Stroke is a lethal disease, but it disables more than it kills. Stroke is the second leading cause of death and the most frequent cause of permanent disability in adults worldwide, with 90% of survivors having residual deficits. The pathophysiology of stroke is complex and involves a strong inflammatory response associated with oxidative stress and activation of several proteolytic enzymes. The current study was designed to investigate the effect of arginase inhibitors (L-citruline and L-ornithine) against ischemic stroke induced in rats by middle cerebral artery occlusion (MCAO). MCAO resulted in alteration in rat behavior, brain infarct, and edema associated with disruption of the blood-brain barrier (BBB). This was mediated through overexpression of arginase I and II, inducible NOS (iNOS), malondialdehyde (MDA), advanced glycation end products (AGEs), TNF-α, and IL-1β and downregulation of endothelial nitric oxide synthase (eNOS). Treatment with L-citruline and L-ornithine and the standard neuroprotective drug cerebrolysin ameliorated all the deleterious effects of stroke. These results indicate the possible use of arginase inhibitors in the treatment of stroke after suitable clinical trials are done.

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Diabetes mellitus is an endocrine disorder that is associated with several microvascular and macrovascular complications in addition to complications within the central nervous system (CNS). Diabetic encephalopathy secondary to chronic hyperglycemia is mediated through oxidative stress, increased advanced glycation end products (AGEs), and impairment in cerebral insulin signaling. The Aim of the work was to investigate whether inhibition of aldose reductase and arginase enzyme can protect against vascular and behavior complications. Diabetes was induced in male wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg). Eight weeks later, diabetic rats were orally treated with ferulic acid (20 mg/kg), cinnamaldehyde (20 mg/kg), norvalline (50 mg/kg), ornithine (200 mg/kg) and citrulline (50 mg/kg) every day for 8 weeks. Body weight, blood glucose, serum AGEs level, blood pressure and behavioral change in memory and cognition were investigated at the end of the study. Streptozotocin caused a state of hyperglycemia associated with both vascular and behavioral complications as evidenced by the elevation in blood pressure and reduction in the Y-maze score and elevation in the transfer latency in the elevated plus maze. Blockade of aldose reductase and arginase enzyme ameliorated some of these complications without exerting any hypoglycemic effect. These results suggest the possible effectiveness of aldose reductase and arginase inhibitors in the management of diabetic vascular and behavioral complications together with conventional antidiabetic therapy.