Abstract
The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell–cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase.
Highlights
Stroke is a major cause of death and disability worldwide (Feigin et al, 2020)
Stroke has been reported to drive a neurogenic burst with affects the two adult neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus (Arvidsson et al, 2002; Parent et al, 2002; Parent, 2003; Thored et al, 2006; Kernie and Parent, 2010)
In a longitudinal analysis performed on a mouse model of cortical ischemia by permanent middle cerebral artery occlusion (MCAO) induced by ligature, we found that cortical stroke has a triphasic effect on the total number of cells in proliferation at the SVZ, first with an early acute reduction of proliferation on post-stroke day 1, a second slow increase with a maximum on post-stroke day 14 and, a reduction of proliferating cells at 28 days after ischemia onset
Summary
Stroke is a major cause of death and disability worldwide (Feigin et al, 2020). Clinical interventions to restore blood flow, mechanical or pharmacological clot removal, are the only two therapies currently approved for patient use. An alternative/additional beneficial effect may be derived from the fact that neuroblasts have been described to form new astrocytes that contribute to the formation of the glial scar, to protect neurons from glutamate-induced excitotoxicity or even to release neurotrophic factors that contribute to tissue repair (Arvidsson et al, 2002; Zhang et al, 2004a,b; Thored et al, 2006; Jin et al, 2010; Butti et al, 2012; Wang et al, 2012; Faiz et al, 2015) Consistent with this positive role, post-stroke SVZ neurogenesis inhibition after stroke impedes recovery after ischemia and exacerbates neurological deficits (Jin et al, 2010), whereas transplantation of neural precursor cells causes a neurological improvement indicating that this process participates in post-stroke recovery (Bacigaluppi et al, 2009). These studies will provide insights on the intrinsic regulatory mechanisms controlling NSCs activation upon stroke in both niches and about the type of stimuli that mediates NSCs priming and activation
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