Abstract
Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters’ alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid β peptide aggregation in Alzheimer’s disease (AD) and dopamine (DA) levels in Parkinson’s disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline.
Highlights
The concern for neurodegeneration, a worldwide expanding set of diseases, stimulated the research on risk factors related to the lifestyle of the population, leading to interesting findings on the association between dysmetabolism and brain impairment
glucagon-like peptide-1 (GLP-1) is degraded by a dipeptidyl-peptidase IV (DPP IV), a serine aminopeptidase expressed in the different organ, such as liver, pancreas, gut, and brain (Hopsu-Havu and Glenner, 1966; Smith et al, 2019)
It has been observed that peripheral administration of lixisenatide for 40 days (50 nmol/kg bw, twice-daily) in high-fat fed mice with established obesity, insulin resistance, and impaired cognition resulted in marked improvement in recognition memory, which was associated with up-regulation of hippocampal expression of neurotrophic tyrosine kinase receptor type 2 and mammalian target of rapamycin genes involved in modulating synaptic plasticity and longterm potentiation
Summary
The concern for neurodegeneration, a worldwide expanding set of diseases, stimulated the research on risk factors related to the lifestyle of the population, leading to interesting findings on the association between dysmetabolism and brain impairment. GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP-1RAS) AS NEUROPROTECTIVE AGENTS IN DIABETES-ASSOCIATED COGNITIVE IMPAIRMENT
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