Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats
Free Radical Biology and Medicine
Mitochondria-mediated oxidative stress and neuronal apoptosis play an important role in early brain injury following subarachnoid hemorrhage (SAH). Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce oxidative stress and cellular apoptosis by maintaining mitochondrial function under stress. The objective of this study is to investigate the effects of PACAP on mitochondria dysfunction - induced oxidative stress and neuronal apoptosis in both vivo and vitro models of SAH. PACAP Knockout CRISPR and exogenous PACAP38 were used to verify the neuroprotective effects of PACAP in rats after endovascular perforation - induced SAH as well as in primary neuron culture after hemoglobin stimulation. The results showed that endogenous PACAP knockout aggravated mitochondria dysfunction - mediated ATP reduction, reactive oxygen species accumulation and neuronal apoptosis in ipsilateral hemisphere at 24 h after SAH in rats. The exogenous PACAP38 treatment provided both short- and long-term neurological benefits by attenuating mitochondria - mediated oxidative stress and neuronal apoptosis after SAH in rats. Consistently, the exogenous PACAP38 treatment presented similar neuroprotection in the primary neuron culture after hemoglobin stimulation. Pharmacological inhibition of adenylyl cyclase (AC) or extracellular signal-regulated kinase (ERK) partly abolished the anti-oxidative stress and anti-apoptotic effects provided by PACAP38 treatment after the experimental SAH both in vivo and in vitro, suggesting the involvement of the AC-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and ERK pathway. Collectively, PACAP38 may serve as a promising treatment strategy for alleviating early brain injury after SAH.
Fang, Yuanjian; Shi, Hui; Huang, Lei; Ren, Reng; Lenahan, Cameron; Xiao, Jie; Liu, Yu; Liu, Rui; Sanghavi, Rajvee; Li, Chenguang; Chen, Sheng; Tang, Jiping; Yu, Jun; Zhang, John H.; and Zhang, Jianmin, "Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats" (2021). LLU Faculty Publications. 271.