Caspase-3 Modulates Regenerative Response After Stroke

Abstract

Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently, however, accumulating data indicate that caspase-3 also participates in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its selfrenewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke. STEM CELLS 2014;32:473-486

Old, new and emerging functions of caspases

“…85 Furthermore, in a mouse model of stroke, cleaved caspase-3 levels were increased in neuronal precursor cells (NPCs) during stroke recovery, without any associated increase in apoptosis. 86 Inhibition of caspase-3 activity significantly promoted the proliferation and migration of NPCs indicating that caspase-3 limits selfrenewal capacity of regenerating neurons. Mechanistically, this was attributed to the ability of caspase-3 to reduce phosphorylation of Akt.…”

“…Mechanistically, this was attributed to the ability of caspase-3 to reduce phosphorylation of Akt. 86 Differentiation of muscle progenitor cells into myotubes and myofibres also requires caspase-3. 87 Later studies demonstrated the involvement of caspase-9 in this process.…”

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

“…In this regard, selectins and CAMs are the most relevant molecules involved in the adhesion process (Stanimirovic and Satoh 2000;Wang et al 2007;Petri et al 2008). In an attempt to estimate the role of neuroinflammation in apoptosis, we used the effector cleaved caspase-3, which is considered the main marker in apoptosis (He et al 2006;Wang et al 2013;Fan et al 2014). …”

5,7-Dimethoxycoumarin inhibits neuronal apoptosis by targeting caspase-3 expression in rats with acute cerebral infarction

“…It is reported that during cerebral infarction in animals the rate of neuronal apoptosis is very high [6]. One of the important factors expressed in higher level and associated with the induction of neuronal apoptosis is the caspases [7][8][9]. In the brain tissue samples of cerebral infarction patients the expression of caspase-3 has been found to be markedly higher [10].…”