Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke

• Published in: The Journal of clinical investigation Vol. 118; no. 1; pp. 133 - 148
• Main Authors: Shyu, Woei-Cherng, Lin, Shinn-Zong, Chiang, Ming-Fu, Chen, Der-Cherng, Su, Ching-Yuan, Wang, Hsiao-Jung, Liu, Ren-Shyan, Tsai, Chang-Hai, Li, Hung
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2008
• Subjects: Alzheimer's disease; Angiogenesis; Animals; Apoptosis - drug effects; bcl-X Protein - metabolism; Biomedical research; Bone marrow; Brain; Caspase 3 - metabolism; Cell Hypoxia - drug effects; Cells, Cultured; Cerebellar Cortex - metabolism; Cerebellar Cortex - pathology; Cerebral Infarction - drug therapy; Cerebral Infarction - metabolism; Cerebral Infarction - pathology; Cerebral ischemia; Complications and side effects; Disease; Disease Models, Animal; Enzyme Activation - drug effects; Female; Glucose; Health aspects; Humans; Ischemia; Janus Kinase 2 - metabolism; Male; Mice; Nervous system; Neurites - metabolism; Neurites - pathology; Neurogenesis; Neuronal Plasticity - drug effects; Neuropeptides; Neuropeptides - metabolism; Neuropeptides - pharmacology; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Risk factors; Secretogranin II - metabolism; Secretogranin II - pharmacology; STAT3 Transcription Factor - metabolism; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Stroke; Veins & arteries; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI32723

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.