Voluntary Exercise and Neurotrophin Signaling Affect the Development and Presentation of Painful Neuropathy

Abstract

Diabetic neuropathy (DN) is the most common and debilitating complication of type 1 and type 2 diabetes with approximately half of all patients developing neuropathy during the course of their lives. Additionally, patients with prediabetes also develop neuropathy, often presenting with painful symptoms, including burning and stinging sensations, as well as hyperalgesia and allodynia. Research suggests that altered neurotrophism may account for the development and maintenance of PDN, resulting in a dying back of peripheral neurons, leading to pain. Furthermore, patients suffering from painful diabetic neuropathy (PDN) have few therapeutic options, as pharmaceuticals are rarely effective and are only palliative in nature. However, recent research suggests that exercise may be beneficial in reducing PDN. The purpose of this work was to test the effects of obesity and a high-fat diet on the development of DN, to investigate how diabetes alters neurotrophins and to determine if voluntary exercise is capable of reducing PDN. Initial studies used a model of obese, type 2 diabetes and investigated if voluntary exercise could reverse PDN. Diabetes resulted in mechanical allodynia, yet because these mice did not exercise, no benefit was gained; however, there was a significant correlation between physical activity and mechanical withdrawal thresholds. Additionally, we found that glial cell line-derived neurotrophic factor (GDNF) was decreased in the diabetic mice. These results suggest that diabetes does alter neurotrophin levels, which may lead to PDN. Next, using a high-fat diet to induce prediabetes, we found increased levels of nerve growth factor (NGF) protein, a neurotrophin known to mediate pain signaling, in the periphery, while exercise normalized these levels. Furthermore, prediabetes resulted in a switching of axonal phenotypes in the skin, increasing peptidergic nerve fibers, which was reversed with exercise. These results suggest that increased NGF plays a critical role in mediating pain sensation in prediabetes and that exercise is capable of reversing this increase. Particularly, this study suggests that the ratio of peptidergic to nonpeptidergic axons may mediate the occurrence of PDN and may be more clinically significant than overall fiber density measures. Finally, we demonstrated that high-fat diet-induced PDN was reversed with a blocking antibody to NGF. In addition to decreases in mechanical withdrawal thresholds, anti-NGF treatment also normalized NGF levels within the DRG as well as normalizing epidermal innervation. Taken together, these studies demonstrate that exercise is capable of attenuating PDN, possibly through mediating NGF levels. It therefore appears that exercise and anti-NGF treatment are effective therapeutic strategies to prevent and reverse PDN.