Eyup S. Akarsu

Interleukin-6 levels and HPA axis activation in breast cancer patients with major depressive disorder

An association or a casual link has been proposed between the neuroendocrinological and neuroimmunological changes attributed to either depression or cancer. This study investigated whether breast cancer patients with and without major depression exhibit plasma interleukin-6 abnormalities and dexamethasone suppression test results. Four groups, each consisting of 30 women (1--healthy women, 2--patients with major depression, 3--breast cancer patients without major depression, 4--breast cancer patients with major depression), were compared to each other. Psychiatric evaluations were made by structured clinical interview for DSM-IV. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma levels of interleukin-6 were measured. A dexamethasone suppression test was applied. Breast cancer patients with major depression had markedly higher plasma levels of interleukin-6 than the other group. All breast cancer patients with depression had abnormal dexamethasone suppression test results. These findings suggest a hypothalamo-pituitary-adrenal axis activation and plasma levels of interleukin-6 and plasma interleukin-6 elevation and plasma levels if interleukin-6 and plasma levels of post cortisol concentrations. Evidence for a casual link or association of major depression with immune and endocrinological activation needs to be investigated further.

Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs

Changes in dopaminergic and serotonergic levels and metabolites in cerebral cortex, corpus striatum and hippocampus were investigated during the first 6-h of withdrawal in ethanol-dependent Wistar rats. Ethanol was given by a liquid diet for 21 days. The concentration of ethanol was 7.2% (v/v) for the last 15 days of the exposure. After 2, 4 and 6 h of ethanol withdrawal, and after audiogenic stimulus (100 dB for 60 s) at 6 h of ethanol withdrawal, various brain regions were assayed for levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT) and 5-HIAA. Behavioral signs of ethanol withdrawal and blood ethanol levels were also evaluated in other parallel groups of ethanol-dependent rats. Significant decreases in 5-HT levels and significant increases in HVA levels in striatum were found during the first 6 h of ethanol withdrawal and after the audiogenic seizures. In hippocampus, 5-HIAA levels were significantly reduced after 2 h of ethanol withdrawal and after the audiogenic seizures. 5-HIAA levels significantly increased after 2 h of ethanol withdrawal in cerebral cortex. Significant increases in both DA and 5-HT levels were also found in cerebral cortex after the audiogenic seizures. The results suggest that the levels of DA, 5-HT and their metabolites are altered by ethanol withdrawal. Furthermore, this may suggest that DA and 5-HT may be involved in the first 6 h of ethanol withdrawal syndrome 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).

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.

Inhibition of pentylenetetrazol-induced seizures in rats by prostaglandin D2

This study was undertaken to evaluate the role of brain PGD2 activity during PTZ induced seizures in rats. Potentiation of endogenous PGD2 activity caused an anti-convulsant effect. Thus, after PGD2 injection (5 microg/icv) the latency of generalized tonic clonic convulsions was prolonged. ZK 118.182, a stable analogue of PGD2, dose-dependently inhibited the incidence and the intensity of seizures when injected at doses of 1-100 ng/icv. But on the other hand, inhibition of PGD2 activity either by a D-type PG receptor antagonist (AH 6809; 50 ng/icv) or by a PGD synthase inhibitor (sodium selenite; 0.2 microg/icv) produced a proconvulsant effect by increasing the incidence and the intensity of the seizures. These findings indicate that endogenous PGD2 activity in the brain may have a specific inhibitory role for the initiation and propagation of PTZ induced seizures in rats.

Effects of bromocriptine and haloperidol on ethanol withdrawal syndrome in rats

The effects of bromocriptine and haloperidol, either alone or in combination, on ethanol withdrawal syndrome (EWS) have been investigated in rats. Bromocriptine (5 mg/kg 1P) inhibited wet dog shakes behavior and catatonia but potentiated the intensity of abnormal gait. The latency of the audiogenic seizures was prolonged by bromocriptine treatment. Haloperidol (0.5 mg/kg SC) decreased the intensity of stereotyped behavior but potentiated catatonia and agitation. It did not antagonize the behaviors induced by bromocriptine when injected in combination except the increased latency of the audiogenic seizures. The total intensity score of the EWS was not significantly different from that in untreated control. The results suggest that brain dopaminergic system may be involved to a limited extent in mediating the EWS in rats.

Effects of chronic ethanol administration on serotonin metabolism in the various regions of the rat brain.

Changes in serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA), its major metabolite, in cerebral cortex, corpus striatum and hippocampus were investigated at 10th and 21st days of chronic ethanol ingestion in Wistar rats. Ethanol (7.2% v/v) was given to rats in a modified liquid diet. Biochemical analysis was performed in two groups of ethanol-treated and control rats (n = 6 for each group). Rats in each group were decapitated at the 10th and 21st days of ethanol consumption. Brains were removed and cerebral cortex, corpus striatum and hippocampus were dissected. 5-HT and 5-HIAA levels were measured in respective brain regions by using high performance liquid chromatography. In cerebral cortex and corpus striatum, 5-HT levels were significantly lower than control at the 10th day of ethanol consumption. At the 21st day, the levels tended to remain low, but not significantly different statistically. In hippocampus, 5-HIAA levels were significantly higher than control at 10th day of ethanol consumption. Increased 5-HIAA level returned to control values at the 21st day of ethanol consumption. Our results suggest that, 5-HT clearly seems to play a critical role in the brain at the 10th day of chronic ethanol consumption.

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.

Antiseizure activity of insulin: insulin inhibits pentylenetetrazole, penicillin and kainic acid-induced seizures in rats

The present study was undertaken to evaluate the antiseizure activity spectrum of insulin against various behavioral seizure models in rats. Insulin was injected intraperitoneally (i.p.) at a test dose of 1 U/kg. Dextrose (3 g/kg) was administered simultaneously with insulin to counteract its hypoglycemic effect and induce a normoglycemic state. Insulin was found to significantly decrease the incidence, intensity and mortality rate and prolong the latency of generalized tonic-clonic convulsions induced by pentylenetetrazole (60 mg/kg i.p.) and significantly decrease the intensity and mortality rate and prolong the latency of generalized tonic-clonic convulsions induced by penicillin (2000 U/intracerebrocortical). Insulin was not only found to prolong the latency of all the seizure components but was found to reduce the incidence of focal myoclonic twitches and generalized tonic-clonic convulsions induced by kainic acid (12 mg/kg i.p.) as well. Insulin was shown to be ineffective to suppress ouabain (5 micrograms/intracerebroventricular) induced seizures. These findings indicate that insulin possesses a broad spectrum of antiseizure activity in rats. Interaction with brain Na(+)-K(+)-ATPase has been discussed as a possible mechanism of action.

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)‐α elevation were investigated in rats. LPS (Escherichia coli O111:B4; 50 µg/kg, intraperitoneally) produces a dual body temperature response, in which initial hypothermia precedes fever. Serum TNF‐α 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‐α 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‐α 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‐α levels, a fact which may, at least partly, explain the antihypothermic effect of nimesulide.