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

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.

Neuroprotective Effects of Cannabidiol but Not Δ9-Tetrahydrocannabinol in Rat Hippocampal Slices Exposed to Oxygen-Glucose Deprivation: Studies with Cannabis Extracts and Selected Cannabinoids

“…ECM changes in composition and assembly in neurological disorders compromise the physiological neurons-glia, neuron-neuron interactions [59]. This pathological disassembly of the ECM had also been demonstrated in different experimental models of ischemia [60,61]. It will be of extreme interest to understand through which mechanism CBD allows the maintenance of tissue integrity after the ischemic insult.…”

M2 microglial small extracellular vesicles reduce glial scar formation via the miR-124/STAT3 pathway after ischemic stroke in mice

“…After removing excess primary antibodies, the samples were incubated with fluorescence-tagged secondary antibodies at room temperature for 1 h. Excess secondary antibodies were removed, and the samples were incubated with 4, 6-diamidino-2-phenylindole (DAPI, BIOTIUM-23002, Life Technologies) for 10 min at room temperature. The samples were then imaged using laser scanning confocal microscopy (Leica, Soloms, Germany) 27 .…”

Integrative Analysis Identified IRF6 and NDST1 as Potential Causal Genes for Ischemic Stroke

“…NDST1 encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in biosynthesis of heparan sulfate, which play roles in triglyceride-rich lipoprotein clearance (27), stroke (28, 29), and allergic airway inflammation through the regulation of recruitment of inflammatory cells to the airways by mediating interaction of leukocytes with the vascular endothelium (30). Suppression of NDST1 in endothelial cells results in reduced responsiveness to VEGFA (31), which plays important role in cardiovascular diseases.…”