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Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice
- Source :
- The Journal of pharmacology and experimental therapeutics, vol 374, iss 1, J Pharmacol Exp Ther
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
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 subcutaneous 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 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes 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, whereas 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 day/wk. Similar local effects were noted with the nonselective 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.
- Subjects :
- 0301 basic medicine
Administration, Topical
Motor nerve
Pharmacology
Neurodegenerative
Inbred C57BL
Mice
0302 clinical medicine
Muscarinic acetylcholine receptor
Pharmacology & Pharmacy
Diabetes
Pain Research
Peripheral Nervous System Diseases
Pharmacology and Pharmaceutical Sciences
Atropine
Topical
5.1 Pharmaceuticals
Administration
Molecular Medicine
Female
Chronic Pain
Development of treatments and therapeutic interventions
medicine.drug
Type 1
Muscarinic Antagonists
Diabetes Mellitus, Experimental
03 medical and health sciences
Drug Discovery and Translational Medicine
Experimental
medicine
Diabetes Mellitus
Animals
Peripheral Neuropathy
Metabolic and endocrine
Hypoalgesia
5.2 Cellular and gene therapies
business.industry
Prevention
Antagonist
Neurosciences
Muscarinic antagonist
medicine.disease
Pirenzepine
Mice, Inbred C57BL
030104 developmental biology
Peripheral neuropathy
Diabetes Mellitus, Type 1
business
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics, vol 374, iss 1, J Pharmacol Exp Ther
- Accession number :
- edsair.doi.dedup.....811fff31c46b26470b6f2a7d9748e80e