Normalisation of glucose metabolism by exendin‐4 in the chronic phase after stroke promotes functional recovery in male diabetic mice

Augestad, Ingrid Lovise; Dekens, Doortje; Karampatsi, Dimitra; Elabi, Osama F.; Zabala, Alexander; Pintana, Hiranya; Larsson, Martin; Nyström, Thomas; Paul, Gesine; Darsalia, Vladimer; Patrone, Cesare

doi:10.1111/bph.15524

Cited by 14 publications

(27 citation statements)

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“…After 2-and 4-months of dietary change leading to weight loss, mice were subjected to stroke and functional recovery was tracked over 8 weeks. As reported previously [33,37,43], T2D significantly impaired forepaw grip strength recovery in comparison with age-matched non-T2D mice (p < 0.0001 and p < 0.01 in Study 1 and 2 respectively; Fig. 2g, h, r, s).…”

Section: Long-term Dietary Change Leading To Weight Loss Before Stroke Improves Post-stroke Functional Recovery In Association With the Fsupporting

confidence: 86%

“…Vascular remodelling plays a key role in post-stroke recovery [66]. In a recent study [37], we found a significant increase in striatal vessel density in the peri-infarct region compared to the respective contralateral striatum, in both T2D/Ob and non-T2D mice at 8 weeks post-stroke, indicating a post-stroke angiogenic effect. However, this effect was smaller in the T2D/Ob group.…”

Section: Discussionmentioning

confidence: 60%

“…The angiogenic response to ischemic brain injury correlates with improved functional outcome after stroke, in both rodents and humans [34]. Moreover, there is emerging evidence that T2D impairs this stroke-induced reparative neovascularization process, impeding functional recovery [35][36][37]. Whether pre-stroke weight loss can enhance neurological recovery after stroke by regulating angiogenesis remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke

Karampatsi

Zabala

Wilhelmsson

et al. 2021

Cardiovasc Diabetol

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Background Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms. Methods T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy. Results Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum. Conclusion The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population.

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Section: Long-term Dietary Change Leading To Weight Loss Before Stroke Improves Post-stroke Functional Recovery In Association With the Fsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke

Karampatsi

Zabala

Wilhelmsson

et al. 2021

Cardiovasc Diabetol

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“…Reparative angiogenesis is important for good functional recovery after stroke ( 65 , 66 ) and is associated with an increase in cerebral blood volume and cerebral blood flow ( 67 ). Chronic glucagon-like peptide-1 receptor activation can stimulate angiogenesis and mediate post-stroke functional recovery by improving vascular remodeling in the recovery phase ( 68 ). Diabetic animals showed impaired neovascularization and prominent vascular injury after cerebral ischemia ( 62 , 69 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Diabetes on Post-stroke Recovery: A Systematic Narrative Review

et al. 2021

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Background: Patients with stroke often have comorbid diabetes. Considering its detrimental effects on brain function, diabetes may increase the risk of poor recovery.Methods: The aim of this review was to investigate the effect of diabetes on post-stroke recovery by a systematic review. Several specific aspects of post-stroke recovery, including activities of daily living (ADL), motor, cognitive, and quality of life (QOL) recovery, were examined. We searched the PubMed, SCOPUS, Embase, and Cochrane Library databases for relevant studies on the effect of diabetes on post-stroke recovery, published until May 26, 2021. A total of 52,051 potentially relevant articles were identified. After reading the titles and abstracts and assessing their eligibility based on full-text articles, 34 publications were included in this review.Results: Of 29 studies that assessed ADL recovery after stroke, 22 studies suggested that diabetes had a negative effect on recovery of ADL after stroke. Regarding motor recovery, only one out of four studies showed that diabetes had some effect on motor recovery after stroke. Of the two studies on cognitive recovery, one reported that diabetes was an independent predictor of poor cognitive recovery after stroke. Three studies on QOL reported that a poor QOL after stroke was associated with the presence of diabetes.Conclusions: The current review suggests that the post-stroke recovery of ADL seems to be poorer in patients with diabetes than patients without diabetes. Further, there are insufficient data to conclude the effect of diabetes on motor and cognitive recovery, but it may have some influence on the quality of life after stroke.Systematic Review Registration: doi: 10.37766/inplasy2021.11.0032, identifier: INPLASY2021110032.

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“…The largest challenge to the cells is likely to be in the early stages following cell transplantation, and several neuroprotective agents have been explored to promote survival including neurotrophic factors, anti-apoptotic agents, and anti-oxidants [14,17] (reviewed in [13]). Glucagon-like peptide-1 receptor agonists (GLP-1R) are employed in the treatment of type 2 diabetes [18,19] but have recently been of interest in their potential to modify the progression of a range of neurological disorders [20,21] including PD [22,23]. Convincing preclinical data [22,24,25] led to a randomised controlled trial of the first GLP-1R agonist to be used in the treatment of diabetes, exendin-4 which showed a mild but significant beneficial effect on the motor scores of people with PD [26].…”

Section: Introductionmentioning

confidence: 99%

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

Elabi

Davies

Lane

2021

IJMS

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Cell therapy is a promising treatment for Parkinson’s disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons. 6-OHDA lesioned Sprague Dawley rats received intra-striatal grafts of dopaminergic ventral mesencephalic cells from embryonic day 14 Wistar rat embryos. Transplanted rats then received either saline or L-dopa (12 mg/kg) administered every 48 h prior to, and following cell transplantation. Peripheral GLP-1R agonist administration (exendin-4, 0.5 μg/kg twice daily or liraglutide, 100 μg/kg once daily) commenced immediately after cell transplantation and was maintained throughout the study. Graft survival increased under administration of exendin-4, with motor function improving significantly following treatment with both exendin-4 and liraglutide. However, this effect was not observed in rats administered with L-dopa. In contrast, L-dopa treatment with liraglutide increased graft volume, with parallel increases in motor function. However, this improvement was accompanied by an increase in leukocyte infiltration around the graft. The co-administration of L-dopa and exendin-4 also led to indicators of insulin resistance not seen with liraglutide, which may underpin the differential effects observed between the two GLP1-R agonists. Overall, there may be some benefit to the supplementation of grafted patients with GLP-1R agonists but the potential interaction with other pharmacological treatments needs to be considered in more depth.

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Normalisation of glucose metabolism by exendin‐4 in the chronic phase after stroke promotes functional recovery in male diabetic mice

Abstract: Total number of figures: 6 Supporting files: 1 (containing 3 figures) DECLARATIONS AVAILABILITY OF DATA AND MATERIALSThe data that support the findings of this study are available from the corresponding author upon reasonable request.

Cited by 14 publications

References 87 publications

Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke

Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke

Effect of Diabetes on Post-stroke Recovery: A Systematic Narrative Review

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

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