Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

Abstract

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 M 1 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 postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of streptozotocin-diabetic mice dosedependently (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.

Emerging roles of keratinocytes in nociceptive transduction and regulation

“…However, the roles of KCs AChRs in neurotransmission have not been illustrated. Topical administration of M1 receptor antagonist reversed mechanical allodynia and thermal hypoalgesia in a mouse model of DPN, whereas this study did not demonstrate whether these neuroprotective effects were attributed to KCs M1 receptors (Jolivalt et al, 2020).…”

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy

“…The development of new therapies to encourage neuroregeneration might take advantage of the finding that paresthesias predict subsequent pain to choose individuals most likely to benefit from treatment to prevent incident pain. Indeed, the recent discovery that muscarinic M1 receptor antagonism enhances mitochondrial activity and drives nerve regeneration and neuroprotection has been confirmed in multiple cell and animal models of peripheral neuropathies [32][33][34][35], providing a novel treatment and preventive strategy.…”

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

“…Pharmacologically inhibiting M 1 R with the selective antagonist pirenzepine (PZ) activates the AMPK/PGC-1α pathway, enhances mitochondrial function and promotes neurite outgrowth in vitro . PZ treatment also prevented and/or reversed multiple indices of diabetic and chemotherapy-induced peripheral neuropathies in rodent models of these conditions ( 7 , 33 , 34 ). Most pertinent to our present studies, topical administration of the specific M 1 R antagonist MT7 to the eye both prevented and reversed corneal sensory nerve loss caused by topical delivery of the neurotoxic HIV envelope protein gp120 ( 32 ).…”