Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders

Abstract

Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists. Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders. Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.

Pharmacokinetics and efficacy of PT302, a sustained-release Exenatide formulation, in a murine model of mild traumatic brain injury

“…Such insulin release is “glucose-dependent”, only occurring when blood levels are elevated (Campbell and Drucker, 2013b; Drucker, 2018; Gallwitz, 2014), and thus the use of incretin mimetics is not associated with the classical hypoglycemic liability of most other T2DM medications. Notably, these incretins and incretin mimetics additionally provide trophic and protective actions on pancreatic β-cells (Campbell and Drucker, 2013a; Chon and Gautier, 2016; Drucker, 2018; Koehler et al, 2015; Russell, 2013), which our previous studies and those of others demonstrate translate to neurons (Athauda et al, 2017; Athauda and Foltynie, 2016; Hölscher, 2018; Kim et al, 2017; Li et al, 2016; Li et al, 2012; Li et al, 2010a; Li et al, 2009; Perry et al, 2007; Perry et al, 2002a; Perry et al, 2002b; Salcedo et al, 2012) that similarly express GLP-1R and GIPR (Athauda and Foltynie, 2016, 2018; Hölscher, 2018; Kim et al, 2017; Li et al, 2016; Salcedo et al, 2012; Verma et al, 2018).…”

Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease

“…GIP injection ip., had protective effects on spatial learning in memory tasks and also reduced plaque formation and amyloid load in a different AD mouse model (Figueiredo et al, 2010). See (Ji et al, 2016; Verma et al, 2018) for a review.…”

“…The increased levels of expression of alpha-synuclein in the brain induced by MPTP were reduced by the drug. In addition, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of the growth factor BDNF (Ji et al, 2016; Li et al, 2016c; Li Y. et al, 2017; Verma et al, 2017, 2018).…”

Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury

“…Contrary to the cellular pathways that incretins activate in the pancreas, those activated in brain remain to be fully characterized (Glotfelty et al, 2019). Multiple studies have proposed signaling pathways downstream to GLP-1R or GIPR activation in neurons (Perry and Greig, 2003;Li et al, 2010b;Holscher, 2014;McGrath et al, 2015;Kim et al, 2017;Athauda and Foltynie, 2018;Verma et al, 2018). In general, stimulation of either incretin receptors leads to the activation of the cAMP/PKA/CREB pathway that induces neuroprotection, inhibits apoptosis, regulates expression of genes that promote cell survival, and enhances memory formation (Glotfelty et al, 2019).…”

“…This pathway also appears involved in GLP-1R mediated anti-inflammation (Wu et al, 2018). Agonist binding to the incretin receptors also activates the PI3K protein, which triggers several intracellular pathways involving the PKC, AKT/PKB, and MAPK proteins that ultimately promote cell proliferation and regulate expression of genes interfering with apoptotic processes (Perry and Greig, 2003;Holscher, 2014;McGrath et al, 2015;Kim et al, 2017;Athauda and Foltynie, 2018;Verma et al, 2018).…”