Overexpressing glyoxalase 1 attenuates acute hyperglycemia-exacerbated neurological deficits of ischemic stroke in mice

Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However; intensive controlling of blood glucose by using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1); a detoxifying enzyme of glycotoxins; on acute hyperglycemia-aggravated ischemic brain injury. In the present study; adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins; ER stress formation; and caspase 3/7 activation in MG-treated Neuro-2A cells; and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen; a potent GLO1 stimulator; after surgery; alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia. Altogether; our data substantiate that; in ischemic brain injury; GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.