Seizure susceptibility and electroencephalogram power spectra alterations at various phases of the lipopolysaccharide-induced hypothermic response in biotelemetered rats.

The neuronal excitability has been evaluated at various phases of lipopolysaccharide (LPS; E. coli O111:B4, 250 µg/kg, ip)-induced hypothermia including the initial phase, the plateau (including the nadir) and the end of the response in biotelemetered adult Wistar rats. The latency of pentylenetetrazole-induced seizures (60 mg/kg, ip) was lower at the initial phase, but a clear anticonvulsive activity was observed at the end of the hypothermic response. Seizure parameters did not change at the nadir. There was no electroencephalogram (EEG) spike-wave activity generation at either phase of the LPS-induced hypothermia. Meanwhile, the power of the 12-32 Hz beta band of the EEG spectra increased at the initial phase. This increment persisted at the plateau where there was also a decrease in the 1-4 Hz delta power. The data indicate that spike-wave activity is not facilitated during LPS-induced hypothermia but, proconvulsant and anticonvulsant activities occur sequentially depending on the phase of the response. The EEG power spectra also change. These effects may not be attributed merely to the reduction of body temperature. Thus, it is possible that pathophysiological mechanisms involved in the development of hypothermia may also be responsible for neuronal excitability changes in rats.

Nadroparine blunts lipopolysaccharide-induced hypothermia and behavioral depression in mice.

INTRODUCTION: Despite the use of appropriate antimicrobial therapy and intensive care support, sepsis remains a major cause of morbidity and mortality in surgical clinics. Low-molecular weight heparin treatment may reduce mortality and end-organ failure in sepsis. The purpose of this study was to compare the effects of low-molecular weight heparins such as nadroparine, enoxaparine, and dalteparine on lipopolysaccharide-induced acute phase reaction in mice. METHODS: Lipopolysaccharide was injected intraperitoneally to produce a systemic inflammatory response and septic shock-like effects in adult male BALB/c mice. Mices were treated with low-molecular weight heparins (nadroparine, enoxaparine, dalteparine) and unfractioned heparin in different doses and times. Rectal temperature and spontaneous locomotor activity of the mice were evaluated. RESULTS: Lipopolysaccharide (1 mg/kg, intraperitoneal) produced a hypothermia that occurred 20 minutes after injection. Nadroparine pretreatment (23.75 U/kg, sc) 2 hours before lipopolysaccharide challenge, but not synchronous injection, inhibited the hypothermic response. Pretreatment with equivalent doses of enoxaparine or dalteparine had no effect on the hypothermia. The high dose of lipopolysaccharide (60 mg/kg, intraperitoneal) caused more profound hypothermia and also inhibited spontaneous locomotor activity 24 hours after injection. Synchronous nadroparine administration partially attenuated the hypothermia and significantly abolished the depression of spontaneous locomotor activity. CONCLUSIONS: The results suggest that some low-molecular weight heparins such as nadroparine might be beneficial in high-risk surgical patients because of their potential anti-inflammatory action, in addition to their efficiency in preventing thrombo-embolic complications.

Escherichia coli lipopolysaccharides produce serotype-specific hypothermic response in biotelemetered rats.

We investigated whether LPS-induced hypothermia develops in a serotype-specific manner in biotelemetered conscious rats. Two different Escherichia coli serotypes of LPSs were injected at a dose of 250 mug/kg ip. E. coli O55:B5 LPS elicited an initial hypothermia and subsequent fever, but E. coli O111:B4 LPS caused more potent monophasic hypothermia. Serum tumor necrosis factor (TNF)-alpha levels were dramatically elevated at the initial phase of the hypothermia induced by both LPSs. This elevation tended to subside at the nadir of E. coli O55:B5 LPS-induced response but progressively increased at the nadir of E. coli O111:B4 LPS hypothermia. Serum IL-10 levels were moderately elevated at the initial phase of the hypothermia and persisted at the same level at the nadir of each LPS-induced response. No change was observed at the serum IL-18 levels. A selective cyclooxygenase (COX)-1 enzyme inhibitor, valeryl salicylate (20 mg/kg sc), abolished the hypothermia without any effect on the elevated cytokine levels. Another COX-1-selective inhibitor, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560; 1 mg/kg sc) inhibited hypothermic responses as well. Meanwhile, cytokine levels were also reduced by SC-560 treatment. These findings suggest that LPS-induced hypothermia may have serotype-specific characteristics in rats. E. coli O111:B4 LPS has more potent hypothermic activity than E. coli O55:B5 LPS; that may presumably be related to its higher or sustained capability to release antipyretic cytokines, such as TNF-alpha. COX-1 enzyme may be involved in the generation of the hypothermia, regardless of the type of LPS administered.

