Selective antagonism of muscarinic receptors is neuroprotective in peripheral
Authors Calcutt NA, Smith DR, Frizzi K, Sabbir MG, Chowdhury SK, Mixcoatl-Zecuatl T,
Saleh A, Muttalib N, Van der Ploeg R, Ochoa J, Gopaul A, Tessler L, Wess J,
Jolivalt CG, Fernyhough P
Submitted By Corinne Jolivalt on 1/31/2017
Status Published
Journal The Journal of clinical investigation
Year 2017
Date Published 2/1/2017
Volume : Pages 127 : 608 - 622
PubMed Reference 28094765
Abstract Sensory neurons have the capacity to produce, release, and respond to
acetylcholine (ACh), but the functional role of cholinergic systems in adult
mammalian peripheral sensory nerves has not been established. Here, we have
reported that neurite outgrowth from adult sensory neurons that were maintained
under subsaturating neurotrophic factor conditions operates under cholinergic
constraint that is mediated by muscarinic receptor-dependent regulation of
mitochondrial function via AMPK. Sensory neurons from mice lacking the
muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth,
confirming the role of M1R in tonic suppression of axonal plasticity.
M1R-deficient mice made diabetic with streptozotocin were protected from
physiological and structural indices of sensory neuropathy. Pharmacological
blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035,
or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced
mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs
prevented or reversed indices of peripheral neuropathy, such as depletion of
sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in
diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral
neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel
or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved
for clinical use against other conditions, prompt translation of this
therapeutic approach to clinical trials is feasible.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego
Corinne JolivaltUniversity of California San Diego