ABSTRACT
Title
Protective effects of antioxidants during acute inflammatory pain: the role of 4-Hydroxynonenal, an endogenous aldehyde
Authors
C. Muscoli1,2, C. Dagostino1,2, F. Lauro1,2, S. Ilari2, D. Ventrice3, E. Vizza3, F. Casale1, M. Scalzo1, M.Rizzo4, N.Costa1, MC. Strongoli5, E. Palma1, D. Salvemini6, V. Mollace1,2
1 Faculty of Pharmacy, University of Catanzaro "Magna Graecia", Roccelletta di Borgia, Catanzaro, Italy; 2 Centro del Farmaco, IRCCS San Raffaele Pisana, Roma; 3 CETA, ARPACal, Italia; 4 Dept. of Pharmaceutical Sciences, University of Catania, Italy; 5 ISN-CNR, Catanzaro, Italy; 6 Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, USA
1 Faculty of Pharmacy, University of Catanzaro "Magna Graecia", Roccelletta di Borgia, Catanzaro, Italy; 2 Centro del Farmaco, IRCCS San Raffaele Pisana, Roma; 3 CETA, ARPACal, Italia; 4 Dept. of Pharmaceutical Sciences, University of Catania, Italy; 5 ISN-CNR, Catanzaro, Italy; 6 Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, USA
Abstract
The generation of free radicals and PG plays a crucial role in the enhanced pain sensitivity experienced during inflammatory diseases.
Superoxide is implicated in the development and in the maintenance of the hyperalgesia; it stimulates the production of cytokine, damages endotelial cells, increases the microvascular permeability, recruit neutrophils and contribute to the formation of the peroxynitrite (PN) and lipid peroxidation products. 4-hydroxy-2-nonenal (HNE) is the most abundant and reactive carbonyl species, generated through peroxidation of omega 6-polyunsaturated fatty acids, such as linoleic acid and arachidonic acid. HNE is produced at high concentrations (1 mM to 5 mM) in response to oxidative insults and has been proposed to mediate many of the toxic effects of reactive oxygen species (ROS) in vivo, where its highly diffusible nature may account for the actions of free radical formation far from the site of injury.
Here we show that removal of free radicals by MnTBAP was able to block the thermal hyperalgia in a well-established model of carrageenan-induced inflammation and hyperalgesia. This effect was associated with inhibition of edema, PGE2 release and lipid peroxidation in the paw exudates.
In particular, we report that HNE, an endogenous, a,b-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress is a powerful hyperalgesic mediator and that removal of HNE by antioxidant during acute inflammation exerts anti-hyperalgesic effect. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by antioxidants. These findings demonstrate that HNE is a nociceptive mediator that promote acute pain, neuropeptide release, and neurogenic inflammation.
Our results also provide a mechanism-based rationale for developing novel analgesic or antioxidant agents that target free radicals and HNE production.
Superoxide is implicated in the development and in the maintenance of the hyperalgesia; it stimulates the production of cytokine, damages endotelial cells, increases the microvascular permeability, recruit neutrophils and contribute to the formation of the peroxynitrite (PN) and lipid peroxidation products. 4-hydroxy-2-nonenal (HNE) is the most abundant and reactive carbonyl species, generated through peroxidation of omega 6-polyunsaturated fatty acids, such as linoleic acid and arachidonic acid. HNE is produced at high concentrations (1 mM to 5 mM) in response to oxidative insults and has been proposed to mediate many of the toxic effects of reactive oxygen species (ROS) in vivo, where its highly diffusible nature may account for the actions of free radical formation far from the site of injury.
Here we show that removal of free radicals by MnTBAP was able to block the thermal hyperalgia in a well-established model of carrageenan-induced inflammation and hyperalgesia. This effect was associated with inhibition of edema, PGE2 release and lipid peroxidation in the paw exudates.
In particular, we report that HNE, an endogenous, a,b-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress is a powerful hyperalgesic mediator and that removal of HNE by antioxidant during acute inflammation exerts anti-hyperalgesic effect. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by antioxidants. These findings demonstrate that HNE is a nociceptive mediator that promote acute pain, neuropeptide release, and neurogenic inflammation.
Our results also provide a mechanism-based rationale for developing novel analgesic or antioxidant agents that target free radicals and HNE production.