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Abstract

Phagocytic cells contain NADPH oxidase that they use for host defense by catalyzing the production of superoxide. Bacterial lipopolysaccharide (LPS) has been found to stimulate NADPH oxidase in mobile and sessile macrophages and microglia. It also evokes fever in homeothermic animals and men, a reaction mediated by central nervous system (CNS) activities. The purpose of the present study was to determine whether reactive oxygen species are involved in LPS-induced fever. In rabbits we found that plasma hydroperoxide levels increased and catalase activity decreased 15 min after LPS injection and that fever started with a similar latency, while plasma levels of tumor necrosis factor-alpha (TNFalpha) increased 30 min after the injection. Treating rabbits with methylene blue or aspirin did not affect TNFalpha secretion but prevented the LPS-induced rise of hydroperoxides and the inactivation of catalase, abolishing fever. Incubation of human blood with nitroblue tetrazolium and LPS increased the number of formazan-positive neutrophils from 10 +/- 5 to 52 +/- 9%. Adding LPS to blood preincubated with either methylene blue, alpha-lipoic acid, or aspirin respectively decreased the number of formazan-positive neutrophils to 0.9 +/- 0.8, 0.8 +/- 0.9, or 2.0 +/- 0.9%, disclosing the antioxidant capacity of these drugs. Systemic application of 80 mg/kg alpha-lipoic acid elicited heat-loss reactions within 15 min and decreased core temperature by 2.2 +/- 0.3 degrees C within 2 h. Alpha-lipoic acid applied 45 min after LPS induced antipyresis within 15 min, and this antipyresis was associated with a decrease of elevated hydroperoxide levels and restoration of catalase activity. Our results show that fever is prevented when the production of reactive oxygen species is blocked and that an elevated body temperature returns to normal when oxygen radical production decreases. Estimation of plasma dihydrolipoic acid (DHLA) levels following injection of 80 mg/kg alpha-lipoic acid in afebrile and febrile rabbits revealed that this acid is converted into DHLA, which in afebrile rabbits increased the plasma DHLA concentration from 2.22 +/- 0.26 microg/ml to peak values of 8.60 +/- 2.28 microg/ml DHLA within 30 min and which in febrile rabbits increased it from 0.84 +/- 0.22 microg/ml to peak values of 3.90 +/- 0.94 microg/ml within 15 min. Methylene blue, aspirin, and alpha-lipoic acid, which all cross the blood-brain barrier, seem to act not only on peripheral tissues but also on the CNS. Brain structures that have been shown to sense oxidative stress are vicinal thiol groups attached to the NMDA subtype of glutamate receptor. Their reduction by thiol-reducing drugs like dithiothreitol or DHLA has been found to increase glutamate-mediated neuronal excitability, while the opposite effect has been observed after their oxidation. Because we found that systemic application of alpha-lipoic acid in the afebrile state elicits hypothermia and in the febrile state is antipyretic, we think this type of NMDA receptor is involved in thermoregulati...

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

“…This peroxide-mediated inhibition of COX activity can also explain why APAP is not active in peripheral sites of inflammation, where the concentration of peroxide is greater than that encountered in brain. Similarly, low doses of APAP has been suggested to reduce the oxidative stress (20; 21) that has been implicated in prostaglandin release and fever (22; 23). …”

Hyperbilirubinemia exaggerates endotoxin-induced hypothermia

“…12,13,52,53 In these studies, the febrile response to LPS was attenuated by antioxidants, whether water-soluble (such as methylene blue, dithiothreitol, aspirin, lipoic acid, natural antioxidants purified from spinach, or apocynin) 12,13,52 or lipid-soluble (such as resveratrol and lipoic acid). 12,53 Of those 4 studies, one 53 involved administering an extremely high dose of LPS (4 mg/kg) to rats, whereas 3 other studies 12,13,52 used 1-100 mg/kg doses in rabbits, the species that is »100 times more sensitive to LPS than rats. Interestingly, the high sensitivity of rabbits to LPS has been explained by the agile production of ROS in this species without a concomitant increase in the protective antioxidative enzymes.…”

“…54 On the other hand, the relative resistance of rats to LPS has been ascribed to an increased activity of the endogenous antioxidant systems. 54,55 It should also be noted that several ROS scavengers used in the studies discussed above 12,13,52,53 inhibit the synthesis of PGE 2 , the principle mediator of fever, 56,57 by acting on COX 14,58-60 and secretory phospholipase A 2.…”

“…Riedel et al 12,13 has proposed that oxidative stress is a crucial component in the pathogenesis of LPS fever, but the data used to substantiate their proposal are difficult to interpret. Riedel et al 12,13 observed an attenuation of LPS fever by high doses of dithiotreitol, methylene blue, aspirin, or a-lipolic acid and attributed fever-attenuating effects of these compounds to their free radical-scavenging action.…”

“…Riedel et al 12,13 has proposed that oxidative stress is a crucial component in the pathogenesis of LPS fever, but the data used to substantiate their proposal are difficult to interpret. Riedel et al 12,13 observed an attenuation of LPS fever by high doses of dithiotreitol, methylene blue, aspirin, or a-lipolic acid and attributed fever-attenuating effects of these compounds to their free radical-scavenging action. However, all these compounds are nonselective radical scavengers; they also inhibit cyclooxygenase (COX), 14 guanylyl cyclase, 15 and secretory phospholipase A 2 16 -important enzymes participating in the inflammatory response to LPS.…”