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Urolithin A-activated Autophagy but Not Mitophagy Protects Against Ischemic Neuronal Injury by Inhibiting ER Stress in Vitro and in Vivo

Urolithin A-activated Autophagy but Not Mitophagy Protects Against Ischemic Neuronal Injury by Inhibiting ER Stress in Vitro and in Vivo

Anil Ahsan, Yan-Rong Zheng, Xiao-Li Wu, Wei-Dong Tang, Meng-Ru Liu, Shi-Jia Ma, Lei Jiang, Wei-Wei Hu, Xiang-Nan Zhang, Zhong Chen

CNS Neurosci Ther. 2019 Sep;25(9):976-986.

PMID: 30972969

Abstract:

Aim:
Mitochondrial autophagy (mitophagy) clears damaged mitochondria and attenuates ischemic neuronal injury. Urolithin A (Uro-A) activates mitophagy in mammal cells and Caenorhabditis elegans. We explored neuroprotection of Uro-A against ischemic neuronal injury.
Methods:
Mice were subjected to middle cerebral artery occlusion. The brain infarct and neurological deficit scores were measured. The N2a cells and primary cultured mice cortical neurons were subjected to oxygen-glucose deprivation and reperfusion (OGD/R). Uro-A was incubated during OGD/R, and cell injury was determined by MTT and LDH. Autophagosomes were visualized by transfecting mCherry-microtubule-associated protein 1 light chain 3 (LC3). The protein levels of LC3-II, p62, Translocase Of Inner Mitochondrial Membrane 23 (TIMM23), and cytochrome c oxidase subunit 4 isoform 1 (COX4I1) were detected by Western blot. The ER stress markers, activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), were determined by reverse transcription-polymerase chain reaction (RT-PCR).
Results:
Urolithin A alleviated OGD/R-induced injury in N2a cells and neurons and reduced ischemic brain injury in mice. Uro-A reinforced ischemia-induced autophagy. Furthermore, Uro-A-conferred protection was abolished by 3-methyladenine, suggesting the requirement of autophagy for neuroprotection. However, mitophagy was not further activated by Uro-A. Instead, Uro-A attenuated OGD/R-induced ER stress, which was abolished by 3-methyladenosine. Additionally, neuroprotection was reversed by ER stress inducer.
Conclusion:
Urolithin A protected against ischemic neuronal injury by reinforcing autophagy rather than mitophagy. Autophagy activation by Uro-A attenuated ischemic neuronal death by suppressing ER stress.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1143700	Urolithin A		1143-70-0	Price

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