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Page 2 of 5 Wu et al. Neuroimmunol Neuroinflammation 2019;6:4 I http://dx.doi.org/10.20517/2347-8659.2019.07

atherosclerosis, anti-thrombosis, and promotion of endothelial repair and angiogenesis which are protective
in endothelial injury, atherosclerosis, and cardiovascular diseases [9-11] .

[12]
Adiponectin is abundant in peripheral circulation, representing about 0.01% total plasma proteins , and has
[10]
a rapid turnover rate . Decreased circulating adiponectin level is noted in obesity for increased oxidative
stress in accumulated fat [13,14] . Clinically, hypoadiponectinemia has been noted in various diseases, such as
ischemic stroke [15,16] , coronary artery disease, insulin resistance and diabetes, hypertension, dyslipidemia,
[17]
metabolic syndrome, hepatic steatosis and fibrosis, and cancer . On the contrary, hyperadiponectinemia
has been noted in congestive heart failure and chronic kidney disease [18,19] .

ADIPONECTIN IS PROTECTIVE AGAINST CEREBRAL ISCHEMIC INJURY
Exogenous accumulation from the circulation but not endogenous production in damaged
brain tissues after cerebral ischemic injury
In many pre-clinical studies, adiponectin has been consistently shown to be protective against cerebral
ischemic injury. However, the expression of adiponectin after cerebral ischemic injury is not endogenous in
ischemic cerebral tissues but exogenous from the peripheral circulation.

There are studies exploring the expression profiles of adiponectin after middle cerebral artery occlusion
[20]
(MCAO) in mice and rats. The study by Yatomi et al. showed that, plasma adiponectin levels peaked
soon at 1-3 h, decreased later, reached the nadir in 48 h, and then returned to baseline gradually in the rat
after MCAO. However, the expression pattern of adiponectin in ischemic cerebral hemisphere differed.
Adiponectin showed higher levels in ischemic cerebral hemisphere than non-ischemic one during 72 h to
7 days after ischemia/reperfusion injury. Moreover, its expression was evident in endothelium only, not in
neurons, glia, or macrophages. Finally, its expression in the endothelium of ischemic hemisphere seemed to
be exogenous from the circulation but not endogenous from damaged cerebral hemispheres since there was
no mRNA expression of adiponectin detected by reverse transcription polymerase chain reaction in these
[21]
area. Another study by Shen et al. showed similar findings. They found that adiponectin started to rise
1 h in ischemic hemisphere after cerebral ischemia/reperfusion injury in mice, peaked in 3 days and lasted
till 7 days. They found the expression of adiponectin occurred only in vascular endothelial cells but not in
neurons or glial cells. Furthermore, they could not find the mRNA expression of adiponectin in ischemic
cerebral hemisphere. Taken together, adiponectin accumulates in vascular endothelial cells instead of de
novo generation in ischemic brain after cerebral ischemic injury.

Adiponectin alleviates cerebral ischemic injury through multi-mechanisms
Adiponectin is protective against cerebral ischemic injury and the mechanisms accounting for this are diverse.
[22]
The study by Nishimura et al. reported that adiponectin exerted a cerebroprotective action through an
endothelial nitric oxide synthase (eNOS)-dependent mechanism in cerebral ischemic injury. They showed that
adenovirus-mediated delivery of adiponectin augmented the status of phosphorylation of endothelial nitric
oxide synthase and reduced the infarction volume in adiponectin knockout (APN-KO) mice.

Another important mechanism of adipoenctin being protective against cerebral ischemic injury is anti-
[23]
inflammation. The study by Chen et al. showed that exogenous supplement of gAd via jugular vein
reduced cerebral infarct size, neurological deficits, and expression of endogenous matrix metalloproteinase
9, interleukin (IL)-1β, tumor necrosis factor-α and IL-8, and inhibited the translocation of nuclear factor (NF)-
κB from cytoplasm into the nucleus in the rat after MCAO. The indirect evidence of its anti-inflammatory
[24]
mechanism comes from another study by Jung et al. . They found more rolling leukocyte and leukocyte
adhesion were observed in the APN-KO mice than in the wide type mice after cerebral ischemia/reperfusion
injury. They proposed that adiponectin inhibits the interaction between the endothelium and leukocytes and
hence alleviates the inflammatory insult in cerebral ischemic injury.