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Theranostics 2018; 8(21):5814-5827. doi:10.7150/thno.28252 This issue Cite

Research Paper

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

Yacine Khelif¹, Jérôme Toutain¹, Marie-Sophie Quittet¹, Sandrine Chantepie², Xavier Laffray², Samuel Valable¹, Didier Divoux¹, Fernando Sineriz³, Emanuelle Pascolo-Rebouillat³, Dulce Papy-Garcia², Denis Barritault^2,3, Omar Touzani^1*, Myriam Bernaudin^1✉*

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.
* Authors contributed equally to the work

✉ Corresponding author: bernaudinfr

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, stroke, heparan sulfate mimetics.

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