Cocaine-and amphetamine-regulated transcript modulates peripheral immunity and protects against brain injury in experimental stroke

Ischemic stroke can induce immediate activation and later inhibition of the peripheral immune system which may contribute to a worse outcome. Cocaine-and amphetamine-regulated transcript (CART) peptides have been reported to have neuroprotective and immunomodulatory effects in various cell and animal experimental models, respectively. In this study, CART’s role in experimental stroke and the relevant immune-regulating mechanisms was investigated. In male C57BL/6 mice subjected to 120 min of middle cerebral artery occlusion (MCAO), with or without CART treatment or sham operation, peripheral immune parameters and serum catecholamins (CAs) were analyzed. CART reduced blood CD4+/CD8+ ratio and pro-inflammatory cytokine expression in MCAO mice at 24 h, while upregulated spleen CD4+/CD8+ ratio and enhanced anti-inflammatory cytokines expressions in MCAO mice at 96 h. In addition, in comparison to control mice, CART-treated mice demonstrated elevated serum CAs at 6 and 24 h, whereas reduced serum levels of CAs and blood regulatory T (Treg) cells at 96 h. The cytokine expression, infarct volume and neurological deficits in mouse brain were also measured. CART reduced post-stroke infarct volume and improved neurological functions, with reduced expression of inflammatory factors in the injured brain. Findings indicate that CART plays an important role in modulating post-stroke immune response and exerts a neuroprotective effect in experimental stroke. Findings also suggest that the possible mechanism of CART’s protective action in stroke is the regulation of the sympathetic nervous system (SNS) pathway since CAs, Treg cells and interleukin (IL)-10 are the major modulators of SNS.

Research highlights
► CART regulates systemic cellular immune response after stroke, that is, CD4+/CD8+ ratio and CD4+CD25+FOXP3+T cells in blood and spleen after MCAO at 6, 24 and 96 h.
► CART’s effects on stroke-induced changes of circulating cytokines such as TNF-α, IFN-γ, IL-4 and IL-10 in serum after MCAO at different time points.
► CART protects against brain injury after stroke through modulating systemic immune response.
► The mechanism relates to effect of CART on the serum Catecholamine (CA) level.