A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Autor: Casselini CM; Department of Internal Medicine, Strelitz Diabetes Center, Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA, USA., Parson HK; Department of Internal Medicine, Strelitz Diabetes Center, Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA, USA., Frizzi KE; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Marquez A; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Smith DR; Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, R4046 - 351 Taché Ave, Winnipeg, MB, R2H 2A6, Canada., Guernsey L; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Nemmani R; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Tayarani A; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Jolivalt CG; Department of Pathology, University of California San Diego, La Jolla, CA, USA., Weaver J; Department of Internal Medicine, Strelitz Diabetes Center, Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA, USA., Fernyhough P; Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, R4046 - 351 Taché Ave, Winnipeg, MB, R2H 2A6, Canada.; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada., Vinik AI; Department of Internal Medicine, Strelitz Diabetes Center, Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA, USA., Calcutt NA; Department of Pathology, University of California San Diego, La Jolla, CA, USA. ncalcutt@ucsd.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 Mar 25; Vol. 147 (1), pp. 60. Date of Electronic Publication: 2024 Mar 25.
DOI: 10.1007/s00401-024-02710-4
Abstrakt: Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M 1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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