RT Journal Article
SR Electronic
T1 Topical delivery of muscarinic receptor antagonists prevents and reverses peripheral neuropathy in female diabetic mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.265447
DO 10.1124/jpet.120.265447
A1 Corinne G Jolivalt
A1 Katie E Frizzi
A1 May Madi Han
A1 Andre J Mota
A1 Lucie S Guernsey
A1 Lakshmi P. Kotra
A1 Paul Fernyhough
A1 Nigel A Calcutt
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/04/23/jpet.120.265447.abstract
AB Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor selective muscarinic antagonist pirenzepine when delivered by sub-cutaneous injection, oral gavage or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6hr post-delivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of streptozotocin-diabetic mice dose-dependently (0.1-10.0%) prevented tactile allodynia, thermal hypoalgesia and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia while withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 days per week. Similar local effects were noted with the non-selective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies.SIGNIFICANCE STATEMENT Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.