Overexpression of PGC-1α reduces inflammation and protects against focal cerebral ischaemia/reperfusion injury

Abstract

Introduction: Cerebral ischaemia and subsequent reperfusion can cause brain damage. Herein we investigate the impact of PGC-1α expression following I/R injury with overexpressed PGC-1α versus wild-type mice. Material and methods: Focal cerebral I/R was performed in the wild-type and transgenic mouse models. In both mouse groups we evaluated the redox status by measuring reactive oxygen species (ROS) content, infarct volumes, neurological scoring, protein (western blot analysis), and cytokine (enzyme-linked immunosorbent assay) expression. Results: The results showed that PGC-1α expression was significantly down-regulated in I/R injury compared to the sham mice. I/R injury increased ROS levels and further up-regulated apoptosis. PGC-1α-overexpressed mice down-regulated I/R injury-induced neurological deficit scores and infarct volume. In addition, compared to WT mice during I/R injury, PGC-1α-overexpressed mice significantly down-regulated inflammatory proteins (NF-kB, COX-2, NLRP3) and cytokine (TNF-α, IL-1β, IL-6) expressions. I/R injured mice showed severe decline in Nrf-2, HO-1, and NQO1 expressions. Conclusions: Importantly, PGC-1α/Nrf-2 suppression during cerebral I/R injury causes overall brain damage through increased oxidative stress, neuro-inflammation, and apoptosis. PGC-1α-overexpressed mice promoted cytoprotection through Nrf-2 regulation during cerebral ischaemia/reperfusion (I/R) injury. Thus, PGC-1α overexpression leads to lesser injury following ischaemia, thereby preserving mitochondrial activity. PGC-1α might act as therapeutic target protein and thereby protect against cerebral damage during I/R injury.

Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium

“…NRF1 and EER-alpha both play key roles in mediating mitochondrial biogenesis and oxidative metabolism [ 23 , 32 ]. Alongside NRF2, these transcription mediators are activated by PGC1-alpha and not only increase mitochondrial protein synthesis but also have numerous effects on oxidative stress and inflammation by reducing reactive oxygen species (ROS), stimulating the release of antioxidants, and suppressing the proinflammatory nuclear factor kappa B (NF-κB) signaling pathway ( Figure 2 ) [ 26 , 33 , 34 ].…”