Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke.
Secretoneurin (SN), a neuropeptide derived from secretogranin II, promotes neurite outgrowth of immature cerebellar granule cells. SN also aids in the growth and repair of neuronal tissue, although the precise mechanisms underlying the promotion of brain tissue neuroprotection and plasticity by SN are not understood. Here, in a rat model of stroke and in ischemic human brain tissue, SN was markedly upregulated in both neurons and endothelial cells. SN-mediated neuroprotection rescued primary cortical cell cultures from oxygen/glucose deprivation. SN also induced expression of the antiapoptotic proteins Bcl-2 and Bcl-xL through the Jak2/Stat3 pathway and inhibited apoptosis by blocking caspase-3 activation. In addition, rats with occluded right middle cerebral arteries showed less cerebral infarction, improved motor performance, and increased brain metabolic activity following i.v. administration of SN. Furthermore, SN injection enhanced stem cell targeting to the injured brain in mice and promoted the formation of new blood vessels to increase local cortical blood flow in the ischemic hemisphere. Both in vitro and in vivo, SN not only promoted neuroprotection, but also enhanced neurogenesis and angiogenesis. Our results demonstrate that SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway.
Shyu
Woei-Cherng
WC
Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Republic of China.
Lin
Shinn-Zong
SZ
Chiang
Ming-Fu
MF
Chen
Der-Cherng
DC
Su
Ching-Yuan
CY
Wang
Hsiao-Jung
HJ
Liu
Ren-Shyan
RS
Tsai
Chang-Hai
CH
Li
Hung
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D053381:Secretogranin II / Q000378:metabolism / Q000494:pharmacology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D009479:Neuropeptides; D018696:Neuroprotective Agents; C506135:SCG2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053381:Secretogranin II; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D051020:bcl-X Protein; C506138:secretogranin 2, mouse; C506141:secretogranin 2, rat; C081159:secretoneurin; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3