Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease

Abstract

Introduction: Accumulating evidence supports the evaluation of glucagon-like peptide-1 (GLP-1) receptor (R) agonists for the treatment of the underlying pathology causing Parkinson's Disease (PD). Not only are these effects evident in models of PD and other neurodegenerative disorders but recently in a randomized, double-blind, placebo-controlled clinical trial, a GLP-1R agonist has provided improved cognition motor functions in humans with moderate PD.

Areas covered: In this mini-review, we describe the development of GLP-1R agonists and their potential therapeutic value in treating PD. Many GLP-1R agonists are FDA approved for the treatment of metabolic disorders, and hence can be rapidly repositioned for PD. Furthermore, we present preclinical data offering insights into the use of monomeric dual- and tri-agonist incretin-based mimetics for neurodegenerative disorders. These drugs combine active regions of GLP-1 with those of glucose-dependent insulinotropic peptide (GIP) and/or glucagon (Gcg).

Expert opinion: GLP-1Ragonists offer a complementary and enhanced therapeutic value to other drugs used to treat PD. Moreover, the use of the dual- or tri-agonist GLP-1-based mimetics may provide combinatory effects that are even more powerful than GLP-1R agonism alone. We advocate for further investigations into the repurposing of GLP-1R agonists and the development of classes of multi-agonists for PD treatment.

Keywords: Glucagon-like peptide-1 (GLP-1); Parkinson’s disease; brain trauma; glucagon (Gcg); glucose-dependent insulinotropic peptide (GIP); incretin mimetics; microglia; neurodegeneration.

Figure 1.

Amino acid architecture of endogenous secretin proteins and of Exendin-4/Exenatide. (a) The incretins GLP-1 and GIP along with the related secretin protein Gcg, are structurally similar proteins produced in the gut and pancreas. These proteins act in a glucose-dependent manner and remain short-lived following their production due to rapid degradation by dipeptidyl peptidase-4 (DPP-IV). (b) A naturally occurring analog of GLP-1, known as Exendin-4 (Ex-4) and commercially as Exenatide was discovered in the venom of the Gila monster and has allowed for the production of a wide variety of long-acting drugs for the treatment of metabolic diseases. Figure adapted from Glotfelty et al., 2019.

Figure 2.

Pathology of Parkinson’s Disease (PD) in the midbrain and mitigation through GLP-1R activation. (a) In the midbrain of PD patients, loss of dopaminergic neurons is visible via decreased immunostaining of tyrosine hydroxylase (TH) (brown), the precursor to dopamine. In animal models of PD, including the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) lesion methods, similar loss of dopaminergic neurons in the midbrain is observed. (b) A microenvironment comparison of a healthy and PD afflicted midbrain. Dopaminergic neuron dysfunction, reduced dopamine transmission, α-synuclein deposition within neurites, and eventual death may arise from a variety of genetic or environmental factors that cause mitochondrial dysfunction and high amounts of oxidative stress. The accumulation of reactive oxygen species (ROS), neuronal α-synuclein, and dying cells are some of the components that contribute to a proinflammatory environment in the PD midbrain. Highly dynamic surveying microglial cells respond to this milieu by altering their activation state and producing proinflammatory cytokines and chemokines that cascade to further evoke reactive astrocyte activation from their resting quiescent state. These astrocytes secrete a neurotoxic factor that selectively ablates subsets of neurons and oligodendrocytes and further exacerbates the already chronically inflamed region. Though inflammation is an immune response necessary for repair, chronic inflammation is especially detrimental. (c) Upon activation of GLP-1 receptor (GLP-1R), a multitude of downstream pathways are activated that mitigate the effects of PD pathology, most notably the major upstream secondary messenger cyclic adenosine monophosphate (cAMP). Upregulation of cAMP induces downstream effector proteins that ameliorate inflammation, oxidative stress, and apoptosis, which provides neuroprotection and proliferative capabilities for neurite outgrowth (see Athauda and Foltynie, 2016b and Glotfelty et al., 2019 for more detailed signaling pathways). Restoration of insulin signaling through the upregulation of active insulin receptor substrate-1 (IRS-1) and downstream proteins provide additional neuroprotection (see Athauda and Foltynie, 2016a and Hölscher, 2020). This, coupled with increased production of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), contributes to the amelioration of deficits associated with PD.

Figure 3.

Incretin-based mimetics as possible PD treatments. (a) Many FDA-approved GLP-1R agonists are available on the market and several have been tested in human clinical trials for PD (red line), while multi-agonists incorporating elements of GLP-1, GIP, and Gcg have proven efficacious in preclinical models of PD among other neurodegenerative injuries and diseases (gray line). (B) Several questions remain as to which of these to repurpose or develop further into a treatment for PD. Amino acid structures adapted from Glotfelty et al., 2019.