GSK-3β as a target for protection against transient cerebral ischemia

Abstract

Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke-related brain damage. We showed recently that a glycogen synthase kinase-3β (GSK-3β) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3β inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3β inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood-brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of β-catenin and zonula occludens-1 but decreased β-catenin phosphorylation while suppressing the expression of GSK-3β. These results indicate that GSK-3β inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/β-catenin signaling pathway.

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

“…The Wnt/β-catenin signaling pathway has been considered a potential therapeutic target in preventing cell death for an extensive amount of time [ 18 , 40 , 41 ]. The down-regulation of Wnt ligands and increased antagonistic activity have been observed in neurodegenerative and excitotoxic disorders [ 42 , 43 , 44 ].…”

“…The activity of GSK-3β leads to the degradation of downstream survival markers such as β-catenin through ubiquitination. Furthermore, canonical Wnt signals, which are lipid-modified glycoproteins, have been reported to inactivate GSK-3β through phosphorylation and thereby promote cell survival [ 18 ]. A recent study reported that motor exercise stimulated the canonical Wnt/β-catenin pathway for recovering from focal cerebral ischemic reperfusion injury in juvenile rats.…”

Analgecine inhibits NF-kB to regulate microglia polarization by TLR4 MyD88-dependent and MyD88-independent pathways in ischemic stroke

“…I/RI is a complex pathological process that begins with tissue anoxia and expands with the inflammatory response, which lead to neuronal death [24]. We also found AGC could inhibit the level of pro-inflammatory factors and increase the release of anti-inflammatory cytokines in the serum of MCAO/R-induced rat model.…”

Protective Effects of Rhubarb in Rats with Acute Pancreatitis and the Role of Its Active Compound Rhein on Mitochondria of Exocrine Cells

“…Consistent with our results, a study conducted by Halbrook et al also showed that short-term blockage of AMPK signaling restored exocrine tissue and dramatically reduced fibrosis in established pancreatitis [ 3 ]. Moreover, the PI3K/AKT/mTOR signaling pathway is proven to be correlated with neuroprotection and stimulate cell proliferation [ 32 , 33 ]. Our data demonstrated that rhein upregulated the expression of PI3K, AKT, and mTOR in AR42J cells.…”