Abstract
The development of effective drugs for stroke is urgently required as it is the 2nd largest killer in the world and its incidence is likely to increase in the future. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat acute cerebral ischemic stroke. However, the mechanism of ETBR mediated neural regeneration and repair remains elusive. In this study, a permanent middle cerebral artery occluded (MCAO) rat model was used. Sovateltide (an ETBR agonist) injected intravenously showed better survival and neurological and motor function improvement than control. Higher neuronal progenitor cells (NPCs) differentiation along with better mitochondrial morphology and biogenesis in the brain of sovateltide rats were noted. Exposure of cultured NPCs to hypoxia and sovateltide also showed higher NPC differentiation and maturation. This study shows a novel role of ETBR in NPCs and mitochondrial fate determination in cerebral ischemia, and in improving neurological deficit after stroke.
Highlights
The development of effective drugs for stroke is urgently required as it is the 2nd largest killer in the world and its incidence is likely to increase in the future
We demonstrated that selective stimulation of endothelin B receptors (ETBR) by its agonist, IRL-1620 (INN approved by WHO is sovateltide), could significantly improve neurological and motor functions, with concurrent decrease in infarct volume and oxidative stress damage following permanent middle cerebral artery occlusion (MCAO) in r ats[10,11]
We have shown that administration of sovateltide in newborn rat pups increased vascular endothelial growth factor (VEGF) but had no effect on nerve growth factor (NGF) in postnatal developing brains[5]
Summary
The development of effective drugs for stroke is urgently required as it is the 2nd largest killer in the world and its incidence is likely to increase in the future. We have consistently shown in our preclinical studies carried out using MCAO rat m odel[10,11,12,13], that sovateltide treatment helps in restoration of blood flow, modulation of apoptosis and improvement in neurological and motor functions after cerebral ischemic stroke. These observations indicate a role of ETBR in tissue healing after acute ischemic damage in the brain after stroke. We assessed the mitochondrial biogenesis in the stroked brain using in situ PCR technique to detect mitochondrial DNA content in brain tissues
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