Exendin-4 (Ex-4) is an incretin mimetic agent approved for diabetes treatment and neuronal protection. However, the required frequent injections restrict its clinical application. We prepared Ex-4-loaded poly(d,l-lactide-co-glycolide) nanoparticles (PEx-4) and investigated their effect on cerebral ischemia/reperfusion (IR) injury associated with micturition center damage-induced cystopathy in diabetic rats. Using ten minutes of bilateral carotid artery occlusion combined with hemorrhage-induced hypotension of the IR model in streptozotocin-induced type 1 diabetic (T1DM) Wistar rats, we compared the effects of Ex-4 and PEx-4 on prefrontal cortex edema, voiding function and oxidative stress including cerebral spinal fluid (CSF) reference H2O2 (RH2O2) and HOCl (RHOCl) levels, endoplasmic reticulum (ER) stress, apoptosis, autophagy and pyroptosis signaling in brain and bladder by Western blot and immunohistochemistry. Single injection of PEx-4 displayed higher CSF antioxidant activity and a long-lasting hypoglycemic effect compared to Ex-4 in rats. T1DM and IR primarily enhanced CSF RH2O2, and pIRE-1/caspase-12/pJNK/CHOP-mediated ER stress, caspase-3/PARP-mediated apoptosis, Beclin-1/LC3B-mediated autophagy and caspase-1/IL-1β-mediated pyroptosis signaling in the damaged brains. Our data further evidenced that PEx-4 were more efficient than Ex-4 in attenuating IR-evoked prefrontal cortex edema, the impairment in micturition center and the enhanced level of CSF RH2O2 and HOCl, ER stress, apoptosis, autophagy and pyroptosis parameters in the damaged brains, but had less of an effect on IR-induced voiding dysfunction in bladders of T1DM rats. In summary, PEx-4 with stronger antioxidant activity and long-lasting bioavailability may efficiently confer therapeutic efficacy to ameliorate IR-evoked brain damage through the inhibitory action on oxidative stress, ER stress, apoptosis, autophagy and pyroptosis signaling in diabetic rats.
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