in SDH and CII activities and ATP production after OGD. The findings suggest that CART's neuroprotective mechanism of action may be linked to preservation of mitochondrial function and prevention of energy failure after ischemia-reperfusion injury.

Role of Mitochondria on the Neurological Effects of Cocaine

“…Thus, cocaine may also have some indirect effects on mitochondria through upregulation of CART, which was shown to interact with succinate dehydrogenase subunit B, stimulating its activity and increasing ATP production (Mao et al, 2007). Upregulation of CART could be a neuroprotective mechanism contributing to some adaptive changes observed after repeated cocaine exposure.…”

Improving neurorepair in stroke brain through endogenous neurogenesis-enhancing drugs

“…Several chemicals, peptides, or trophic factors have been reported to improve behavioral recovery when given after stroke. [37][38][39] These drugs mainly target endogenous repair originated from the neuroprogenitor cells in the SVZ. This experimental approach may provide a new potential treatment strategy for stroke patients, enabling a longer treatment window after the onset of stroke, a disorder frequently logistically difficult to treat immediately after occurrence.…”

Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes

“…On the other hand, the inhibitory effect of CART KD on GSIS was still present under stimulation with alpha-KIC indicating that CART may be important for oxidative phosphorylation. CART has been shown to preserve ATP levels after ischemic conditions via interaction with succinate dehydrogenase (SDH, complex II) in neurons (Mao et al, 2007). ATP is indeed an important trigger and amplifying factor of beta-cell exocytosis (Eliasson et al, 1997;Ashcroft and Rorsman, 2013) and the effect of CART KD on insulin secretion was lost after uncoupling with FCCP and blocking ATP synthesis with OM.…”