The neuronal excitability time-dependently changes after lipopolysaccharide administration in mice: possible role of cyclooxygenase-2 induction.

The parameters of pentylenetetrazol (PTZ)-induced seizures have been evaluated at various time intervals after lipopolysaccharide (LPS; Escherichia coli O111:B4, 100 microg/kg, i.p.) administration in mice. A proconvulsant effect occurred 4h after LPS injection with decreased seizure latency and enhanced seizure intensity. In contrast, the incidence of seizures was reduced 18 h after LPS injection. There were no significant alterations on seizure parameters 2, 8, 12, and 24h after LPS treatment. SC-58236, a selective cyclooxygenase (COX)-2 inhibitor (20 or 40 mg/kg, s.c.) treatment alone had no effect on PTZ-induced seizures, but reversed the antiseizure activity observed 18 h after LPS injection. However, SC-58236 treatment partially restored the proconvulsant changes that were observed 4h after LPS administration. On the other hand, COX-1-selective inhibitor valeryl salicylate (20 or 40 mg/kg, s.c.) itself facilitated PTZ-induced seizures. Thus, it was not possible to evaluate the effects of valeryl salicylate on the excitability changes after LPS injection. These results indicate that the parameters of PTZ-induced seizures change time-dependently after LPS treatment, in which proconvulsant and anticonvulsant states could be seen in a sequence. It seems that COX-2 isoenzyme may be involved in the neuronal excitability changes due to LPS.

Sertraline, escitalopram and tianeptine related abnormal movements but not with bupropion: a case report.

It is not scarce that patients experience various extrapyramidal symptoms (EPS) during antidepressant drug therapy. Thus, choice of an antidepressant drug in case of extrapyramidal side effects, at present, is a dilemma. Escitalopram, which is a recently marketed selective serotonin reuptake inhibitors (SSRI), has no such reputation. There is just one case reported for tianeptine that induced abnormal involuntary movements/extrapyramidal side effects. We would like to present a case that was successfully managed with bupropion which had developed EPS during 2 different SSRI (sertraline and escitalopram) and tianeptine therapy.

Characterization of the hypothermic component of LPS-induced dual thermoregulatory response in rats.

We have previously shown that Escherichia coli O111:B4 serotype lipopolysaccharide (LPS) produced a dual change in rectal temperature (Tb), in which hypothermia preceded fever at subthermoneutral ambient temperature (Tamb; 24-26 degrees C) in rats. In this study, the characteristics of the initial hypothermic response were evaluated. Hypothermia was significant when LPS (50 microg/kg, i.p.) was injected at thermoneutral Tamb (30 degrees C). There was no heat loss through tail skin during hypothermia. The open field activity of the rats did not change during this period. However, serum levels of tumor necrosis factor-alpha (TNF-alpha) elevated at the beginning of the hypothermia, whereas serum levels of interleukin (IL)-1beta and interferon (IFN)-gamma remained unchanged. A nonselective cyclooxygenase inhibitor (indomethacin, 5 mg/kg, s.c.) inhibited hypothermia and serum TNF-alpha elevation, which resulted in an acceleration of the subsequent pyrogenic response. Moreover, a nonselective inhibitor of nitric oxide synthase (nitro L-arginine methyl ester (L-NAME), 10 mg/kg, s.c.) not only abolished fever but also prolonged the initial hypothermic response. These data suggest that the hypothermic component of low dose LPS-induced dual response is a regulated decrease in Tb. The data also suggest that hypothermia and fever may occur independently as two different thermoregulatory strategies against immune challenge in rats.

Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats.

The effects of selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors (valeryl salicylate and SC-58236, respectively) on Escherichia coli O111:B4 lipopolysaccharide (LPS)-induced dual thermoregulatory changes and serum tumor necrosis factor-alpha elevation were investigated in rats. LPS (50 microg/kg, intraperitoneal) produced an initial hypothermia that was then followed by fever. Serum tumor necrosis factor-alpha levels elevated at the initial phase of hypothermia. Valeryl salicylate injections (20, 40, and 80 mg/kg, subcutaneous [s.c.]) completely inhibited hypothermia without any effect on the elevated serum tumor necrosis factor-alpha levels and on the subsequent fever. On the other hand, SC-58236 injections (10, 20, and 40 mg/kg, s.c.) only partially abolished the hypothermia. SC-58236 had no effect on the initiation of fever, however completely inhibited the maintenance of fever. The serum tumor necrosis factor-alpha elevation was not reduced by SC-58236 treatment. The combination of valeryl salicylate and SC-58236 also failed to inhibit the initiation of fever. These findings suggest that cycloxygenase-1 may have a predominant role for the development of LPS-induced hypothermia, but cyclooxygenase-1 does not seem to be involved in the mediation of LPS-induced fever. Meanwhile, cyclooxgenase-2 may be critical for the late phase rather than the initiation of the fever response in rats.

