Antipyretic role of the NO-cGMP pathway in the  anteroventral preoptic region of the rat brain

Steiner, Alexandre A.; Antunes‐Rodrigues, José; McCann, Samuel M.; Branco, Luiz Guilherme de Siqueira

doi:10.1152/ajpregu.00391.2001

Cited by 60 publications

(78 citation statements)

References 53 publications

(87 reference statements)

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“…Taken together, these data suggest that fever suppression at near term is due, in part, to a reduced expression of COX-2 in the hypothalamus. Future studies must address the possibility that other factors such as alterations in the elaboration of pyrogenic cytokines or synthesis of antipyretic molecules (17,45) may also play a role.…”

Section: Discussionmentioning

confidence: 99%

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Mouihate¹,

Ms²,

Nakamura

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus. Am J Physiol Regul Integr Comp Physiol 283: R800-R805, 2002; 10.1152/ ajpregu.00258.2002The fever response is blunted at near term. As the enzyme cyclooxygenase-2 (COX-2) plays a critical role in fever development, we measured its expression in rat hypothalamus during pregnancy and lactation. Western blot analysis revealed a 72-kDa COX-2-immunoreactive band in non-immune-challenged, pregnant rats at day 15 of pregnancy. In contrast, it was almost undetectable at near term and at lactation day 5. COX-2 was significantly induced at the 15th day of pregnancy and at the 5th lactating day after intraperitoneal lipopolysaccharide (50 g/kg). However, this COX-2 induction was significantly reduced at near term compared with values before and after term. The protein levels of the EP3 receptor in the hypothalamus, one of the prostaglandin E 2 (PGE2) receptors suggested to be a key receptor for fever induction, were unaffected throughout the pregnancy and lactation in both non-immune-challenged and lipopolysaccharide-treated rats. These data suggest that suppression of fever at near term is associated with a significantly reduced induction of COX-2 by lipopolysaccharide, resulting in a reduced production of PGE 2. Altered expression of the EP3 receptor does not seem to be involved in this fever refractoriness at near term.cyclooxygenase-2; parturition; lipopolysaccharide; prostaglandin receptor; EP3 receptor FEVER, A MAJOR PART of host defense, is thought to be of beneficial and adaptive value (15). Thus the inability to develop a fever response to pathogens can be detrimental (16). An absent or reduced fever has been observed in pregnant animals at near term (14) and, in some circumstances, is associated with abortion or mortality (23). This febrile refractoriness has been observed in many species, including guinea pig (55), rabbits (28), sheep (14), and rats (7,23,24), and has been observed in response to both peripherally injected pyrogens (14, 23, 55) and, to a lesser extent, to centrally infused prostaglandins (7,24,48). The fact that fever suppression is most dramatic in response to systemically administered LPS suggests that several steps in the cascade of responses to peripherally injected LPS may be affected.In response to bacterial pyrogens such as LPS, immunocompetent cells generate endogenous cytokines, which signal to the central nervous system through either humoral or neuronal pathways (for review, see Ref. 8) to induce expression of cyclooxygenase-2 (COX-2) (6, 22). The activity of this enzyme results in the cyclooxygenation of arachidonic acid and subsequently the production of PGE 2 , which acts largely in the anterior hypothalamus/preoptic area (47). COX-2 is present in basal conditions in the brain (3, 41), but in inflammation, it is induced specifically in the endothelium of brain capillaries (18,25). Levels of COX-2 have been correlated to levels of PGE 2 during LPS-induced fever (54). Because...

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Section: Discussionmentioning

confidence: 99%

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Mouihate¹,

Ms²,

Nakamura

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In an effort to study the role of the nitric oxide (NO) system in the regulation of body core temperature, the NO synthase inhibitor N G -monomethyl-L-arginine (L-NMMA) was injected into the anteroventral preoptic region (AVPO) of rats. L-NMMA did not affect the basal body core temperature but enhanced the early stage of LPS fever, indicating that NO plays an antipyretic role in the AVPO (22). It seems that peripherally generated NO contributes to the genesis of fever, whereas brain NO may act as an endogenous antipyretic factor, at least in response to systemic inflammation (22).…”

mentioning

confidence: 97%

“…L-NMMA did not affect the basal body core temperature but enhanced the early stage of LPS fever, indicating that NO plays an antipyretic role in the AVPO (22). It seems that peripherally generated NO contributes to the genesis of fever, whereas brain NO may act as an endogenous antipyretic factor, at least in response to systemic inflammation (22).…”

mentioning

confidence: 97%

Fever

Scholz

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, these increases can be blocked by the nonspecific COX inhibitor indomethacin (31, 44), indicating interactions between COX and NO activity. Oestrogen and progesterone, secreted during pregnancy, increase expression of endothelial NOS within cerebral blood vessels (33), and the neuronal NOS isoform is also increased in the hypothalamus during the late stages of pregnancy (38,47,48).There is growing evidence that NO is involved in thermoregulation through neural signaling (31,42). Neurons containing NOS have been identified in the medial preoptic area (3), a key integrative site for thermoregulatory signals.…”

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confidence: 99%

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

Begg¹,

Kent²,

Mathai³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Begg DP, Kent S, McKinley MJ, Mathai ML. Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide. Am J Physiol Regul Integr Comp Physiol 292: 2174-2178, 2007. First published March 1, 2007; doi:10.1152/ajpregu.00032.2007.-Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (T b) of near-term pregnant rats (day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 g/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, N G -monomethyl-L-arginine citrate (L-NMMA; 280 g), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle ϩ IP LPS did not increase T b, in contrast to the 1.0 Ϯ 0.2°C rise in Tb in dams treated with ICV L-NMMA ϩ IP LPS (P Ͻ 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in T b were 1.5 Ϯ 0.3°C and 1.6 Ϯ 0.4°C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, T b was 60 -70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular L-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain. nitric oxide synthase; N G -monomethyl-L-arginine citrate; lipopolysaccharide; core body temperature; thermoregulation FEVER IS A REGULATED INCREASE in core body temperature (T b ) caused by initiation of heat-conserving and heat-producing systems. It plays a crucial role in the physiological response to infection by pathogens, improving the efficiency of lymphocytes and reducing the replication of many microorganisms (23). Fever can be caused by a number of different stimuli, such as infection with bacteria and viruses (27) or by stress (13,17). It has been widely documented that these factors result in the release of proinflammatory cytokines from macrophages (11). This results in the stimulation of central and peripheral cyclooxygenase (COX) enzymes that catalyze the synthesis of PGs (10). The enzymes COX-1 and COX-2 are the ratelimiting step in the production of PGs, and inhibition of COX blocks the febrile response (39). PGE 2 has been seen traditionally as the final step in the process of fever generation. The febrile response is integral to the body's defense against infection; however, if T b becomes excessively high, it endangers the host, as these temperatu...

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Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain

Cited by 60 publications

References 53 publications

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Fever

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

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