Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke
Woei-Cherng Shyu, … , Chang-Hai Tsai, Hung Li
Woei-Cherng Shyu, … , Chang-Hai Tsai, Hung Li
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):133-148. https://doi.org/10.1172/JCI32723.
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Research Article Cardiology

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

Abstract

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.

Authors

Woei-Cherng Shyu, Shinn-Zong Lin, Ming-Fu Chiang, Der-Cherng Chen, Ching-Yuan Su, Hsiao-Jung Wang, Ren-Shyan Liu, Chang-Hai Tsai, Hung Li

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Figure 2

Pretreatment with SN attenuates OGD-induced toxicity through a specific signaling pathway in PCCs.

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Pretreatment with SN attenuates OGD-induced toxicity through a specific ...
(A–C) Representative microscopic morphology of PCCs under various conditions (control, SN plus OGD, and OGD alone). (D) Cell death assessed by LDH activity in media of PCC cultures with or without 1 μg/l SN before exposure to OGD. SN pretreatment significantly attenuated OGD-induced cell death. (E) The density of MAP-2–immunreactive PCCs was significantly reduced by OGD, but returned to control levels with SN pretreatment. (F) Fluorimetric measurement under OGD. A significant reduction of caspase-3 activity was seen in the SN-pretreated PCCs. (G) A significant reduction of caspase-3+ immunofluorescent cells was observed in the SN-treated group. (H and I) Quantitation of Western blot in PCCs treated with SN under OGD showed significantly increased Bcl-2 expression. (J) Expression of p-Stat3, Stat3, p-Jak2, and Jak2. (K–M) The ratio of p-Stat3 and p-Jak2 to actin protein after SN treatment peaked at about a 2-fold increase in treated cells compared with control cells in a time- and dose-dependent manner. There was no statistically significant difference in Stat3 and Jak2 levels between treated and control cells. (N) Addition of AG490 to OGD-treated cells significantly reduced MAP-2–immunoreactive cell density in PCCs. Data are mean ± SEM. *P < 0.05, **P < 0.01 vs. control. Scale bar: 50 μm.