Glucagon-like peptide-2 rescues memory impairments and neuropathological changes in a mouse model of dementia induced by the intracerebroventricular administration of streptozotocin

Sachie Sasaki-Hamada,Jun-Ichiro Oka,Masaatsu Ikeda

doi:10.1038/s41598-019-50167-3

Sachie Sasaki-Hamada, Jun-Ichiro Oka + Show 1 more

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https://doi.org/10.1038/s41598-019-50167-3

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Abstract

Glucagon-like peptide 2 (GLP-2) is derived from the proglucagon gene expressed in the intestines, pancreas and brain. Our previous study showed that GLP-2 improved lipopolysaccharide-induced memory impairments. The current study was designed to further investigated the potential of GLP-2 in memory impairment induced by intracerebroventricular administration of streptozotocin (ICV-STZ) in mice, which have been used as an animal model of sporadic Alzheimer’s disease (AD). STZ was administered on alternate days (Day-1 and Day-3) in order to induce dementia in male ddY mice. ICV-STZ-treated mice were administered GLP-2 (0.6 μg/mouse, ICV) for 5 days from 14 days after the first ICV administration of STZ. In these mice, we examined spatial working memory, the biochemical parameters of oxidative stress, or neurogenesis. The GLP-2 treatment restored spatial working memory in ICV-STZ-treated mice. ICV-STZ-treated mice showed markedly increased thiobarbituric acid reactive species (TBARS) and decreased glutathione (GSH) levels, and GLP-2 significantly restored these ICV-STZ-induced changes. GLP-2 also significantly restored neurogenesis in the subgranular zone of the dentate gyrus in ICV-STZ-treated mice. We herein demonstrated that GLP-2 significantly restored ICV-STZ-induced memory impairments as well as biochemical and histopathological alterations, and accordingly, propose that the memory restorative ability of GLP-2 is due to its potential to reduce oxidative stress.

Highlights

Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proglucagon in the gut and central nervous system (CNS)[1,2]
We investigated the effects of Glucagon-like peptide 2 (GLP-2) on spatial learning memory, oxidative stress, and neurogenesis using intracerebroventricular administration of streptozotocin (ICV-STZ)-induced Alzheimer’s disease (AD) mice
Swimming speed did not significantly differ among the groups (P > 0.05) (Fig. 2c). These results indicate that GLP-2 improved spatial learning impairments in ICV-STZ-treated mice without inducing motor deficits

Summary

Introduction

Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proglucagon in the gut and central nervous system (CNS)[1,2]. Neuroinflammation, head trauma, impaired glucose/energy metabolism, and diabetes are among the risk factors for sporadic AD10. The intracerebroventricular administration of streptozotocin (ICV-STZ) at a low dosage to rodents does not alter peripheral glucose levels, and is used as an experimental model for sporadic AD11,12. (STZ)-induced impairments in glucose/energy metabolism may be a potential source of oxidative stress, neuroinflammation, neuronal cell death, and cholinergic damage[12,13,14]. ICV-STZ has been shown to induce spatial learning impairments in the Morris water maze (MWM) test and tau phosphorylation in the rodent brain, which had a sporadic AD-like pathology[15]. We investigated the effects of GLP-2 on spatial learning memory, oxidative stress, and neurogenesis using ICV-STZ-induced AD mice

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