Effects of 7-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chromen-4 -one from Swietenia macrophylla King Seed on Oxidized LDL, HOMA Beta and Glucagon like Peptide 1 (GLP-1) Gene Expression in Type 2 Diabetic Rats

Objective: To investigate the relationship of central and peripheral ghrelin during an exendin-4 (Ex-4) intervention to feeding in obese type 2 diabetic rodents. Methods: Animal models of diet-induced obesity (DIO) and type 2 diabetes were developed using male Sprague-Dawley rats fed with a high-fat diet and induced into DIO-streptozotocin diabetic rats. Ex-4 or the glucagon-like peptide-1 (GLP-1) receptor agonist exendin fragment-[9-39] (Ex-9) was intracerebroventricularly (ICV) administered. Multivariate linear regression analysis was performed to investigate potential predictors of food intake after Ex-4 administration. Results: ICV administration of Ex-4 significantly inhibited feeding and decreased weight, plasma active ghrelin, hypothalamic ghrelin, and gastric ghrelin levels. The changes in hypothalamic ghrelin and plasma ghrelin could predict the amount of 8-h average food intake. Central preadministration of Ex-9 followed by treatment with Ex-4 could inhibit the decrease in feeding at 0.5, 2, and 8 h. It could also inhibit the decrease in hypothalamic ghrelin at 0.5, 2, and 8 h, as well as in plasma and gastric ghrelin at 2 and 8 h. Conclusions: In a GLP-1 receptor-dependent manner, central and peripheral ghrelin play a vital role in the inhibition of feeding by Ex-4 administration. Hypothalamic ghrelin, but not plasma ghrelin, may be involved in central Ex-4 inhibition of feeding in the very early feeding period.

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Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats

Clinical Science ◽

10.1042/cs20110374 ◽

2012 ◽

Vol 122 (10) ◽

pp. 473-483 ◽

Cited By ~ 89

Author(s):

Vladimer Darsalia ◽

Shiva Mansouri ◽

Henrik Ortsäter ◽

Anna Olverling ◽

Nino Nozadze ◽

...

Keyword(s):

Cell Proliferation ◽

Stem Cell ◽

Receptor Activation ◽

Diabetic Rats ◽

Stem Cell Proliferation ◽

Ischaemic Brain ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Type 2 Diabetic

Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

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