GSK-3β Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery after Intracerebral Hemorrhagic Stroke

Abstract

Hemorrhagic stroke is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3'-oxime (BIO) as a selective glycogen synthase kinase-3β (GSK-3β) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8- to 10-week-old C57BL/6 mice. BIO (8 μg/kg, IP) was administered following either an acute delivery (0-2 h delay) or a prolonged regimen (every 48 h starting at 3 days post-ICH). At 2 days post-ICH, the acute BIO treatment significantly reduced the hematoma volume. In the perihematoma regions, BIO administration blocked GSK-3β phosphorylation/activation, increased Bcl-2 and β-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of β-catenin, upregulated VEGF and BDNF, and promoted neurogenesis and angiogenesis in peri-injury zones at 14 days after ICH. The BIO treatment also promoted proliferation of neural stem cells (NSCs) and migration of nascent DCX+ neuroblasts from the subventricular zone (SVZ) to the lesioned cortex. BIO improved functional outcomes on both the neurological severity score and rotarod tests. The findings of this study corroborate the neuroprotective and regenerative effects of BIO and suggest that the Wnt/GSK-3β/β-catenin pathway may be explored for the treatment of acute or chronic ICH.

Improved trafficking and expression of luminopsins for more efficient optical and pharmacological control of neuronal activity

“…Immunohistochemistry was performed as described before (Zhao et al, ). Mice were sacrificed by CO 2 overdose 35 days after AAV injection.…”

Intranasal wnt3a Attenuates Neuronal Apoptosis through Frz1/PIWIL1a/FOXM1 Pathway in MCAO Rats

“…Convincingly establishing a role for GSK3␤ in stroke pathology, Kelly et al (2004) showed that inhibition of GSK3␤ with CXhir025 in both OGD in vitro and in vivo rat middle cerebral artery occlusion (MCAO) models increased neuronal cell survival. In the intracerebral hemorrhage mouse model, 6-bromoindirubin-3Ј-oxime, a selective GSK-3␤ inhibitor, acutely administered, reduced hematoma volume by attenuating the expression of GSK-3␤ phosphorylation/activation, which increased the viability of neurons and other cell types (Zhao et al, 2017). These findings suggest that the wnt/GSK-3␤/ ␤-catenin pathway may be further explored for treatment in the pathology of stroke.…”

Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries

“…In this regard, the intraperitoneal delivery of 6-BIO, a GSK3β inhibitor, improved neurological functions, reduced brain hematoma volume, and stimulated regeneration after ICH (Zhao et al, 2017). This was attributed to an upregulation of BDNF, which stimulates the proliferation and migration of neuronal progenitors from the SVZ toward the injured zone, thus increasing the number of newborn neurons within in the peri-hematomal brain region (Zhao et al, 2017). 6-BIO also improved angiogenesis by an increase number of BrdU + /GLUT1 + cells in the peri-hematomal zone during the second phase of hemorrhagic stroke (Zhao et al, 2017).…”

“…In both studies, SAH was associated to a deactivation of the canonical Wnt pathway translated by reduced levels of Wnt1, Wnt3a and Fzd1. In this regard, the intraperitoneal delivery of 6-BIO, a GSK3β inhibitor, improved neurological functions, reduced brain hematoma volume, and stimulated regeneration after ICH (Zhao et al, 2017). This was attributed to an upregulation of BDNF, which stimulates the proliferation and migration of neuronal progenitors from the SVZ toward the injured zone, thus increasing the number of newborn neurons within in the peri-hematomal brain region (Zhao et al, 2017).…”

“…This was attributed to an upregulation of BDNF, which stimulates the proliferation and migration of neuronal progenitors from the SVZ toward the injured zone, thus increasing the number of newborn neurons within in the peri-hematomal brain region (Zhao et al, 2017). 6-BIO also improved angiogenesis by an increase number of BrdU + /GLUT1 + cells in the peri-hematomal zone during the second phase of hemorrhagic stroke (Zhao et al, 2017). As mentioned, the expression Dkk1, a potent endogenous inhibitor of the canonical Wnt pathway, increased in the basal ganglia early after ICH (Li Z. et al, 2017), and was expressed essentially in neurons, and microglia (Wang G. et al, 2019).…”