Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Abstract

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

Figures

Figure 1

Amino acid sequences for GLP-1, Ex4 and the GLP-1 receptor antagonist, Exendin (9-39). The purple shading represents the amino acid substitutions in the Ex4 sequence relative to the GLP-1 sequence (shaded red). Replacement of the alanine with glycine in position 8 renders the peptide protease resistant and improves stability.

Figure 2

Body weight in grams of PYR - intoxicated or SAL animals receiving GLP-1 agonist/antagonist or inactive peptide (IAP) infusions for 14 days. * p≤0.05 PYR vs SAL.

Figure 3

Latency to fall from the inclined screen in PYR - intoxicated or SAL animals receiving GLP-1 agonist/antagonist or inactive peptide (IAP) infusions for 14 days. *** p < 0.001 vs SAL (pooled)

Figure 4

Number of falls during the rotarod test for PYR - intoxicated or SAL animals receiving GLP-1 agonist/antagonist or inactive peptide (IAP) infusions for 14 days. * p < 0.05; ** p ≤ 0.01 vs SAL (pooled)

Figure 5

Transverse sections of sciatic nerve from PYR - intoxicated or SAL animals receiving GLP-1 agonist or inactive peptide (IAP) infusions for 14 days. Luxol fast blue staining (LFB) for myelin (A-D) and neurofilament-positive immunoreactivity (NFI) for the axon (E-H).

Figure 6

Transverse sections of L4 or L5 dorsal root ganglia from PYR - intoxicated or SAL animals receiving GLP-1 agonist or inactive peptide (IAP) infusions for 14 days. LFB staining.