Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats

Fang, Yuanjian; Shi, Hui; Huang, Lei; Ren, Reng; Lenahan, Cameron; Xiao, Jie; Liu, Yu; Li, Rui; Sanghavi, Rajvee; Li, Chenguang; Chen, Sheng; Tang, Jiping; Yu, Jun; Zhang, Junyi; Zhang, Jianmin

doi:10.1016/j.freeradbiomed.2021.08.011

Cited by 13 publications

(8 citation statements)

References 40 publications

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“…Accumulating evidence manifested that damaged mitochondria-mediated oxidative stress is closely related to the mechanism of EBI after SAH [ 37 , 38 ]. Specifically, mitochondrial dysfunction caused by SAH leads to the overplus of ROS, resulting in oxidative stress injury [ 7 ] and ultimately activation of the apoptotic signaling pathway [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats

Liu

Tian

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background and Purpose. Oxidative stress plays a pivotal role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). The CB1R agonist ACEA has been reported to have a neuroprotective effect in many central nervous system diseases. Our study was aimed at exploring the effect and mechanism of ACEA in an experimental SAH model. Method. Endovascular perforation was performed to establish a SAH model of rats. ACEA was administered intraperitoneally 1 h after SAH. The CB1R antagonist AM251 was injected intraperitoneally 1 h before SAH induction. Adenoassociated virus- (AAV-) Nrf1 shRNA was infused into the lateral ventricle 3 weeks before SAH induction. Neurological tests, immunofluorescence, DHE, TUNEL, Nissl staining, transmission electron microscopy (TEM), and Western blot were performed. Results. The expression of CB1R, Nrf1, PINK1, Parkin, and LC3II increased and peaked at 24 h after SAH. ACEA treatment exhibited the antioxidative stress and antiapoptosis effects after SAH. In addition, ACEA treatment increased the expression of Nrf1, PINK1, Parkin, LC3II, and Bcl-xl but repressed the expression of Romo-1, Bax, and cleaved caspase-3. Moreover, the TEM results demonstrated that ACEA promoted the formation of mitophagosome and maintained the normal mitochondrial morphology of neurons. The protective effect of ACEA was reversed by AM251 and Nrf1 shRNA, respectively. Conclusions. This study demonstrated that ACEA alleviated oxidative stress and neurological dysfunction by promoting mitophagy after SAH, at least in part via the CB1R/Nrf1/PINK1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats

Liu

Tian

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The primary cortical neuron culture was prepared from fetal (E17) Sprague Dawley rats, as previously reported. 19 Briefly, fetal rats were euthanized under deep anesthesia, and brain cortex was dissected. Cortex tissues were collected and lysed.…”

Section: Methodsmentioning

confidence: 99%

UDP-Glucose/P2Y14 Receptor Signaling Exacerbates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats

Kanamaru,

Zhu,

Dong

et al. 2024

Stroke

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BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe subtype of stroke with poor outcomes. Abnormal glucose metabolism often occurs after SAH, but the strict control of blood glucose levels is not always beneficial. This study aimed to investigate the contribution of uridine diphosphate glucose (UDP-G), an intermediate of glucose/glycogen metabolism, and its receptor P2Y14 (P2Y purinoceptor 14) to SAH pathology and explored the potential targeted treatments in rats. METHODS: A total of 218 Sprague-Dawley male rats were used. SAH was induced by endovascular perforation. Brain expressions of P2Y14, uridine diphosphate glucose (UDP-G), and its converting enzyme UGP2 (UDP-G pyrophosphorylase-2) were evaluated. Exogenous UDP-G or selective P2Y14 inhibitor was administered intranasally at 1 hour after SAH to explore their potential effects. Intranasal Ugp2 or P2ry14 siRNA was delivered 24 hours before SAH for mechanistic evaluation. Primary neuron culture and hemoglobin stimulation were used as in vitro model of SAH. Post-SAH evaluation included liquid chromatography-mass spectrometry measurement of brain endogenous UDP-G level, neurobehavioral assessments, Western blotting, immunohistochemistry, TUNEL staining, and Nissl staining. RESULTS: There was an acute elevation of endogenous brain UDP-G and UGP2 after SAH, and P2Y14 was expressed in neurons. Although P2Y14 inhibitor decreased neurological dysfunction, neuronal apoptosis, and proapoptotic molecules, exogenous UDP-G exacerbated these outcomes at 24 hours after SAH. Early inhibition of P2Y14 preserved long-term neuronal survival in the hippocampus, amygdala, and cortex with improved neurocognition and depressive-like behavior. In addition, in vivo knockdown of Ugp2 - and P2ry14 -reduced neurological deficits and proapoptotic molecules at 24 hours after SAH, and furthermore in vitro knockdown of P2ry14 -reduced apoptosis in hemoglobin stimulated primary neuron. CONCLUSIONS: These findings suggest a detrimental role of brain UDP-G/P2Y14 signaling in SAH, as a part of glucose metabolic pathology at the tissue level. P2Y14 inhibitor 4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid hydrochloride may serve as a potential therapeutic target in treating patients with SAH.

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“…In a SAH rat model, heat shock protein 22 (hsp22) exerts neuroprotective effects by rescuing mitochondrial function in an AMPK‐PGC1α‐dependent manner and also regulates TFAM/Nrf1‐induced mitochondrial biogenesis and DRP1‐triggered mitochondrial apoptosis, further reducing oxidative stress and brain injury 117 . Fang et al demonstrated that PACAP can reduce mitochondria‐mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage by knocking out the pituitary adenylate cyclase‐activating polypeptide (PACAP) gene and adding exogenous PACAP38 in rat SAH model 118 . Zhang et al demonstrated that puerarin not only inhibited SAH‐induced ROS production but also increased SOD activation after SAH in the mouse SAH model 119 …”

Section: Related Antioxidant Strategies For Sah Treatmentmentioning

confidence: 99%

Connection between oxidative stress and subcellular organelle in subarachnoid hemorrhage: Novel mechanisms and therapeutic implications

Zhang,

Wang

et al. 2023

CNS Neurosci Ther

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Spontaneous subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke, with limited treatment modalities and poor patient outcomes. Previous studies have proposed multiple prognostic factors; however, relative research on treatment has not yet yielded favorable clinical outcomes. Moreover, recent studies have suggested that early brain injury (EBI) occurring within 72 h after SAH may contribute to its poor clinical outcomes. Oxidative stress is recognized as one of the main mechanisms of EBI, which causes damage to various subcellular organelles, including the mitochondria, nucleus, endoplasmic reticulum (ER), and lysosomes. This could lead to significant impairment of numerous cellular functions, such as energy supply, protein synthesis, and autophagy, which may directly contribute to the development of EBI and poor long‐term prognostic outcomes. In this review, the mechanisms underlying the connection between oxidative stress and subcellular organelles after SAH are discussed, and promising therapeutic options based on these mechanisms are summarized.

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Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats

Cited by 13 publications

References 40 publications

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats

UDP-Glucose/P2Y14 Receptor Signaling Exacerbates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats

Connection between oxidative stress and subcellular organelle in subarachnoid hemorrhage: Novel mechanisms and therapeutic implications

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