Regulating the Impact of Hypertension on Stroke: Therapeutic Potential of a Peptide Mimetic of Tyrosine Phosphatase STEP.

Abstract

BACKGROUND: In spite of the advances in understanding the pathophysiology of stroke, successful treatment remains a major challenge. The lack of consideration of preclinical studies with associated comorbidities is a primary factor for the translational failure, as ~94% of patients with stroke have ≥1 preexisting comorbidities. Because hypertension is the most common comorbid condition in patients with stroke and predisposition to hypertension is known to worsen stroke outcome, we evaluated the efficacy of a novel neuroprotective peptide derived from the brain-enriched and neuron-specific tyrosine phosphatase striatal enriched phosphatase (STEP) in attenuating ischemic brain damage under hypertensive conditions. METHODS: Mild ischemic insult was induced in hypertensive rats by middle cerebral artery occlusion for 60 minutes followed by reperfusion for 30 days. In a subset of hypertensive rats, the STEP-mimetic peptide (STEP-peptide) was administered intravenously 6 hours after the onset of the insult. Magnetic resonance imaging scans of the brain were done 1, 7, and 28 days after the insult to assess temporal evolution of ischemic brain damage. Behavioral studies were performed weekly starting 7 days after the onset of the insult. Histopathological staining of brain sections was done 30 days later. RESULTS: The results show that delayed treatment with a single intravenous administration of the STEP-peptide 6 hours after the onset of the insult reduces mortality rate. In the surviving rats, T2-weighted imaging, and diffusion tensor imaging of the brain on post-stroke days 1, 7, and 28 show significant reduction in infarct size and improvement of structural integrity within the infarcted area following treatment. Furthermore, behavioral studies show significant improvement in motor coordination, sensory motor function, and spatial memory over time. CONCLUSIONS: The efficacy of the novel STEP-peptide in mitigating brain damage and improving functional recovery in a preclinical stroke model of hypertension holds promise for the development of potential strategies to treat acute ischemic stroke in the population with hypertension.