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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