Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

Abstract

Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg −1 · d −1 , i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg −1 · d −1 , i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches

“…at microvascular level, or improving vascular health during aging could represent an effective strategy to treat COVID-19 in critical patients. For instance, activation of Nrf2 by drugs (e.g., propofol during mechanical ventilation or oltipraz) (Zhou et al 2020c;Ruan et al 2020a) or by epigenetic compounds (e.g., nicotinamide mononucleotide, resveratrol, histone deacetylase inhibitors) (Csiszár et al 2015;Pooladanda et al 2019;Kiss et al 2019) could rescue, at least partially, stress resilience of both endothelial and cardiac cells in aging individuals affected by COVID-19. Otherwise, regular physical exercise and dietary intake of functional foods (Lionetti et al 2019) has also been shown to activate Nrf2 in the myocardium, as well as across a variety of tissues, and could be advised to frail older people to reduce the risk to develop major CV complications in the case of SARS-CoV-2 infection (McPhee et al 2016;Done and Traustadóttir 2016).…”

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…First, activation of Nrf2 signaling is advantageous in reducing side effects of chemotherapeutic agents. For instance, paclitaxel exposure is associated with induction of mechanical allodynia, while stimulation of Nrf2 signaling by oltipraz significantly reduces this adverse impact via HO-1 induction [71]. Furthermore, peroxisome proliferator-activated receptor gamma (PPARγ) can function as an upstream inducer of Nrf2 signaling in alleviation of paclitaxel-induced mechanical allodynia [72].…”

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms

“…Inhibitors of electron transport chain complexes, which are major ROS producers, decreased pain in neuropathic and inflammatory pain models [ 135 ]. Additionally, it has recently been demonstrated that activators of Nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant defense [ 136 ], significantly reduce pain and delay the onset of pain in various pain models [ 136 , 137 , 138 , 139 , 140 , 141 , 142 ].…”