Abstract
Cognitive dysfunction following stroke significantly impacts quality of life and functional independance; yet, despite the prevalence and negative impact of cognitive deficits, post-stroke interventions almost exclusively target motor impairments. As a result, current treatment options are limited in their ability to promote post-stroke cognitive recovery. Cyclosporin A (CsA) has been previously shown to improve post-stroke functional recovery of sensorimotor deficits. Interestingly, CsA is a commonly used immunosuppressant and also acts directly on endogenous neural precursor cells (NPCs) in the neurogenic regions of the brain (the periventricular region and the dentate gyrus). The immunosuppressive and NPC activation effects are mediated by calcineurin-dependent and calcineurin-independent pathways, respectively. To develop a cognitive stroke model, focal bilateral lesions were induced in the medial prefrontal cortex (mPFC) of adult mice using endothelin-1. First, we characterized this stroke model in the acute and chronic phase, using problem-solving and memory-based cognitive tests. mPFC stroke resulted in early and persistent deficits in short-term memory, problem-solving and behavioral flexibility, without affecting anxiety. Second, we investigated the effects of acute and chronic CsA treatment on NPC activation, neuroprotection, and tissue damage. Acute CsA administration post-stroke increased the size of the NPC pool. There was no effect on neurodegeneration or lesion volume. Lastly, we looked at the effects of chronic CsA treatment on cognitive recovery. Long-term CsA administration promoted NPC migration toward the lesion site and rescued cognitive deficits to control levels. This study demonstrates that CsA treatment activates the NPC population, promotes migration of NPCs to the site of injury, and leads to improved cognitive recovery following long-term treatment.
Highlights
Stroke is a leading cause of death and chronic disability
We investigated the efficacy of endogenous neural precursor cells (NPCs) activation using Cyclosporin A (CsA) to promote cognitive recovery following medial prefrontal cortex (mPFC) stroke
Using the Puzzle Box (PB) and morris water maze (MWM) tasks, we demonstrated that mPFC injury resulted in cognitive deficits across various cognitive domains, detectable as early as 4 days and persisting up to 45 days post-stroke, similar to previous findings in rats (Cordova et al, 2014; Livingston-Thomas et al, 2015)
Summary
Prevalence of post-stroke cognitive dysfunction can be up to 80% of stroke survivors (Sun et al, 2014), including impairments in learning and memory and deficits in executive functions (Zinn et al, 2007; Hofmann et al, 2012; Douiri et al, 2013) Such impairments can persist for years (Poulin et al, 2012) and are associated with higher rates of long-term post-stroke disability (Cumming et al, 2013; Mullick et al, 2015), impacting the quality of life of survivors. It is timely to consider the development of strategies to enhance neural repair for the treatment of post-stroke cognitive deficits
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