Page 24 - Read Online

Wu et al. Neuroimmunol Neuroinflammation 2019;6:4 I http://dx.doi.org/10.20517/2347-8659.2019.07 Page 3 of 5

[25]
Adiponectin exerts anti-oxidation against cerebral ischemic injury as well [25,26] . The study by Song et al.
showed that intracerebral injection of gAd attenuated infarct size and neurological deficits aggravated by
NADPH oxidase activator in mice after MCAO along with increased activities of superoxide dismutase
[26]
(SOD) and catalase, and reduced content of malondialdehyde (MDA). The study by Li et al. reported
similar findings. They showed intraperitoneal supplement of adiponectin improved neurological deficits,
decreased infarct size, and attenuated neuronal injury along with decreased MDA levels and increased SOD
[27]
activity levels in mice after MCAO. The study by Wang et al. reported adiponectin attenuated oxygen
and glucose deprivation-induced neuronal injury and mitochondrial oxidative stress in hippocampal
neuronal HT22 cells as evidenced by attenuated reactive oxygen species and malondialdehyde, and increased
superoxide dismutase and glutathione peroxidase activity.

Also, adiponectin has been related to PKA, CREB, and BDNF in the protection against cerebral ischemic
[28]
injury. The study by Bai et al. reported activation of cAMP/PKA-CREB-BDNF signaling pathway by
adiponectin was protective against ischemia/reperfusion injury with reduced infarct volume, neurological
deficits and brain water content.

Finally, anti-apoptosis after cerebral ischemic injury by adiponectin has been found in in vivo and in vitro
[30]
studies [25-27,29] , including that by our group .
APN-gene modified cell therapy alleviates cerebral ischemic injury
The pre-clinical studies of APN-gene modified cell therapies in the treatment of cerebral ischemic injury
[22]
are growing recently. The study by Nishimura et al. showed that adenovirus-mediated expression of
adiponectin reduced brain infarction volume, increased cerebral blood flow, and improved neurological
[31]
deficits, through an eNOS-dependent mechanism in cerebral ischemic injury. The study by Shen et al.
reported that adiponectin could promote focal angiogenesis in cerebral ischemic injury. They showed that
after MCAO mice receiving intracerebral injection of adeno-associated viral vector carrying the APN
gene had reduced ischemia-induced brain atrophy, improved neurological function and increased number
of microvessels along with increased AMPK phosphorylation and vascular endothelial growth factor
[32]
expression. Furthermore, the study by Miao et al. showed this angiogenetic effect was more significant in
aged mice than young mice.
[30]
Our group showed that pre-treatment of baculovirus-mediated expression of APN through intra-cerebral
injection was protective against cerebral ischemic injury in both normal weight and obese rats through
reducing brain infarct and edema, neurologic deficits, and p38-mediated neuronal apoptosis.

Recently, it has been shown that genetically-transplanted endothelial progenitor cells with adiponectin by
lentivirus could reduce cerebral infarction volume, improve behavior outcome, increase microvessel density,
[33]
and reduce cell apoptosis .
gAd alleviates cerebral ischemic injury
Among adiponectin isoforms, the globular adiponectin has been mostly studied and consistently shown
to be protective against cerebral ischemic injury [23,25,29] . The data regarding whether other isoforms of
adiponectin could exert protection against cerebral ischemic injury are currently lacking and warrant
further studies.

In summary, adiponectin, an adipokine secreted by adipocytes, exists in a relatively large amount in
the peripheral circulation. During the cerebral ischemic injury, it accumulates in the damaged cerebral
vasculature instead of de novo generation by damaged cerebral tissues. It exerts multiple protective
mechanisms against cerebral ischemic injury including eNOS-dependent mechanism, anti-inflammation,
anti-oxidation, anti-apoptosis, and promotion of angiogenesis. Since adiponectin is an adipokine naturally