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Theranostics. 2018 Nov 12;8(21):5814-5827. doi: 10.7150/thno.28252. eCollection 2018.

A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke.

Author information

1
Normandie Univ, UNICAEN, CNRS, CEA, ISTCT/CERVOxy group, GIP CYCERON, 14000 Caen, France.
2
CRRET (EA 4397/ERL CNRS 9215), Université Paris-Est, Université Paris Est Créteil, 94010 Créteil, France.
3
Société OTR3, 4 rue Française, 75001 Paris, France.

Abstract

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.

KEYWORDS:

Neuroprotection; extracellular matrix; functional recovery; heparan sulfate mimetics.; stroke

Conflict of interest statement

Competing interests: This study was in part supported by OTR3 S.A.S, the manufacturer of RGTA® (HSm4131). Authors F. Sineriz, E. Pascolo-Rebouillat, are employees of OTR3, D. Barritault is a significant OTR3 shareholder and RGTA patents inventor and co-owner. All provided technical guidance for these experiments as members of the project steering committee. However, the funding body had no influence on data acquisition, evaluation or presentation.

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