Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Nigel A. Calcutt, Darrell R. Smith, Katie Frizzi, Mohammad Golam Sabbir, Subir K. Roy Chowdhury, Teresa Mixcoatl-Zecuatl, Ali Saleh, Nabeel Muttalib, Randy Van der Ploeg, Joseline Ochoa, Allison Gopaul, Lori Tessler, Jürgen Wess, Corinne G. Jolivalt, Paul Fernyhough; J Clin Invest. doi:10.1172/JCI88321. Published January 17, 2017

Distal dying-back or degeneration of nerve fibers is observed in many axonopathic diseases, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), Friedreich ataxia, Charcot-Marie-Tooth disease type 2, and HIV-associated distal-symmetric neuropathy. There are no therapies for any of these diseases, all of which display some degree of mitochondrial dysfunction. This is pertinent, as the growth-cone motility required to maintain fields of innervation consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling. Maintenance of plastic innervation therefore requires high consumption of ATP for growth-cone motility and maintenance of terminals and synapses. Unmyelinated axons are also more energetically demanding than myelinated axons, consuming 2.5- to 10-fold more energy per action potential. Mitochondria are known to concentrate in regions of high metabolic demand and sensory terminal boutons are packed with mitochondria.

The blockade of muscarinic receptor–mediated inhibition of mitochondrial activity using antimuscarinic drugs may not represent a specific intervention against any one primary pathogenic mechanism and potentially allows broad therapeutic application to all conditions that show diminished energy capacity under stress. Peripheral neuropathy is a major, and largely untreated, cause of human morbidity, with huge associated health care costs. One particularly encouraging implication of our identification of the endogenous M1R-mediated suppression of sensory neuron metabolism is that drugs that modulate this process are already in widespread clinical use for other indications. Moreover, the safety profile of antimuscarinic drugs is well characterized, with over 20 years of clinical application for a variety of indications in Europe and the safe use of topical pirenzepine applied to the eye to treat myopia in children. The therapeutic application of M1R antagonists suggested by our studies could potentially translate relatively rapidly to clinical use.