Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons

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.

Normalization of glucose metabolism by Exendin-4 in the chronic phase after stroke promotes functional recovery in diabetes

“…The positive effects mediated by Ex-4 in stroke recovery could also be mediated by indirect (via glycemia regulation and normalization of insulin resistance) or direct effects occurring in the brain. Interestingly, we show that Exe-4 treatment reversed T2D-induced PV + interneuron atrophy (42). PV + interneurons play key role in neuronal plasticity and thus could have signi cant effects on neurological recovery after stroke (55,56).…”

“…3a). We have previously shown that shortly (2 weeks) after stroke the soma volume of PV + interneurons is decreased in the peri-infarct region of the striatum and, while in Non-T2D mice the soma volume recovers back to normal within 6 weeks after stroke, this atrophy persists in T2D (42). In the present study, potential differences in stroke-induced atrophy of PV + interneurons were also assessed by measuring the soma volume of these neurons in the contralateral and ipsilateral periinfarct striatum.…”

“…Obvious limitations of the study are the lack of histological assessments at intermediate time-points and the reliance on a well-validated (26,42,77,78), but single behavioral readout. Therefore, we acknowledge that our ndings will have to be con rmed by additional studies.…”

“…Mice were gently dragged backward until the grip was released. Ten trials were performed and the highest value was recorded as described previously (42,45). The grip strength test was performed by an experimenter blinded to the treatment groups (Ex-4 vs. vehicle), but not diet (SD vs. HFD) due to the obvious weight differences during the rst weeks after tMCAO.…”

“…The rst aim of this study was to determine whether a delayed treatment after stroke (starting 3 days post-stroke) with the speci c GLP-1R agonist Exendin-4 (Ex-4) (41) improves neurological recovery in a clinically-relevant mouse model of obesity-induced T2D (26,42). We also investigated whether neurological recovery was associated with improved glucose metabolism during the recovery phase.…”