Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA

Abstract

Glucagon-like peptide-1 (GLP-1) is thought to preserve neurons and glia following axonal injury and neurodegenerative disorders. We investigated the neurotrophic and neuroprotective properties of exendin (Ex)-4, a synthetic GLP-1 receptor (GLP-1R) agonist, on adult rat dorsal root ganglion (DRG) neurons and PC12 cells. GLP-1R was predominantly localized on large and small peptidergic neurons in vivo and in vitro, suggesting the involvement of GLP-1 in both the large and small sensory fiber functions. Ex-4 dose-dependently (1 ≤ 10 ≤ 100 nM) promoted neurite outgrowth and neuronal survival at 2 and 7 days in culture, respectively. Treatment with 100 nM Ex-4 restored the reduced neurite outgrowth and viability of DRG neurons caused by the insulin removal from the medium and suppressed the activity of RhoA, an inhibitory regulator for peripheral nerve regeneration, in PC12 cells. Furthermore, these effects were attenuated by co-treatment with phosphatidylinositol-3'-phosphate kinase (PI3K) inhibitor, LY294002. These findings imply that Ex-4 enhances neurite outgrowth and neuronal survival through the activation of PI3K signaling pathway, which negatively regulates RhoA activity. Ex-4 and other GLP-1R agonists may compensate for the reduced insulin effects on neurons, thereby being beneficial for the treatment of diabetic neuropathy.

Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1

“…GLP-1, an incretin, is not only secreted from intestinal L cells, but also is expressed in neurons of the central nervous system 43 . Many studies have revealed that GLP-1 32 , 44 , EX-4 45 - 47 , and other agonists of GLP-1R 40 , 48 have a neuroprotective role against neurodegenerative cell death, traumatic brain injury, and ischemic stroke. Previous reports indicate that the neuroprotective effects of GLP-1 and EX-4 involve reducing infarct size and stoke volume 28 , 32 as well as anti-apoptotic effects 28 , 39 .…”

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

“…Activation of GLP‐1R has also been suggested to attenuate advanced glycation end products‐induced oxidative stress and neuronal apoptosis in SH‐SY5Y cells (Chen et al, ). Moreover, in adult rat dorsal root ganglion neuron cultures, exentin‐4 enhanced neurite outgrowth and neuronal survival through activating PI3K/Akt and suppressing ras homolog gene family, member A (RhoA) pathway caused by the insulin removal (Tsukamoto et al, ). On the other hand, RhoA/Rho‐associated protein kinase (ROCK) plays a pivotal role in the negative regulation of neurite outgrowth, leading to growth cone collapse and neurite retraction (Stankiewicz & Linseman, ).…”

Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats

“…Recently, exendin-4, a GLP-1 receptor agonist, has been reported to facilitate the nerve regeneration after the crush nerve injury [ 30 ]. GLP-1 receptor is localized on large and small peptidergic neurons of adult rat DRG cells [ 42 ], suggesting the involvement of GLP-1 receptor in both the large and small sensory fiber functions. Taken together, these findings indicate that GLP-1 receptor may be new target of therapeutic agents of the nerve regeneration after chemotherapy-induced neuropathy.…”

“…[ 47 ]. Recently, exendin-4 has been reported to enhance neurite outgrowth and neuronal survival through the activation of phosphatidylinositol-3'-phosphate kinase (PI3K) signaling pathway in cultured adult rat DRG neurons and PC 12 cells [ 42 ]. These molecular mechanisms may be involved in the effect of exenatide on oxaliplatin-induced mechanical allodynia.…”