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 8

M1R antagonists are neuroprotective in models of peripheral neuropathy induced by the HIV envelope protein gp120.

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M1R antagonists are neuroprotective in models of peripheral neuropathy i...
(A) Neurite outgrowth in adult sensory neuron cultures exposed to gp120 (1–3 ng/ml) ± 1 μM pirenzepine for 24 hours. Data are shown as mean + SEM of n = 5–8 replicate cultures. *P < 0.05; **P < 0.01, 1-way ANOVA with Tukey’s post-hoc test. (B–C) Unprocessed and (D–E) processed images corneal nerves of the subbasal plexus. Dimensions = 400 × 400 μm, resolution = 384 × 384 pixels. (B) Corneal nerves from a control Swiss Webster mouse. (C) Corneal nerves from a Swiss Webster mouse that received daily eye drops of gp120 for 10 weeks. (D and E) Same images overlaid with tracings of the corneal nerve and an 8 × 8 counting grid. Grid squares bounded by red lines represent those that contain 1 or more corneal nerves. Panel D shows 56/64 sectors that contain nerve (occupancy = 87.5%), and panel E shows 36/64 sectors containing nerve (occupancy = 56.3%). (F) Time course of subbasal plexus nerve density (as percentage of occupancy) in adult female Swiss Webster mice that received daily eye drops of vehicle (solid black line), gp120 (dashed black line), or both gp120 and MT7, where MT7 treatment was initiated either on the same day as gp120 (MT7 prevention, dot/dash green line) or 5 weeks after onset of gp120 treatment (MT7 reversal, dotted red line). Values are shown as mean ± SEM of n = 10. *P < 0.05 for gp120 untreated vs. other groups; **P < 0.01 for gp120 untreated vs. MT7 prevention and vehicle by repeated-measures 2-way ANOVA and Dunnett’s post-hoc test.