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.
Highlights
After many years of research the only recommended treatment for diabetic peripheral neuropathy is good glycemic control [1]
We have recently demonstrated in a rat model of Type 1 diabetes that increased expression/activation of Na+/H+-exchanger-1 may lead to an increase in the formation of advanced glycation end-products that contributed to an increase in oxidative stress and development of peripheral diabetic neuropathy, which was prevented by inhibition of Na+/H+-exchanger-1 [10]
We previously demonstrated that treating a Type 1 diabetic rat model with cariporide, a Na+/H+-exchanger-1 inhibitor, for four weeks after 12 weeks of untreated hyperglycemia improved multiple diabetic neuropathy endpoints [10]
Summary
After many years of research the only recommended treatment for diabetic peripheral neuropathy is good glycemic control [1]. Hyperglycemia is a major contributing factor to the pathology of diabetic complications but the intracellular metabolic pathways linking excess glucose to peripheral nerve injury are not completely understood making identification of effective treatments based on metabolic dysfunction difficult [2,3,4,5]. A consequence of hyperglycemia that has attracted our interest is that inhibition or insufficient activation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase associated with diabetes underlies diversion of excessive glycolytic flux towards the formation of methylglyoxal and α-glycerophosphate [6,7,8,9,10]. Several reports suggest that upregulation of Na+/H+-exchanger-1 activity, recently demonstrated in several tissue-sites for diabetes complications, leads to an increase in cytosolic pH and consequent activation of glucose transport and all enzymes in OPEN ACCESS
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