Exendin-4 Protected against Cognitive Dysfunction in Hyperglycemic Mice Receiving an Intrahippocampal Lipopolysaccharide Injection

Abstract

BackgroundChronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer’s disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study.Methodology/Principal FindingsTen days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 µg/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-κB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection.Conclusions/SignificanceThese findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-κB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases.

Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6

“…In contrast, TNFα, a classic proinflammatory cytokine not enhanced by GLP-1R stimulation in this study, might not inhibit body weight during health (50). Moreover, GLP-1R stimulation has been reported to alleviate CNS inflammation caused by LPS or irradiation (51)(52)(53). Taken together, these data are consistent with the hypothesis that central GLP-1R-induced expression of IL-1β and IL-6 mediates suppression of food intake and body weight, more so than general inflammation.…”

“…However, to bring forth the anti-IL-1 action of EX4 in the cortex, the hippocampus, or the ventral midbrain, a background of an abnormality/perturbation is required. Thus, EX4 alone did not change any of the cytokines or any other inflammatory markers measured in those extrahypothalamic areas at baseline, and the EX4-induced reduction of cytokines was noted only after LPS treatment (51,52). This lack of effect of EX4 on IL-1 in the hippocampus of rats not given LPS was replicated here to indicate that the EX4-induced IL-1β is restricted to the energy balance-regulating hypothalamus.…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…Consistent with this, normalizing hyperglycemia in db/db mice does not improve anxiety-like behavior or spatial memory deficits (Stranahan et al, 2008;Stranahan et al, 2009), whereas these are improved by reducing hippocampal inflammation . Moreover, treating hyperglycemic mice with the antidiabetic drug, extendin-4, has been recently shown to improve cognitive dysfunction by reducing hippocampal inflammation (Huang et al, 2012). Altogether, these data are in favor of the involvement of inflammation-related complex non-exclusive pathophysiological processes in the development of neuropsychiatric symptoms in obesity.…”

Incretins and Amylin: Neuroendocrine Communication Between the Gut, Pancreas, and Brain in Control of Food Intake and Blood Glucose

“…Given that the FDA-approved long-acting GLP-1R analogs, exendin-4 and liraglutide, are able to sufficiently penetrate the blood-brain barrier and act on CNS receptors (81; 87; 111), these neurotrophic properties may have clinical relevance for Alzheimer’s and other dementias. In fact, chronic exendin-4 treatment restores learning and memory deficits in rodents induced by high fat diet feeding (56), or by intra-hippocampal lipopolysaccharide administration (75). Similarly, Holscher and colleagues have demonstrated that chronic liraglutide treatment prevented memory impairments induced by a transgenic mouse model of Alzheimer’s (113) and by diet-induced obesity (112).…”