GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS

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BACKGROUND: Like type-2 diabetes mellitus (T2DM), acute and chronic neurodegenerative disorders (epitomized by traumatic brain injury (TBI)/stroke and Alzheimer's disease (AD)/Parkinson's disease (PD), respectively) are an increasing health, social and economic burden for developed countries. Age is an important risk factor in each disorder and, due to the rising elderly population, T2DM and neurodegenerative disorders are looming threats to healthcare systems across the world. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes underpinning acute and chronic neurodegenerative disorders are lacking, and represent a major scientific and pharmaceutical challenge. Epidemiological data support an association between T2DM and most major neurodegenerative disorders, including AD and PD. Likewise, there is an association between T2DM and stroke incidence and hyperglycemia is linked to poorer outcome in TBI. Common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these disorders. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, we hypothesized that an effective treatment for T2DM could prove beneficial in neurodegenerative disorders.

METHODS: GLP-1-based anti-diabetic drugs (incretin mimetics) represent an effective new strategy to regulate blood glucose and reduce apoptotic death of pancreatic beta-cells in T2DM. GLP-1 and long-acting analogues, although peptides, enter the brain, where the GLP-1 receptor is found present across neurons. We evaluated Exendin-4 and GLP-1 analogues across cellular and in vivo models of neurodegenerative disorders, including TBI, PD, stroke and AD, using clinically translatable doses.

RESULTS: Neurotrophic and neuroprotective actions of GLP-1 receptor stimulation were evident across a broad array of cellular and animal neurodegeneration models together with anti-inflammatory and neurogenesis activities. We will present results on Exendin-4 as an immediate release and sustained release (PT302) formulation across animal models of TBI as representative of its neuroprotective and regenerative activity across neurodegenerative disorders.

CONCLUSIONS: GLP-1 receptor agonists, particularly Exenatide, are being evaluated pre-clinically (in TBI, stroke, AD and PD) and clinically (PD) as a new treatment strategy for neurodegenerative disorders, and results demonstrate significant promise. Further translational and clinical studies are anticipated based on current preclinical and clinical study outcomes.