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

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Abstract

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 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.

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Data availability

Data are available from the corresponding author upon reasonable request.

Abbreviations

CART:

Cardiac autonomic reflex tests

DRG:

Dorsal root ganglion

ICC:

Intra-class coefficient

EVMS:

Eastern Virginia Medical School

HRV:

Heart rate variability

IENF(D):

Intra-epidermal nerve fibre (density)

NIS-LL:

Neuropathy Impairment Score-lower limb

NRS:

Numeric Rating Scale

NSS:

Neuropathy Symptom Scale

NTSS-6:

Neuropathy Total Symptom Score-6

OCR:

Oxygen consumption rate

QOL-DN:

Quality of life-diabetic neuropathy

STZ:

Streptozotocin

TNS:

Toronto Neuropathy Scale

UCSD:

University of California San Diego

UENS:

Utah Early Neuropathy Scale

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Funding

This work was supported by NIH award DK102032 (NAC).

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Authors and Affiliations

  1. Department of Internal Medicine, Strelitz Diabetes Center, Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA, USA

    Carolina M. Casselini, Henri K. Parson, Jessica Weaver & Aaron I. Vinik

  2. Department of Pathology, University of California San Diego, La Jolla, CA, USA

    Katie E. Frizzi, Alex Marquez, Lucie Guernsey, Rakesh Nemmani, Alireza Tayarani, Corinne G. Jolivalt & Nigel A. Calcutt

  3. Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, R4046 - 351 Taché Ave, Winnipeg, MB, R2H 2A6, Canada

    Darrell R. Smith & Paul Fernyhough

  4. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada

    Paul Fernyhough

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Contributions

The original project was conceived by NAC and PF. NAC, PF, CMC, HKP and AIV contributed to the design of the study. Data acquisition was performed by CMC, HKP, KEF, AM, DRS, RN, LG, AT, and JW. All authors contributed to data analysis and the original draft of the manuscript. NAC, PF, CMC, HKP, KEF and CGJ were involved in reviewing and editing the manuscript. All authors have approved the final manuscript. NAC serves as the guarantor of the work, with full access to all study data, and is responsible for the integrity and accuracy of the data analysis.

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Correspondence to Nigel A. Calcutt.

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NAC and PF are co-founders of, and hold equity in WinSanTor Inc., a company which is developing products related to the research described in this paper. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

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Casselini, C.M., Parson, H.K., Frizzi, K.E. et al. A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin. Acta Neuropathol 147, 60 (2024). https://doi.org/10.1007/s00401-024-02710-4

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