Dataset Information

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

ABSTRACT:

Background and purpose

Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice.

Experimental approach

We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry.

Key results

Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor.

Conclusion and implications

Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.

Linked articles

This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

SUBMITTER: Augestad IL

PROVIDER: S-EPMC8820185 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Augestad Ingrid Lovise IL Dekens Doortje D Karampatsi Dimitra D Elabi Osama O Zabala Alexander A Pintana Hiranya H Larsson Martin M Nyström Thomas T Paul Gesine G Darsalia Vladimer V Patrone Cesare C

British journal of pharmacology 20210616 4

<h4>Background and purpose</h4>Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and ...[more]

PMID: 33973246

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Project description:BackgroundThe neuroprotective and proangiogenic potential of ghrelin in acute ischemic stroke has been demonstrated in experimental studies. However, the transferability of these results is limited as ghrelin was administered either before or very early after stroke onset and follow-up was limited to the first days after stroke. The aim of this study was therefore to close and extend this knowledge gap. To this end, we investigated the effect of ghrelin in two different translational animal models, one investigating acute and one investigating long-term structural and functional recovery after experimental stroke.MethodsMiddle cerebral artery occlusion (MCAO) or photothrombotic stroke was induced in 65 adult male Wistar rats. Eleven sham-operated animals served as controls. The rats were treated with either ghrelin, the ghrelin receptor antagonist [D-Lys]-GHRP-6 or a control substance. Up to four weeks after ischemia, behavioral tests such as the cylinder test, the tape removal test, and the rotarod test were performed to examine sensorimotor deficits, and the Morris water maze was performed to examine effects on the acquisition and consolidation of new memories. The structural outcome was determined by a differential analysis of neurogenesis in relation to survival and proliferation of newborn neurons in the post-ischemic brain, angiogenesis and determination of infarct size.ResultsGhrelin treatment improved motor and somatosensory functions and preserved the consolidation of new memories after photothrombotic stroke. As a structural correlate, long-term survival and sustained proliferation of neuronal cells after stroke was significantly increased in ghrelin-treated rats, while angiogenesis remained unaffected. In contrast to these neuroregenerative mechanisms, ghrelin did not induce immediate neuroprotective effects after MCAO.ConclusionsOur results suggest that ghrelin has a significant pro-neuroregenerative effect by enhancing long-term survival and sustained proliferation of neurons in the dentate gyrus and peri-infarct area, thus promoting functional recovery. Overall, ghrelin represents a promising target in the subacute and chronic phase after ischemic stroke.

Project description:AimVasculotide (VT), an angiopoietin-1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long-term neurological outcome after stroke in T1DM rats.MethodsMale Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages.ResultsTreatment of T1DM-stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM-stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM-stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP-1, endothelin-1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non-treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP-1 in macrophages subjected to LPS activation and significantly decreases IL-1β and MMP9 expression in PCN subjected to ischemia under HG conditions.ConclusionDelayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Linked articles

Publications

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

Similar Datasets

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