Abstract
Type 2 diabetes (T2D) hampers recovery after stroke, but the underling mechanisms are mostly unknown. In a recently published study (Pintana et al. in Clin Sci (Lond) 133(13):1367–1386, 2019), we showed that impaired recovery in T2D was associated with persistent atrophy of parvalbumin+ interneurons in the damaged striatum. In the current work, which is an extension of the abovementioned study, we investigated whether somatostatin (SOM)+ interneurons are also affected by T2D during the stroke recovery phase. C57Bl/6j mice were fed with high-fat diet or standard diet (SD) for 12 months and subjected to 30-min transient middle cerebral artery occlusion (tMCAO). SOM+ cell number/density in the striatum was assessed by immunohistochemistry 2 and 6 weeks after tMCAO in peri-infarct and infarct areas. This was possible by establishing a computer-based quantification method that compensates the post-stroke tissue deformation and the irregular cell distribution. SOM+ interneurons largely survived the stroke as seen at 2 weeks. Remarkably, 6 weeks after stroke, the number of SOM+ interneurons increased (vs. contralateral striatum) in SD-fed mice in both peri-infarct and infarct areas. However, this increase did not result from neurogenesis. T2D completely abolished this effect specifically in the in the infarct area. The results suggest that the up-regulation of SOM expression in the post-stroke phase could be related to neurological recovery and T2D could inhibit this process. We also present a new and precise method for cell counting in the stroke-damaged striatum that allows to reveal accurate, area-related effects of stroke on cell number.
Highlights
Type 2 Diabetes (T2D), a major risk factor for stroke, dramatically hampers neurological recovery in the surviving patients (Jorgensen et al 1994; Baird et al 2002; Megherbi et al 2003) and is a strong predictor of persistent dependency on assistance in activities of daily living (ADL)1 3 Vol.:(0123456789)Cellular and Molecular Neurobiology (2021) 41:591–603(Ullberg et al 2015)
We showed that the neurological impairment after stroke in high-fat diet (HFD)-fed mice was similar to healthy, standard diet (SD)-fed mice at 2 weeks after transient middle cerebral artery occlusion (tMCAO) (Pintana et al 2019)
Similar results were obtained when assessing Neuropeptide Y (NPY)+ cells or SOM+/NPY+ co-staining cells (Fig. 2e, f). This increase of SOM+ in SD-fed mice appears to occur in the ischemia injured hemisphere, and not because of a change of SOM+ cells in contralateral striatum, as no differences were detected in cell number between sham brains and contralateral hemispheres (Fig. S2)
Summary
Type 2 Diabetes (T2D), a major risk factor for stroke, dramatically hampers neurological recovery in the surviving patients (Jorgensen et al 1994; Baird et al 2002; Megherbi et al 2003) and is a strong predictor of persistent dependency on assistance in activities of daily living (ADL)1 3 Vol.:(0123456789)Cellular and Molecular Neurobiology (2021) 41:591–603(Ullberg et al 2015). There are several possible mechanisms wherein diabetes leads to stroke. These include vascular endothelial dysfunction, increased early-age arterial stiffness, systemic inflammation and thickening of the capillary basal membrane (Chen et al 2016). Impaired neurological recovery in T2D cannot be explained by only more severe brain damage after stroke (Sweetnam et al 2012; Tulsulkar et al 2016; Dhungana et al 2013) and several mechanisms including impaired vascular restoration (Ergul et al 2015), increased inflammation (Dhungana et al 2013) and impaired stroke-induced neurogenesis (Zhang et al 2016; Pintana et al 2019) have been proposed. We recently showed that impaired stroke recovery in T2D may be associated with increased atrophy of striatal GABA-ergic parvalbumin (PV)+ interneurons (Pintana et al 2019), suggesting diminished neuroplasticity in striatum
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