Neurotoxic effects of acute and subacute formaldehyde exposures in mice.

In this study, the effects of acute and subacute formaldehyde (FA) exposures on spontaneous locomotor activity (SLMA), wet dog shake (WDS) behavior and pentylenetetrazole (PTZ) induced seizures were evaluated in Balb/C mice. SLMA was concentration dependently reduced after acute FA exposures at 1.8, 3.2, 4.5, 6.4, 9.7, and 14.8 ppm. The incidence of WDS behavior was increased only after acute FA exposures at 1.8, 3.2 and 6.4-ppm. PTZ-injections caused more intensive seizures in mice acutely exposed to FA only at 1.8 ppm. Meanwhile, the incidence of PTZ induced seizures was significantly lower after acute FA exposure at 14.8 ppm. SLMA was also reduced after subacute FA exposure at 2.0 ppm for 3 weeks. The inhibitory effects were significant after 1-week exposure at this concentration, but a tolerance developed at the end of the second week. As the concentration increased to 3.2 ppm, SLMA has found to be reduced after 2-week exposure. There was no change either on the incidence of WDS or on the parameters of PTZ-induced seizures, due to the subacute exposures of FA at the respective concentrations. In conclusion, based upon these data, acute and subacute exposures of FA produce a significant behavioral depression on mice. The data also suggest that acute FA exposures at low concentrations (such as 1.8 ppm) may increase the excitability of central nervous system (CNS).

Nimesulide and diclofenac inhibit lipopolysaccharide-induced hypothermia and tumour necrosis factor-alpha elevation in rats.

The effects of nimesulide and diclofenac on lipopolysaccharide (LPS)-induced rectal temperature changes and serum tumour necrosis factor (TNF)-alpha elevation were investigated in rats. LPS (Escherichia coli O111:B4; 50 microg/kg, intraperitoneally) produces a dual body temperature response, in which initial hypothermia precedes fever. Serum TNF-alpha levels rise during the initial phase of the induced hypothermia. Nimesulide, a preferential inhibitor of cyclooxygenase-2 (0.05, 0.5 or 1 mg/kg, subcutaneously) completely abolished the hypothermia, resulting in an acceleration of the fever phase. However, the peak and plateau phases of fever were not changed by nimesulide treatment. Nimesulide (0.5 mg/kg) partially prevented serum TNF-alpha elevation. The non-selective cyclooxygenase inhibitor diclofenac inhibited hypothermia at all doses tested (0.03, 0.3 or 3 mg/kg, subcutaneously) although fever was completely abolished at the 3 mg/kg dose only. Diclofenac also partially abolished the elevation in serum TNF-alpha levels, but at the highest dose only (3 mg/kg). These data suggest that nimesulide and diclofenac can preferentially inhibit LPS-induced hypothermia at doses that do not abolish fever in rats. Both these drugs also reduced elevated TNF-alpha levels, a fact which may, at least partly, explain the antihypothermic effect of nimesulide.

Prostaglandin E2 in the pathogenesis of fever. An update.

Prostaglandin E2 (PGE2) is recognized as a key intermediate in the sequence of events leading to fever. Normally undetectable or barely detectable in brain, it rises selectively on exposure to an infectious noxa and the attendant generation of pyrogenic cytokines outside and, in the case of interleukin (IL)-6, inside the brain. The mechanism by which pyrogens in the circulation promote the appearance of PGE2 within the confines of brain is not clear, and it is not known how PGE2 activation is selective with IL-6 being induced in brain. We have found that the cerebral microvasculature is not suitable as a source of PGE2 in response to blood-borne pyrogens. In addition, we show that IL-6 differs from other pyrogens in being able to stimulate specifically PGE2 synthesis. Nevertheless, brain-derived IL-6 does not appear to be necessary for PGE2 activation and the attendant fever. We conclude that signal-transducing mechanisms operating across the blood-brain barrier are most critical for the development of the febrile response to a systemic noxa.