Abstract
Type 2 diabetes (T2D) hampers stroke recovery though largely undetermined mechanisms. Few preclinical studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 months with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurological recovery by upper-limb grip strength at 1 and 6 weeks after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochemistry (IHC) at 2 and 6 weeks after tMCAO. Obesity/T2D impaired neurological function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 weeks after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 weeks. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 weeks after stroke in both non-diabetic and obese/T2D mice. However, after 6 weeks, this effect selectively persisted in obese/T2D mice. We show in a preclinical setting of clinical relevance that obesity/T2D impairs neurological functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.
Highlights
Stroke is the number one cause of permanent disability and a major social and economic burden [1,2,3]
We show that obesity/Type 2 diabetes (T2D) induced by 12 months of high-fat diet (HFD) feeding dramatically hampers recovery without exacerbating neuronal or white matter injury
We demonstrate that the obesity/T2D-induced impairment of the recovery of forelimb sensorimotor function after stroke correlates with transient changes in the turnover of neural stem cell (NSC) and neuroblasts in striatum and with a dramatic decrease in hippocampal neurogenesis
Summary
Stroke is the number one cause of permanent disability and a major social and economic burden [1,2,3]. The ones employing more physiological and clinically relevant obese/T2D models (induced by high-fat diet (HFD)) have mostly focused on the acute outcome (infarct size and neurological impairment) after stroke and, in the cases with more long-term outcome measures, the increase in the stroke injury was likely a determinant factor for decreased neurological recovery (reviewed in [11]). At present, it is undetermined whether T2D induced by a chronic obesogenic diet affects long-term stroke recovery and if so, whether this effect is related to the impairment of brain’s self-repair mechanisms
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