TITLE:
Treatment of peripheral diabetic neuropathy in Zucker diabetic fatty (ZDF) rats with cariporide
AUTHORS:
Sergey Lupachyk, Hanna Shevalye, Pierre Watcho, Alexander Obrosov, Irina G. Obrosova, Mark A. Yorek
KEYWORDS:
Diabetic Neuropathy; Sodium/Hydrogen Exchanges; Oxidative Stress
JOURNAL NAME:
Journal of Diabetes Mellitus,
Vol.4 No.1,
February
24,
2014
ABSTRACT:
To determine the
effect of Na+/H+-exchanger-1 on diabetic neuropathy in Type 2 diabetes Zucker
diabetic fatty (ZDF) rats and lean controls were treated with cariporide (10 or
20 mg/kg/d), a Na+/H+-exchanger-1 inhibitor, for 4 weeks at 15 weeks of age.
Neuropathy endpoints included motor (MNCV) and sensory (SNCV) nerve conduction
velocities, thermal nociception, tactile allodynia and intraepidermal nerve
fiber density. Advanced glycation endproduct and markers of oxidative stress
including nitrated protein levels in sciatic nerve and dorsal root ganglion
were also evaluated. Expression of Na+/H+-exchanger-1 in dorsal root ganglion
neurons was increased in ZDF rats. At 15 weeks of age ZDF rats displayed
hyperglycemia, MNCV and SNCV deficits, thermal hypoalgesia and tactile allodynia.
At 20 but not 10 mg/kg/d, cariporide significantly improved MNCV and SNCV
deficits, thermal hypoalgesia and tactile allodynia. Cariporide treatment was
also associated with reduction of diabetes-induced accumulation of advanced
glycation end-product (AGE), oxidative stress and nitrated proteins in sciatic
nerve and dorsal root ganglion neurons. In conclusion, these findings support
an important role for Na+/H+-exchanger-1 in peripheral diabetic neuropathy, and
provide rationale for development of Na+/H+-exchanger-1 inhibitors for
treatment of diabetic neural complications.