Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy
Nigel A. Calcutt, … , Corinne G. Jolivalt, Paul Fernyhough
Nigel A. Calcutt, … , Corinne G. Jolivalt, Paul Fernyhough
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):608-622. https://doi.org/10.1172/JCI88321.
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Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

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.

Authors

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

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Figure 7

M1R antagonists are neuroprotective in models of CIPN.

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M1R antagonists are neuroprotective in models of CIPN. (A) Paw thermal r...
(A) Paw thermal response latency (left panel) and IENF profiles (right panel) in female Swiss Webster mice (C), DCA-exposed mice (DCA), and DCA-exposed mice treated with pirenzepine (10 mg/kg/d s.c. last given 24 hours before assay) for 8 weeks during DCA exposure (DCA+PZ). (B) Paw withdrawal threshold (left panel) and thermal response latency (right panel) in female Swiss Webster mice (C), paclitaxel-exposed mice (PX), and paclitaxel-exposed mice treated with pirenzepine (10 mg/kg/d s.c. for 4 weeks following the last paclitaxel exposure and last given 24 hours before assay; PX+PZ). Data in A–B are shown as group mean + SEM of n = 9–12/group. *P < 0.05; **P < 0.01; ****P < 0.0001 vs. control by 1-way ANOVA with Dunnett’s post-hoc test. Neurite outgrowth in adult sensory neuron cultures exposed to (C) paclitaxel (0.3 μM) or (D) oxaliplatin (3 μM) for 1 day in the absence/presence of 1 μM (C) or 0.1–10 μM (D) pirenzepine. Data are shown as mean ± SEM of n = 5–8 replicates/group. (C) **P < 0.01, 1-way ANOVA with Tukey’s post-hoc test. (D) *P < 0.05 vs. oxaliplatin alone by 1-way ANOVA with Dunnett’s post-hoc test.