Abstract
Introduction: Due to the limitation in current treatment window for stroke, the development of delayed stroke treatment is needed. The two main cellular processes of neural repair after stroke are axonal sprouting and neurogenesis. Inhibitory chondroitin sulfate proteoglycans (CSPGs) are increased within the glial scar and perineuronal net after ischemic brain injury, which might play a critical role in blocking neuroblasts migration, axonal regrowth and sprouting. Recently, a novel small peptide memetic of the CSPG receptor (PTP σ) wedge region named ISP (Intracellular Sigma Peptide) is generated and has capabilities to target PTP σ and relieve CSPGs inhibition in the models of spinal cord injury. Here, we aimed to determine whether post-stroke ISP treatment could improve functional recovery in a mouse model of ischemia. Methods: Mice were subjected to tMCAO followed by treatment of ISP or vehicle daily for 4 weeks beginning 24h or 7 days post-tMCAO. Motor and sensorimotor functions were measured prior to MCAO and at 1, 2, 3 and 4 weeks post-stroke using locomotion analysis and adhesion removal test. Cognitive function was also assessed with Barnes maze test at 4 weeks post-stroke. Neurogenesis and axonal sprouting was evaluated using genetic labeling and immunohistochemical analysis. Results: Our results show that continuous ISP treatment starting at 24 hours post stroke improves both survival and long-term functional recovery after stroke and 7 day post-stroke treatment improves the functional recovery. Correlated with the improved behavior measurements, immunohistochemical analysis revealed that post-stroke ISP treatment increased the total number of newly generated neuroblast cells migrating towards the peri-infarct area as well as a robust sprouting/regeneration of serotonergic axons around the stroke peri-infarct area. Conclusions: Our data suggest that inhibition of PTP σ/CSPGs signaling by ISP stimulates functional recovery after stroke via promoting neuroblast migration and axonal growth. Pharmacological targeting of the PTP σ/CSPGs interaction is therefore a potential novel therapeutic strategy for stroke treatment, which may provide a prolonged treatment window for improving functional recovery after stroke.
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