Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffe from diabetes. There is no FDA-approved therapy to prevent neuropathy or reverse the distal degenerative neuropathy already present in many newly diagnosed diabetic patients. Recent clinical and experimental studies have emphasized that retraction of the peripheral terminals of small sensory axons as an early feature of diabetic neuropathy. This offers a window of opportunity to halt or reverse the dying-back of peripheral terminals before neuronal death. We have recently discovered that muscarinic M1 receptor antagonists can enhance axonal outgrowth from adult rat sensory neurons grown under defined in vitro conditions and also prevent distal neuropathy in diabetic rodents. This prompts us to propose that adult peripheral neurons are under constant cholinergic constraint that moderates the growth capacity of axon terminals and that manipulating this endogenous system offers a novel therapeutic approach to reversing early diabetic neuropathy. We will investigate the mechanism of cholinergic constraint in adult sensory neurons and determine whether diabetes alters this process as part of the pathogenic mechanism of diabetic neuropathy. We will also demonstrate the therapeutic potential of manipulating this endogenous cholinergic constraint mechanism to reverse established distal neuropathy in diabetic rodents and use corneal confocal microscopy to illustrate that preclinical efficacy of a therapeutic can be rapidly translated to demonstrable efficacy in diabetic subjects with peripheral neuropathy.
Our primary aim is to investigate the mechanism of cholinergic constraint that limits peripheral nerve growth, regeneration and plasticity in adults and to use this information to develop a novel therapeutic approach to reverse diabetic neuropathy. The goal is to promote rapid translation of our experimental findings to the treatment of patients with existing diabetic neuropathy.
| Daugherty, Daniel J; Marquez, Alexandra; Calcutt, Nigel A et al. (2018) A novel curcumin derivative for the treatment of diabetic neuropathy. Neuropharmacology 129:26-35 |
| Villalón, Eric; Barry, Devin M; Byers, Nathan et al. (2018) Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor axons. Exp Neurol 306:158-168 |
| Calcutt, Nigel A; Smith, Darrell R; Frizzi, Katie et al. (2017) Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. J Clin Invest 127:608-622 |
| Aghanoori, Mohamad-Reza; Smith, Darrell R; Roy Chowdhury, Subir et al. (2017) Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats. Exp Neurol 297:148-157 |
| Jones, Maria R; Villalón, Eric; Northcutt, Adam J et al. (2017) Differential effects of myostatin deficiency on motor and sensory axons. Muscle Nerve 56:E100-E107 |
| Jolivalt, Corinne G; Frizzi, Katie E; Guernsey, Lucie et al. (2016) Peripheral Neuropathy in Mouse Models of Diabetes. Curr Protoc Mouse Biol 6:223-55 |
| Rocca, Celine J; Kreymerman, Alexander; Ur, Sarah N et al. (2015) Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation. Invest Ophthalmol Vis Sci 56:7214-23 |
