Potential role of myo-inositol to improve ischemic stroke outcome in diabetic mouse

Brain edema is one of the critical factors causing hightened disability and mortality in stroke patients, which is exaggerated further in diabetic patients. Organic osmolytes could play a critical role in the maintenance of cytotoxic edema. The present study was aimed to assess the role of myo-inositol, an organic osmolyte, on stroke outcome in diabetic and non-diabetic animals. In situ brain perfusion and acute brain slice methods were used to assess transport of myo-inositol across the blood-brain barrier and uptake by brain cells using non-diabetic (C57BL/6) and diabetic (streptozotocin-induced) mice, respectively. In vitro studies were conducted to assess the role of myo-inositol during and after ischemia utilizing oxygen glucose deprivation (OGD) and reperfusion. Further, the expression of transporters, such as SGLT6, SMIT1 and AQP4 were measured using immunofluorescence. Therapeutic efficacy of myo-inositol was evaluated in a transient middle cerebral artery occlusion (tMCAO) mouse model using non-diabetic (C57BL/6) and diabetic (db/db) mice. Myo-inositol release from and uptake in astrocytes and altered expression of myo-inositol transporters at different OGD timepoints revealed the role of myo-inositol and myo-inositol transporters during ischemia reperfusion. Further, hyperglycemic conditions reduced myo-inositol uptake in astrocytes. Interestingly, in in-vivo tMCAO, infarct and edema ratios following 24 h reperfusion decreased in myo-inositol treated mice. These results were supported by improvement in behavioral outcomes in open-field test, corner test and neurological score in both non-diabetic and db/db animals. Our data suggest that myo-inositol and myo-inositol transporters may provide neuroprotection during/following stroke both in non-diabetic and diabetic conditions.