The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo

Abstract

Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen-glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.

The Essential Oil from Acori Tatarinowii Rhizome (the Dried Rhizome of Acorus tatarinowii Schott) Prevents Hydrogen Peroxide‐Induced Cell Injury in PC12 Cells: A Signaling Triggered by CREB/PGC‐1α Activation

“…It was determined that the pretreatment time of ATEO for cytoprotection was 48 h (Supplementary Figure 2). Similar results were observed in pretreatment of ZLN005 (2 μM), a PGC-1α activator with known antioxidant capability [26]. Additionally, ATEOtreated cultures did not show abnormal nuclear morphology in PC12 cells (Figure 2(c)), which was consistent with the finding in safe concentration range.…”

“…In this study, the cellular mechanism of ATEO against oxidative stress was investigated. PC12 cells were selected as the cell model due to their phenotypic characteristics of sympathetic neurons [25,26]. We evaluated whether ATEO had a beneficial effect on H 2 O 2 -stressed PC12 cells, including a PGC-1α-mediated increase of cell viability, decrease of ROS level, and upregulation of antioxidant protein expression.…”

3-<em>n</em>-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke

“…25,26 Multiple studies have shown that OGD-induced neuronal oxidative damage can be significantly attenuated by activating the Nrf2/HO-1 pathway. [27][28][29] AMPK regulates cellular energy metabolism, and its activation helps bring metabolic processes into balance. AMPK activates the Nrf2/ HO-1 signaling axis, suggesting tight cooperation between signaling pathways controlling cellular redox and energy homeostasis.…”

PGC‐1α, a potential therapeutic target against kidney aging

“…ZLN005 regulates PGC‐1α transcription through muscle cell‐specific transcription factors such as MEF2 and improves insulin resistance and dyslipidemia in db/db diabetic mice (Zhang, Shao, et al, ; Zhang, Zhou, et al, ). Additionally, ZLN005 exhibits neuroprotective and retinoprotective effects in mice (Satish, Philipose, Rosales, & Saint‐Geniez, ; Xu et al, ). However, the cardioprotective effect of ZLN005 is dependent on SIRT1 but not PGC‐1α activation (Li et al, ).…”