Alexander E. Merkler, MD

Kuroki T, Tanaka R, Shimada Y, Yamashiro K, Ueno Y, Shimura H, et al. Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice. Stroke. 2016


Hyperglycemia exacerbates acute brain injury and leads to worse outcomes in patients with ischemic stroke. In animal models of acute ischemic stroke, hyperglycemia is associated with increased infarct volume, increased blood-brain–barrier permeability, and hemorrhagic transformation. In order to avoid hyperlgycemia-induced brain injury, normoglycemia is recommended, and typically attained via use of insulin. Unfortunately, up to now, insulin has failed to show improvement in short-term outcomes in human studies and hypoglycemia, a not uncommon consequence of exogenous insulin is associated with further brain injury.[1] Exendin-4 is an agonist of Glucagon-like peptide-1 (a hormone secreted by the small intestines) that mitigates hyperglycemia in diabetes and has a low risk of hypoglycemia. In addition, exendin-4 has shown been shown to reduce oxidative stress and inflammation.

In the current article by Dr. Kuroki et al, the authors assess the protective effect of exendin-4 in a murine model of transient hyperglycemia in acute ischemic stroke using middle cerebral artery occlusion (MCAO). All mice underwent a 60 minute MCAO and were randomly assigned to four groups: 1) Transient hyperglycemia, 2) Transient hyperglycemia treated with insulin, 3) Transient hyperglycemia treated with exendin-4, or 4) control (no hyperglycemia). Histopathological evaluation was performed at 24 hours and 7 days after ischemic stroke.

Consistent with prior data, mice with induced hyperglycemia had significantly increased infarct volume, brain edema, and hemorrhagic transformation as compared with the control. In addition, hyperglycemia was associated with an increase in blood-brain-barrier disruption, more activation of matrix metalloproteinase-9, and a higher degree of neutrophilic infiltration in infracted tissue. Mice treated with Exendin-4, but not insulin, had attenuated levels of matrix metalloproteinase-9, decreased levels of TNF-α, and decreased neutrophilic infiltration. Furthermore, mice treated with Exendin-4 had significantly less total infarct volume at 24h and at 7 days after ischemic injury as compared to not only the control group, but also the insulin treated group. Finally, hyperglycemia decreased 7-day survival and the mice treated with Exendin-4, but not insulin had an improved survival rate.
Hyperglycemia is common in patients with ischemic stroke and leads to increased blood-brain-barrier disruption, increased inflammation, increased stroke volume, increased hemorrhagic transformation, and overall worse outcomes. Treatment of hyperglycemia in acute stroke is paramount, but by how much and by what mechanism is yet to be determined. Exendin-4 shows promise as a neuroprotective agent that can lower glucose levels and improve outcomes in acute ischemic stroke.