Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model

Abstract

Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1α, IL-1β and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP.

Contralateral monoarthritis exacerbated chronic constriction injury-induced pain hypersensitivity through upregulating inducible nitric oxide synthase

“…A previous study has reported that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the proinflammatory (IL-1α and IL-1β) and anti-inflammatory (IL-10) cytokines. 32 In our study, 1400W partly reversed the pain behavior from the animal receiving MA + CCI. It is possible that part of this rescue effect can be attributed to the ameliorated CCI pain.…”

The impact of postsynaptic density 95 blocking peptide (Tat‐NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate‐induced epileptogenesis

“…Therefore, we hypothesized that iNOS is a potential promoter of epileptogenesis. Our studies in rats have also demonstrated that 1400W, when administered soon after KA‐induced SE, significantly reduced neuroinflammation and epileptogenesis and also reduced neuropathic pain following nerve injury (Puttachary, Sharma, Verma, et al, ; Staunton, Barrett‐Jolley, Djouhri, & Thippeswamy, ), suggesting its role in dampening neuronal hyperexcitability. In a recent organophosphate (OP) toxicity study, we showed that 1400W could suppress OP‐induced upregulation of iNOS, 3‐nitrotyrosine, gliosis, pro‐inflammatory cytokines/chemokines, neurodegeneration, and SRS (Putra et al, ).…”

3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

“…NO similarly, has been associated with the secondary phase of damage after TBI, and is marked by elevated inducible NO synthase (iNOS) in ipsilateral brain regions, ( Üçal et al, 2017 ; Wang and Doré, 2007 ); it is generally not detectable in normal brain. Induced by a variety of inflammatory stimuli such as cytokines, iNOS and COX-2 gene expression requires the activation of the transcriptional factor NF-κB ( Billiar, 1995 ; Huang et al, 2016 ; Poligone and Baldwin, 2001 ; Taylor et al, 1998 ), which, if excessive, can likewise aggravate brain damage after TBI ( Staunton et al, 2018 ). Our results demonstrate that DP treatment significantly reduces TBI-induced upregulation of iNOS and COX-2, further supporting that anti-inflammation plays a key role in the mechanisms underpinning the neuroprotective actions of DP.…”