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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Research Article Neuroscience

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 6

M1R antagonism prevents nerve-conduction deficits and tactile allodynia in diabetic neuropathy.

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M1R antagonism prevents nerve-conduction deficits and tactile allodynia ...
(A) SNCV (left panel) and 50% paw withdrawal threshold (PWT, right panel) to von Frey filaments (right panel) in control female Sprague-Dawley rats (C), STZ-diabetic rats (STZ), and diabetic rats treated with pirenzepine at 10 mg/kg/d s.c. for the last given 24 hours before assay (STZ+PZ) after 8 weeks of diabetes. Data are shown as mean ± SEM of n = 8–12/group. ***P < 0.001; ****P < 0.0001 vs. control by 1-way ANOVA with Dunnett’s post-hoc test. (B) Time course of sciatic MNCV in male Wistar rats (open circles), STZ-diabetic rats (black circles), and STZ-diabetic rats treated with pirenzepine (5 mg/kg/d s.c.) for 8 weeks of diabetes (red squares). Data are shown as mean ± SEM of n = 5–8/group. ****P < 0.0001 vs. control by repeated-measures 2-way ANOVA with Dunnett’s post-hoc test. (C) Paw flinching in response to subdermal injection of 50 μl 0.5% formalin to the dorsal hind paw of female Sprague-Dawley rats (C), diabetic rats (STZ), and diabetic rats treated with pirenzepine (10 mg/kg/day s.c.) daily from onset of diabetes for 8 weeks and last given 24 hours before assay (STZ+PZ). Phase 1 represents the sum of flinches during minutes 1–2, 6–7, and 11–12, and phase 2 represents the sum of flinches during minutes 16–17, 21–22, 26–27, 31–32, 36–37, 41–42, 46–47, 51–52, 56–57, and 61–62 after paw formalin injection. Data are shown as mean + SEM of n = 8–11/group. *P < 0.05; **P < 0.01 vs. STZ by 1-way ANOVA with Dunnett’s post-hoc test.