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 4

M1R antagonism prevents and reverses diabetic sensory neuropathy.

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M1R antagonism prevents and reverses diabetic sensory neuropathy. (A) Th...
(A) Thermal response latency and paw skin IENF density in female C57BL/6 (Ctrl, control) and STZ-diabetic mice ± pirenzepine (0.1–10 mg/kg/d s.c.) after 4 weeks of diabetes. Data are shown as mean ± SEM of n = 11–12. *P < 0.05; ****P < 0.0001 vs. control by 1-way ANOVA with Dunnett’s post-hoc test. (B) Thermal response latency and paw skin IENF density in WT and M1R-KO mice after 6 weeks (thermal response) or 12 weeks (IENF) of STZ-induced diabetes. Data are shown as mean ± SEM of n = 3–7. **P < 0.01; ***P < 0.001 vs. WT by 1-way ANOVA with Dunnett’s post-hoc test. (C) Thermal response latency in Swiss Webster, STZ-diabetic, and STZ-diabetic mice with pirenzepine (10 mg/kg/day s.c.) from 14 weeks. Data are shown as mean ± SEM of n = 8–10. ***P < 0.001 vs. control by repeated-measures 2-way ANOVA and Dunnett’s post-hoc test. (D) Thermal response latency in female C57BL/6 mice, STZ-diabetic mice, and STZ-diabetic mice with pirenzepine (10 mg/kg/d s.c.) up to 8 weeks, when treatment was withdrawn. Data are shown as mean ± SEM of n = 8–10. ***P < 0.001 vs. control by repeated-measures 2-way ANOVA and Dunnett’s post-hoc test. Groups as indicated by key in C. (E) Paw IENF density in mice where thermal response latency shown in C (14 weeks and 21 weeks of diabetes) and D (8 weeks and 17 weeks of diabetes), normalized to IENF of control mice at same time. The mean − SEM of control mice at each time point defined lower limit of control group range, and mean + SEM of STZ-diabetic mice at each time point defined upper limit of diabetic group range. Data are shown as mean ± SEM of n = 8–10. **P < 0.01 vs. start or cessation of treatment in same cohort by unpaired t test. (F) Paw thermal response latency in male C57BL/6 mice, db/db mice, and C57BL/6 or db/db mice with pirenzepine (10 mg/kg/d s.c.) from 12 weeks onwards. Data are shown as mean ± SEM of n = 9–10. ***P < 0.001 vs. db/db by repeated-measures 2-way ANOVA and Dunnett’s post-hoc test.