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Delayed treatment with a p53 inhibitor enhances recovery in stroke brain.

ABSTRACT: OBJECTIVE:Cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ). Most of these new cells die shortly after injury. The purpose of this study was to examine a novel strategy for treatment of stroke at 1 week after injury by enhancing the survival of ischemia-induced endogenous NPCs in SVZ. METHODS:Adult rats were subjected to a 90-minutes middle cerebral artery occlusion. A p53 inhibitor pifithrin-alpha (PFT-alpha) was administered to stroke rats from days 6 to 9 after middle cerebral artery occlusion. Locomotor behavior was measured using an activity chamber. Proliferation, survival, migration, and differentiation of endogenous NPCs were examined using quantitative reverse transcription polymerase chain reaction, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and immunohistochemistry. RESULTS:PFT-alpha enhanced functional recovery as assessed by a significant increase in multiple behavioral measurements. Delayed PFT-alpha treatment had no effect on the cell death processes in the lesioned cortical region. However, it enhanced the survival of SVZ progenitor cells, and promoted their proliferation and migration. PFT-alpha inhibited the expression of a p53-dependent proapoptotic gene, termed PUMA (p53-upregulated modulator of apoptosis), within the SVZ of stroke animals. The enhancement of survival/proliferation of NPCs was further found in SVZ neurospheres in tissue culture. PFT-alpha dose-dependently increased the number and size of new neurosphere formation. INTERPRETATION:Delayed treatment with a p53 inhibitor PFT-alpha is able to modify stroke-induced endogenous neurogenesis and improve the functional recovery in stroke animals.

SUBMITTER: Luo Y

PROVIDER: S-EPMC2690614 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Delayed treatment with a p53 inhibitor enhances recovery in stroke brain.

Luo Yu Y Kuo Chi-Chung CC Shen Hui H Chou Jenny J Greig Nigel H NH Hoffer Barry J BJ Wang Yun Y

Annals of neurology 20090501 5

<h4>Objective</h4>Cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ). Most of these new cells die shortly after injury. The purpose of this study was to examine a novel strategy for treatment of stroke at 1 week after injury by enhancing the survival of ischemia-induced endogenous NPCs in SVZ.<h4>Methods</h4>Adult rats were subjected to a 90-minutes middle cerebral artery occlusion. A ...[more]

PMID: 19475672

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Project description:Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesions. HSm bind to growth factors, protect them from enzymatic degradation and increase their bioavailability, which promotes tissue repair. As the ECM is altered during stroke and HSm have been shown to restore the ECM, we investigated the potential of HSm4131 (also named RGTA-4131®) to protect brain tissue and promote regeneration and plasticity after a stroke. Methods: Ischemic stroke was induced in rats using transient (1 h) intraluminal middle cerebral artery occlusion (MCAo). Animals were assigned to the treatment (HSm4131; 0.1, 0.5, 1.5, or 5 mg/kg) or vehicle control (saline) groups at different times (1, 2.5 or 6 h) after MCAo. Brain damage was assessed by MRI for the acute (2 days) and chronic (14 days) phases post-occlusion. Functional deficits were evaluated with a battery of sensorimotor behavioral tests. HSm4131-99mTc biodistribution in the ischemic brain was analyzed between 5 min and 3 h following middle cerebral artery reperfusion. Heparan sulfate distribution and cellular reactions, including angiogenesis and neurogenesis, were evaluated by immunohistochemistry, and growth factor gene expression (VEGF-A, Ang-2) was quantified by RT-PCR. Results: HSm4131, administered intravenously after stroke induction, located and remained in the ischemic hemisphere. HSm4131 conferred long-lasting neuroprotection, and significantly reduced functional deficits with no alteration of physiological parameters. It also restored the ECM, and increased brain plasticity processes, i.e., angiogenesis and neurogenesis, in the affected brain hemisphere. Conclusion: HSm represent a promising ECM-based therapeutic strategy to protect and repair the brain after a stroke and favor functional recovery.

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Delayed treatment with a p53 inhibitor enhances recovery in stroke brain.

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Delayed treatment with a p53 inhibitor enhances recovery in stroke brain.

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