Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Calcutt, Nigel A.; Smith, Daniel R.; Frizzi, Katie; Sabbir, Mohammad Golam; Chowdhury, Subir; Mixcoatl-Zecuatl, Teresa; Saleh, Anas; Muttalib, Nabeel; Ploeg, Randy Van der; Ochoa, Joseline; Gopaul, Allison; Tessler, Lori; Wess, Jürgen; Jolivalt, Corinne G.; Fernyhough, Paul

doi:10.1172/jci88321

Cited by 77 publications

(93 citation statements)

References 84 publications

(108 reference statements)

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“…Reduced AMP kinase signaling is thought to be involved in diabetic neuropathy (Calcutt et al, 2017; Roy Chowdhury et al, 2012) and our RNAseq pathway analysis identified the activation of the AMP kinase pathway as a function of J147 treatment (Fig. 2D).…”

Section: Resultsmentioning

confidence: 85%

A novel curcumin derivative for the treatment of diabetic neuropathy

et al. 2018

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Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy.

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Section: Resultsmentioning

confidence: 85%

A novel curcumin derivative for the treatment of diabetic neuropathy

et al. 2018

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“…DRGs were isolated and dissociated using previously described methods (Calcutt, et al, 2017). Neuron-enriched cells were cultured in Hams F12 media supplemented with Bottenstein’s N2 without insulin (0.1 mg/ml transferrin, 20 nM progesterone, 100 μM putrescine, 30 nM sodium selenite 0.1 mg/ml BSA; all additives were from Sigma, St Louis, MO, USA; culture medium was from Caisson labs, USA).…”

Section: Methodsmentioning

confidence: 99%

“…There is mounting evidence that diabetes suppresses mitochondrial function in dorsal root ganglia (DRG) (Chowdhury et al, 2010; Freeman et al, 2016; Ma et al, 2014; Roy Chowdhury et al, 2012; Sas et al, 2016; Urban et al, 2012). We have previously proposed that hyperglycemia-induced down-regulation of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ co-activator 1-α (PGC-1α) signaling axis can result in axon degeneration and failure to regenerate (Calcutt et al, 2017; Chowdhury, et al, 2013; Fernyhough, 2015; Roy Chowdhury, et al, 2012). However, there is also a growing appreciation that hyperglycemia is not the sole initiating factor in the pathogenesis of diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

Aghanoori

Smith

Chowdhury

et al. 2017

Experimental Neurology

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Diabetic neuropathy affects approximately 50% of diabetic patients. Down-regulation of mitochondrial gene expression and function has been reported in both human tissues and in dorsal root ganglia (DRG) from animal models of type 1 and type 2 diabetes. We hypothesized that loss of direct insulin signaling in diabetes contributes to loss of mitochondrial function in DRG neurons and to development of neuropathy. Sensory neurons obtained from age-matched adult control or streptozotocin (STZ)-induced type 1 diabetic rats were cultured with or without insulin before determining mitochondrial respiration and expression of mitochondrial respiratory chain and insulin signaling-linked proteins. For in vivo studies age-matched control rats and diabetic rats with or without trace insulin supplementation were maintained for 5 months before DRG were analyzed for respiratory chain gene expression and cytochrome c oxidase activity. Insulin (10nM) significantly (P<0.5) increased phosphorylation of Akt and P70S6K by 4-fold and neurite outgrowth by 2-fold in DRG cultures derived from adult control rats. Insulin also augmented the levels of selective mitochondrial respiratory chain proteins and mitochondrial bioenergetics parameters in DRG cultures from control and diabetic rats, with spare respiratory capacity increased by up to 3-fold (P<0.05). Insulin-treated diabetic animals exhibited improved thermal sensitivity in the hind paw and had increased dermal nerve density compared to untreated diabetic rats, despite no effect on blood glucose levels. In DRG of diabetic rats there was suppressed expression of mitochondrial respiratory chain proteins and cytochrome c oxidase activity that was corrected by insulin therapy. Insulin elevates mitochondrial respiratory chain protein expression and function in sensory neurons and this is associated with enhanced neurite outgrowth and protection against indices of neuropathy.

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“…In drug discovery, appropriately 20%–25% of clinical trials fail for safety reasons, meaning that drug‐repurposing studies have recently received significant attention as an attractive strategy to identify unexpected pharmacological effects of clinically approved drugs, which have already been evaluated in terms of pharmacokinetics, toxicity and clinical safety. A recent study screened several hundred compounds of a chemical library and reported that pirenzepine, a selective antagonist for muscarinic acetylcholine type 1 receptors, enhances neurite outgrowth and has a beneficial effect on diabetic neuropathy in rodents . Similarly, another study identified 5‐hydroxydecanoate (a mitochondrial ATP‐sensitive K + channel antagonist) and minoxidil (an approved drug for hypertension and alopecia) from approximately 300 compounds of a chemical library as having a protective effect against paclitaxel‐induced peripheral neuropathy .…”

Section: Introductionmentioning

confidence: 99%

“…A recent study screened several hundred compounds of a chemical library and reported that pirenzepine, a selective antagonist for muscarinic acetylcholine type 1 receptors, enhances neurite outgrowth and has a beneficial effect on diabetic neuropathy in rodents. 9 Similarly, another study identified 5-hydroxydecanoate (a mitochondrial ATP-sensitive K + channel antagonist) and minoxidil (an approved drug for hypertension and alopecia) from approximately 300 compounds of a chemical library as having a protective effect against paclitaxel-induced peripheral neuropathy. 10,11 However, the number of compounds available for screening in these studies was relatively small, and no study to date has sought to identify drugs that can protect against oxaliplatin-induced peripheral neuropathy.…”

Section: Introductionmentioning

confidence: 99%

New pharmacological effect of fulvestrant to prevent oxaliplatin‐induced neurodegeneration and mechanical allodynia in rats

Yamamoto

Yamashita

Ito

et al. 2018

Intl Journal of Cancer

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Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose‐limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small‐molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high‐throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin‐induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin‐induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin‐induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin‐induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy.

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Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Cited by 77 publications

References 84 publications

A novel curcumin derivative for the treatment of diabetic neuropathy

A novel curcumin derivative for the treatment of diabetic neuropathy

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

New pharmacological effect of fulvestrant to prevent oxaliplatin‐induced neurodegeneration and mechanical allodynia in rats

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