Activation of LRP6 with HLY78 Attenuates Oxidative Stress and Neuronal Apoptosis via GSK3β/Sirt1/PGC-1α Pathway after ICH

Abstract

Background. Oxidative stress and neuronal apoptosis have important roles in the pathogenesis after intracerebral hemorrhage (ICH). Previous studies have reported that low-density lipoprotein receptor-related protein 6 (LRP6) exerts neuroprotection in several neurological diseases. Herein, we investigate the role of LRP6 receptor activation with HLY78 to attenuate oxidative stress and neuronal apoptosis after ICH, as well as the underlying mechanism. Methods. A total of 199 CD1 mice were used. ICH was induced via injection of autologous blood into the right basal ganglia. HLY78 was administered via intranasal injection at 1 h after ICH. To explore the underlying mechanism, LRP6 siRNA and selisistat, a Sirt1 selective antagonist, were injected intracerebroventricularly at 48 h before ICH induction. Neurobehavioral tests, Western blot, and immunofluorescence staining were performed. Results. The expression of endogenous p-LRP6 was gradually increased and expressed on neurons after ICH. HLY78 significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased oxidative stress and neuronal apoptosis, as well as increased expression of p-GSK3β, Sirt1, and PGC-1α, as well as downregulation of Romo-1 and C-Caspase-3. LRP6 knockdown or Sirt1 inhibition abolished these effects of HLY78 after ICH. Conclusion. Our results suggest that administration of HLY78 attenuated oxidative stress, neuronal apoptosis, and neurobehavioral impairments through the LRP6/GSK3β/Sirt1/PGC-1α signaling pathway after ICH.

Curculigoside Attenuates Endoplasmic Reticulum Stress-Induced Epithelial Cell and Fibroblast Senescence by Regulating the SIRT1-P300 Signaling Pathway

“…Additionally, the SIRT1-P300 signaling pathway has been reported to alter the acetylation levels of GSK3β, thereby regulating its activity [75,76]. Moreover, the phosphorylation level of GSK3β is regulated by SIRT1 [77]. Therefore, further experimental research is needed to elucidate the upstream and downstream relationships between CCG-mediated GSK3β and the SIRT1-P300 signaling pathway.…”

The Critical Role of Sirt1 in Subarachnoid Hemorrhages: Mechanism and Therapeutic Considerations

“…Furthermore, it is noticeable that the NAD+/NADH ratio plays a pivotal role in the regulation of mitochondrial biogenesis. In response to NAD+, Sirt1 deacetylates multiple lysine residues in PGC-1α, thus leading to its activation [ 88 ]. Resveratrol, an activator of Sirt1, reduced mitochondrial dysfunction-induced oxidative stress following a SAH by improving mitochondrial biogenesis via the PGC-1α pathway [ 89 ].…”

Natural Compounds for SIRT1-Mediated Oxidative Stress and Neuroinflammation in Stroke: A Potential Therapeutic Target in the Future

“…As a novel lycorine derivative, HLY78 has shown antiapoptotic effects in tumors, ICH, and SAH [ 146 , 147 , 148 ]. After intranasal administration of HLY78 1 hour after ICH, it reduced oxidative stress and the extent of neuronal damage in the perihematomal region.…”

“…Therefore, HLY78 may prove to be an effective drug for the treatment of ICH. Additionally, GSK3β/Sirt1/PGC-1α signaling was partially involved in the antiapoptotic and antioxidative effects [148]. 7 Oxidative Medicine and Cellular Longevity 3.1.2.…”