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Background: The therapeutic efficacy of stem cell therapy in many diseased organs based greatly on their paracrine effect. The neural stem cells are thought to have a role in improving the neurological functional, recovery, and reduction of cerebral infarction caused by cerebral ischemia/ reperfusion [I/R] injury in rats.Objective: This study was conducted to look at the histological alterations in the rat cerebral cortex after ischemia-reperfusion [I/R] injury and to assess any potential neuroprotective effects of neural stem cells conditioned media [NSC-CM] on on those changes.Material and Methods: Thirty adult male albino rats weighing about 150 - 250 gm each were used in the present work. The animals were equally divided into 3 groups [10 rats each]. Group A was subdivided into negative control group, A1, [5 rats], not subjected to any intervention, and the sham-control group, A2 [5 rats], the animal of which were subjected to a midline cervical incision with exposure of both common carotid arteries followed by closure of the incision. Group B included rats subjected to brain [I/R] to induce transient global brain ischemia. Group C included rats subjected to I/R injury [as group B] and received 1.5 ml NSC-CM injected slowly through the tail vein at 3 h, 24 h, and 48 h after ischemia onset. Animals were anaesthetized using ether inhalation, the cerebrum was dissected and fixed in 10% neutral buffered formalin and specimens from them were taken and processed for examination by light microscopes.Results: NSC-CM significantly ameliorated neurological defects by reducing cerebral infarct volume, significant inhibition of cell apoptosis in the ischemic cerebral hemisphereConclusion: NSC-CM might be an alternative and effective therapeutic intervention for ischemic stroke.