Nortriptyline Hydrochloride

Peripheral neuropathy, defined as damage to peripheral nerves, affects approximately 1% of adults worldwide. More than 200 causes of peripheral neuropathy exist, with symptoms ranging in severity from mild toe numbness to debilitating symptoms that can require a wheelchair. Diabetes is the most common cause of neuropathy, affecting approximately 206 million people worldwide.

Peripheral neuropathy is typically length-dependent, which means that symptoms appear in the longest nerve axons (toes) and progress proximally over time. Peripheral neuropathy is typically symmetric and affects sensory axons more than motor axons. Diabetic neuropathy, which is often associated with both sensory symptoms, such as pain, tingling, or numbness; mild weakness; and autonomic symptoms, such as orthostatic hypotension, accounts for more than 50% of peripheral neuropathy in Western populations. Other causes of neuropathy include hereditary causes, such as Charcot-Marie-Tooth disease, toxic neuropathy from medications (chemotherapies [eg, cisplatin, paclitaxel, vincristine], amiodarone, or HIV nucleotide reverse transcriptase inhibitors [eg, stavudine, zalcitabine]); alcohol; vitamin deficiencies such as vitamin B 12 ; and monoclonal gammopathies. Up to 27% of adults with neuropathy have no identifiable etiology for their neuropathy after diagnostic testing. Recommended initial testing includes blood glucose (for diabetes), serum B 12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein electrophoresis with immunofixation (for monoclonal gammopathies). First-line medications for neuropathic pain are the α2-δ calcium channel subunit ligands, such as gabapentin and pregabalin; serotonin norepinephrine reuptake inhibitors, such as duloxetine and venlafaxine; and tricyclic antidepressants, such as amitryptyline and nortriptyline. Pain often persists despite medical management. At least a 50% reduction in pain was observed in 38% of those with painful diabetic peripheral neuropathy receiving 1200 mg of gabapentin daily. Combination drug therapies for neuropathic pain may provide added benefit. The prognosis of peripheral neuropathy depends on its underlying cause, but complete reversal of nerve damage is uncommon even in cases for which there are available treatments.

Peripheral neuropathy affects approximately 1% of adults worldwide and may cause sensory, motor, and autonomic symptoms. Diabetes is the most common cause of peripheral neuropathy in Western countries. First-line therapies for neuropathic pain include gabapentin, pregabalin, duloxetine, and amitriptyline.

Previous studies have highlighted the significance of RNA-binding proteins and alternative splicing (AS) in the progression of complex diseases, but the specific involvement of AS in heart failure (HF) remains unclear. This study aimed to elucidate the role of RNA-binding motif single-stranded interacting protein 1 (RBMS1), an RNA-binding protein, in the development of HF by regulating AS and its effect on cardiac fibrosis.

The level of RBMS1 was investigated in the hearts of both HF patients and mice. Fibroblast-specific knockout RBMS1 mice were generated to investigate the role of RBMS1 in cardiac fibrosis and HF. Unbiased RNA sequencing and RNA immunoprecipitation combined with RNA pull-down were conducted to identify the downstream effector of RBMS1 in fibroblasts.

RBMS1 expression was increased in murine hearts following myocardial infarction, as well as in the hearts of patients with ischaemic cardiomyopathy and hypertrophic cardiomyopathy. Moreover, RBMS1 levels in the hearts of HF patients were positively associated with cardiac fibrosis. Furthermore, fibroblast-specific ablation of RBMS1 improved cardiac dysfunction by mitigating myocardial fibrosis. Mechanistically, RBMS1 regulated the alternative splicing of LIM domain 7 (LMO7) by binding to intron 19 and splicing out exon 20, resulting in the formation of the LMO7-Δe20 isoform, which thus activated the transforming growth factor (TGF)-β1 pathway by upregulating activator protein 1. More importantly, overexpression of LMO7-Δe20 in mice resulted in cardiac fibrosis and cardiac dysfunction, which was ablated after treatment with TGF-β1 pathway inhibitor SB431542. In addition, SB431542 attenuated the RBMS1-driven fibrogenesis in human cardiac fibroblasts. Strikingly, pharmacologically inhibiting RBMS1 by low-dose nortriptyline or antisense oligonucleotide-mediated RBMS1 deficiency alleviated myocardial fibrosis and improved cardiac function in HF mice.

These findings unveil a critical role of RBMS1 in regulating cardiac fibrosis through controlling the splicing of LMO7 to activate the TGF-β1 pathway. Genetic ablation or pharmacological inhibition of RBMS1 improves cardiac function in mice, suggesting its potential as a therapeutic target for HF.