Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat

Nov 14, 2021Brain research bulletin

Silent information regulator 1 may reduce oxidative stress damage after stroke in rats through a specific protective pathway

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Abstract

SIRT1 knockdown reduced cell viability and increased oxidative stress in astrocytes after ischemia/reperfusion injury.

Knocking down SIRT1 led to decreased expression of protective proteins such as PGC-1α, PPARγ, Nrf2, HO-1, and NQO1.
The reduction in SIRT1 also suppressed the activity and interactions of PGC-1α and PPARγ.
SIRT1 overexpression resulted in increased levels of protective proteins but was diminished by knocking down PGC-1α or PPARγ.
In vivo experiments indicated that SIRT1 may mediate neuroprotection through the PGC-1α/PPARγ pathway following ischemic stroke.

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OBJECTIVE: Astrocytes mediate brain defense against oxidative stress-induced injury. Silent information regulator 1 (SIRT1) has anti-oxidative stress effects in many diseases and is highly expressed in astrocytes. However, the neuroprotective effects of SIRT1 on astrocytes after cerebral ischemia/reperfusion injury are unclear. Therein, we aim to investigate the protective effect of SIRT1 on oxidative stress injury after ischemic stroke and possible mechanisms.

METHODS: We evaluated the effects of SIRT1 in astrocytes after cerebral ischemia/reperfusion injury using oxygen-glucose deprivation/recovery (OGD/R) in astrocytes in vitro and middle cerebral artery occlusion in rats in vivo. siRNA was injected intracerebroventricularly 24 h before Middle cerebral artery (MCA) occlusion (MCAO)/reperfusion(R) to silence SIRT1.

RESULTS: SIRT1 knockdown reduced cell viability, increased oxidative stress, and decreased PGC-1α, PPARγ, Nrf2, heme oxygenase (HO)-1, and NAD(P)H: oxidoreductase-1 (NQO1) expression. Moreover, SIRT1 knockdown also suppressed PGC-1α activity, the PGC-1α/PPARγ interaction, and the PPARγ/PPRE interaction. Similarly, in our in vivo experiments, SIRT1 overexpression and PGC-1α or PPARγ knockdown reduced PGC-1α, PPARγ, Nrf2, HO-1, and NQO1 protein expression and blocked the PGC-1α/PPARγ interaction. SIRT1 overexpression plus PPARγ knockdown inhibited the interaction of PPARγ with PPRE. Nrf2 knockdown blocked Nrf2 expression and downstream proteins induced by SIRT1 overexpression.

CONCLUSION: Overall, our data indicated that SIRT1 directly mediated the PGC-1α/PPARγ pathway in response to focal cerebral ischemia/reperfusion-induced neurological deficit, providing insights into the treatment of focal cerebral ischemia/reperfusion injury.

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