المؤلفون: Casselini, Carolina M.¹ (AUTHOR), Parson, Henri K.¹ (AUTHOR), Frizzi, Katie E.² (AUTHOR), Marquez, Alex² (AUTHOR), Smith, Darrell R.³ (AUTHOR), Guernsey, Lucie² (AUTHOR), Nemmani, Rakesh² (AUTHOR), Tayarani, Alireza² (AUTHOR), Jolivalt, Corinne G.² (AUTHOR), Weaver, Jessica¹ (AUTHOR), Fernyhough, Paul^3,4 (AUTHOR), Vinik, Aaron I.¹ (AUTHOR), Calcutt, Nigel A.² (AUTHOR) ncalcutt@ucsd.edu

المصدر: Acta Neuropathologica. 2024, Vol. 147 Issue 1, p1-17. 17p.

مستخلص: 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. [ABSTRACT FROM AUTHOR]

المؤلفون: Aghanoori, Mohamad-Reza^1,2,3 (AUTHOR) mohammadreza.aghanoo@ucalgary.ca, Agarwal, Prasoon^2,4,5 (AUTHOR), Gauvin, Evan¹ (AUTHOR), Nagalingam, Raghu S.^6,7 (AUTHOR), Bonomo, Raiza⁸ (AUTHOR), Yathindranath, Vinith⁹ (AUTHOR), Smith, Darrell R.¹ (AUTHOR), Hai, Yan¹⁰ (AUTHOR), Lee, Samantha¹⁰ (AUTHOR), Jolivalt, Corinne G.¹¹ (AUTHOR), Calcutt, Nigel A.¹¹ (AUTHOR), Jones, Meaghan J.¹⁰ (AUTHOR), Czubryt, Michael P.^6,7 (AUTHOR), Miller, Donald W.⁹ (AUTHOR), Dolinsky, Vernon W.^2,4 (AUTHOR), Mansuy-Aubert, Virginie⁸ (AUTHOR), Fernyhough, Paul^1,2 (AUTHOR)

المصدر: Cellular & Molecular Life Sciences. Apr2022, Vol. 79 Issue 4, p1-1. 1p.

مستخلص: Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer’s disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPβ, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPβ overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPβ can be a promising therapeutic approach. [ABSTRACT FROM AUTHOR]