Adiponectin Prevents Cerebral Ischemic Injury Through Endothelial Nitric Oxide Synthase–Dependent Mechanisms

Abstract

Background-Adiponectin is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. A low level of plasma adiponectin is associated with increased mortality after ischemic stroke; however, the causal role of adiponectin in ischemic stroke is unknown. Methods and Results-To explore the role of adiponectin in the development of acute cerebral injury, we subjected adiponectin-deficient (APN-KO) and wild-type (WT) mice to 1 hour of middle cerebral artery occlusion followed by 23 hours of reperfusion. APN-KO mice exhibited enlarged brain infarction and increased neurological deficits after ischemia-reperfusion compared with WT mice. Conversely, adenovirus-mediated supplementation of adiponectin significantly reduced cerebral infarct size in WT and APN-KO mice. APN-KO mice showed decreased cerebral blood flow during ischemia by laser speckle flowmetry methods. Adiponectin colocalized within the cerebral vascular endothelium under transient ischemic conditions by immunohistochemical analysis. Phosphorylation of endothelial nitric oxide synthase in ischemic brain tissues and the production of nitric oxide metabolites in plasma were attenuated in APN-KO mice compared with WT mice. Adenovirus-mediated administration of adiponectin stimulated endothelial nitric oxide synthase phosphorylation and nitric oxide metabolites during cerebral ischemia in both WT and APN-KO mice. Neuronal nitric oxide synthase expression during ischemia did not differ between WT and APN-KO mice. Adenovirusmediated delivery of adiponectin did not affect brain infarction in mice deficient in endothelial nitric oxide synthase. Conclusions-These data provide causal evidence that adiponectin exerts a cerebroprotective action through an endothelial nitric oxide synthase-dependent mechanism. Adiponectin could represent a molecular target for the prevention of ischemic stroke.

Blood biomarkers of insulin resistance in acute stroke patients treated with intravenous thrombolysis: Temporal profile and prognostic value

“…Among adipokines, our biomarker panel did not include relevant molecules such as adiponectin. In agreement with our main hypothesis, linking insulin resistance with a poorer stroke outcome, both preclinical studies in rat [38] and mice [39] models of focal cerebral ischemia demonstrated a strikingly positive effect of adiponectin on cerebral flow and infarct size. Moreover, 5-year survival rate after first ever ischemic stroke was found to be higher in patients who had a lower adiponectin level determined within the first 24 hours after stroke onset [40].…”

Adiponectin protects rat hippocampal neurons against excitotoxicity

“…The present results are consistent with other recent studies suggesting a neuroprotective role of adiponectin. Adiponectin-deficient mice exhibit enlarged brain infarction and increased neurological deficits after ischemia reperfusion compared to wild-type mice, and adenovirus-mediated supplementation of adiponectin reverses the deficit in adiponectin deficient mice and improves protection in wild-type mice (Nishimura et al 2008). Elevated plasma adiponectin attenuates cardiac ischemia/reperfusion damage in mice (Shinmura et al 2007;Gonon et al 2008).…”

“…It has been reported previously that adiponectin protects neuroblastoma SH-SY5Y cells against cytotoxicity induced by 1-methyl-4-phenlyl-2,3,6-tetrahydropyridine acetaldehyde or 1-Methyl-4-phenylpyridinium ion (MPP+), and that adiponectin also exerts a cerebroprotective action attenuating cerebral ischemic injury (Jung et al 2006;Nishimura et al 2008). Excessive glutamate receptor signaling has been linked to neuronal death in epilepsy, stroke, AD, PD, and amyotrophic lateral sclerosis (Fan and Raymond 2007;O'Neill and Witkin 2007;Palop et al 2007).…”

“…Expression of AdipoR1 and AdipoR2 was observed in hippocampal neurons in mice, GT1-7 cell line derived from mouse hypothalamic neurons in rat, and the pituitary, nucleus basalis and hypothalamus in humans (Jeon et al 2009;Wen et al 2008;Guillod-Maximin et al 2009;Psilopanagioti et al 2009). Adiponectin-knockout mice exhibit enlarged brain infarction and increased neurological deficits after ischemia reperfusion compared to wild-type mice, while adenovirus-mediated supplementation of adiponectin significantly reduces cerebral infarct size in both wild-type and adiponectin-deficient mice (Nishimura et al 2008), suggesting that adiponectin may have neuroprotective activity. Jeon et al (2009) observed that preloading adiponectin centrally via lateral ventrical injection in mice attenuated subsequent neuronal damage from kainic acid-induced seizure activity in hippocampal neurons.…”

Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin

“…Furthermore, both adiponectin and exercise exhibit antidiabetic, antiinflammatory, antiatherogenic and cardio-protective properties (13). Recent evidence also suggests that adiponectin has neuroprotective effects in the CNS (14,15) in addition to its peripheral effects (13,16).…”