Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 Ameliorates
Stroke-Induced Brain and Bladder Injury in Type I Diabetic Rats
Abstract
Background and Purpose: The risk for stroke is higher in patients with
diabetes by hyperglycemia induced oxidative stress and is commonly
associated with diabetic cystopathy. We hypothesized glucagon-like
peptide-1 receptor agonist exendin-4 (Ex-4) with hypoglycemic effect and
neuroprotection may attenuate global cerebral ischemia (IR) induced
brain and bladder injury in diabetic rats. Experimental Approach: Ten
minutes of bilateral carotid artery occlusion combined with
hemorrhage-induced hypotension (30 mmHg) (IR) was induced in female
Wistar rats with streptozotocin-induced type I diabetes. Prefrontal
cortex edema was evaluated by T2-weighted magnetic resonance. Voiding
function was determined by a transcystometry. Endoplasmic reticulum (ER)
stress, apoptosis, autophagy and pyroptosis were determined by western
blot and immunohistochemistry. Key Results: Diabetes increased the
levels of ER stress associated proteins including pIRE-1, cleaved
caspase-12, pJNK, ATF4, ATF6 and CHOP, apoptosis associated caspase 3
and PARP proteins expression, autophagy associated proteins Beclin-1 and
LC3-II proteins expression and pyroptosis associated caspase 1 and IL-1β
proteins expression in the prefrontal cortex and bladders. IR led to a
significantly prefrontal cortex edema and voiding dysfunction and
further enhanced ER stress, apoptosis, autophagy and pyroptosis in brain
and bladder of the diabetic rats. Diabetes thickened the lamina propria
layers and increased bladder Masson’s trichrome stain. Intraperitoneal
Ex-4 treatment significantly attenuated prefrontal cortex edema, ER
stress, apoptosis, autophagy and pyroptosis in brains and bladders and
improved bladder dysfunction. Conclusion and Implications: Glucagon-like
peptide-1 receptor agonist Ex-4 ameliorates stroke-induced brain injury
and bladder dysfunction in diabetic rats through inhibiting ER stress,
apoptosis, autophagy and pyroptosis signaling.