α-lipoic acid suppresses neuronal excitability and attenuates colonic hypersensitivity to colorectal distention in diabetic rats

Abstract

Aim

Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes.

Methods

Streptozotocin was used to induce diabetes in adult female rats. Colonic sensitivity was measured by behavioral responses to colorectal distention in rats. The excitability and sodium channel currents of colon projection DRG neurons labeled with DiI were measured by whole-cell patch-clamp recordings. The expressions of NaV1.7 and NaV1.8 of colon DRGs were measured by western blot analysis.

Results

ALA treatment significantly increased distention threshold in responding to colorectal distension in diabetic rats compared with normal saline treatment. ALA treatment also hyper-polarized the resting membrane potentials, depolarized action potential threshold, increased rheobase, and decreased frequency of action potentials evoked by ramp current stimulation. Furthermore, ALA treatment also reduced neuronal sodium current densities of DRG neurons innervating the colon from rats with diabetes. In addition, ALA treatment significantly downregulated NaV1.7 and NaV1.8 expression in colon DRGs from rats with diabetes.

Conclusion

Our results suggest that ALA plays an analgesic role, which was likely mediated by downregulation of NaV1.7 and NaV1.8 expressions and functions, thus providing experimental evidence for using ALA to treat colonic hypersensitivity in patients with diabetic visceral pain.

Keywords:

• diabetes
• colonic hypersensitivity
• dorsal root ganglion
• voltage-gated sodium channels
• α-lipoic acid

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (31400947 to HHZ, 81471041 to JH, 81230024 and 81471137 to GYX) and from the Science and Technology Development Program of Suzhou (SYS201472 to JH). This work was also supported by grants from the Jiangsu Youth Medical Talents Project (QNRC2016874 to HHZ). This work was also supported by grants from the Priority Academic Program Development of Jiangsu Higher Education Institutions of China and from the preponderant clinic group project of the Second Affiliated Hospital of Soochow University (XKQ2015001 and XKQ2015008). The authors also wish to thank Shufen Hu from the Institute of Neuroscience of Soochow University for valuable advice on the sodium current recordings.

Author contributions

YS researched and analyzed data and wrote the manuscript. PPY researched, analyzed data and wrote the manuscript. ZYS researched data. YF researched data. D-MH reviewed and edited the manuscript. JH reviewed and edited the manuscript. G-YX designed the experiments and edited the manuscript. H-HZ performed, designed, and supervised the experiments and edited the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.