Efficacy of glucagon-like peptide-1 mimetics for neural regeneration.

Abstract

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L cells in response to nutrient ingestion and exhibits insulinotropic properties by stimulating specific G protein-linked receptors (GLP-1Rs) on pancreatic β cells. Several GLP-1 mimetics, such as exenatide (exendin-4 (Ex-4)), liraglutide, and lixisenatide, have been developed and approved as treatments for patients with type 2 diabetes. These peptides show bioactivities almost identical to those of GLP-1 and have a substantially longer plasma half-life than GLP-1 because of their resistance to dipeptidyl peptidase-4, a GLP-1 degrading enzyme. GLP-1Rs are found in not only the pancreas but also the extrapancreatic tissues, including the nervous tissues (Harkavyi and Whitton, 2010). It is important to note that GLP-1 mimetics can cross the blood brain barrier and directly act on neurons in the central nervous system. In addition to the inhibition of appetite, the neuroprotective properties of GLP-1 have been receiving increasing attention. Recent studies have suggested that GLP-1 mimetics confer beneficial effects in neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and stroke, and multiple sclerosis (Holscher, 2014). In particular, the neuroprotective properties of Ex-4 have been demonstrated in animal and cell culture models of PD. A single-blinded clinical trial with 45 PD patients revealed that the treatment with Ex-4 significantly improved the cognition and memory of patients (Aviles-Olmos et al., 2013). The beneficial effects of GLP-1 mimetics on the peripheral nervous system (PNS) have also been reported. Both GLP-1 and Ex-4 delivered via osmotic minipumps prevented axonal degeneration in a rat model of pyridoxine-induced neuropathy (Perry et al., 2007). Treatment of streptozotocin (STZ)-induced diabetic mice with Ex-4 for 4 weeks restored motor and sensory nerve conduction velocities and hypoalgesia without normalizing blood glucose levels (Himeno et al., 2011). In addition, repeated intraperitoneal injections of Ex-4 significantly promoted axonal regeneration and functional recovery following sciatic nerve crush injury in normal adult rats (Yamamoto et al., 2013). These findings are in agreement with in vitro studies that revealed that GLP-1 and Ex-4 promoted neurite outgrowth of rat pheochromocytoma-derived PC12 cells (Perry et al., 2002) and adult mouse dorsal root ganglion (DRG) neurons (Himeno et al., 2011). Together these results provide further evidence of the direct actions of Ex-4 on the PNS; however, the underlying mechanisms remain unclear. Our recent study (Tsukamoto et al., 2015) aimed to elucidate the precise localization of GLP-1R in adult rat DRG in vivo and in vitro as well as to determine the neurotrophic and neuroprotective properties of Ex-4 in adult rat DRG neurons.