Sirri Bilge

Effect of prenatal levetiracetam exposure on motor and cognitive functions of rat offspring

PURPOSE We aimed to establish the physical, motor, and cognitive teratogenic effect of levetiracetam exposure throughout pregnancy in rats. METHODS Thirty-two Sprague-Dawley pregnant female rats were divided into four groups. Groups 1-3 were treated with different doses of levetiracetam (25, 50, 100 mg/kg/d) from gestational days 1 to 18. Group 4 (control group) was treated with the same volume of saline. The day of occurrence for pinna detachment, incisor eruption, eye opening, ear opening, and fur development were also monitored. Righting reflex, negative geotaxis, and grip response were evaluated as measures of the development of reflexes. The cognitive and motor developments were established with T-maze, holeboard, Y-maze, locomotor activity, and passive avoidance test. RESULTS Levetiracetam exposure at 25, 50 and 100 mg/kg/d doses did not affect the timing of physical landmark developments. The dose of 100 mg/kg/d resulted in a significant delay in reaction time of the surface righting reflex compared to the control group. Two higher dose groups (50 and 100 mg/kg/d) had delay in the appearance of negative geotaxis reflex compared to the control group. Both groups maternally exposed to 50 and 100 mg/kg/d had a lower percentage of grip strength response comparing to control group on the first day of testing. On the second test day, only pups prenatally exposed to 100 mg/kg/d levetiracetam persistently had a significantly lower percentage of response. We could not find a significant difference between groups in tests for the locomotor activity, memory, and learning (T- and Y-maze, passive avoidance test), and explorative behavior (holeboard tests). CONCLUSION We showed that levetiracetam had only a transient impact on reflex maturation and no impact on physical and cognitive function in offspring of rats exposed to the drug during pregnancy. Levetiracetam may become a promising candidate for the treatment of epileptic women in pregnancy.

Protective effect of vitamin A on ARA-C induced intestinal damage in mice.

Background Cytarabine (ARA-C) has been used for many years in the treatment of patients with leukemia and lymphoma. Gastrointestinal ulceration and mucositis are two of the well-known side effects of ARA-C. We set out to investigate whether vitamin A (VA) can help prevent ARA-C-induced mucosal lesions in mice. Materials and methods Mice were divided into 5 groups. Group I (control group) received only saline; group II received ARA-C plus saline; group III received ARA-C plus VA; group IV received ARA-C plus a lipid solution, and group V received VA alone. VA (5000 IU/kg) was administered orally to the mice once daily for 7 days. ARA-C (3.6 mg) was administered intraperitoneally for 5 days to groups II, III and IV, starting on the third day of VA treatment. Intestinal segments from the proximal end of the jejunum of treated mice were isolated. Results There was improved mucosal integrity, less necrosis and increased villus length with advanced mucosal proliferation in crypts in the VA plus ARA-C group when compared to the ARA-C groups without VA. Conclusion We conclude that VA has a protective effect against ARA-C-induced mucosal damage in mice.

Antidepressant-like effects of echo-planar magnetic resonance imaging in mice determined using the forced swimming test

Echo-planar magnetic resonance imaging (EP-MRI), which is novel variant of MRI, is thought to have antidepressant properties in humans and animal models. Using the forced swimming test (FST), we investigated which monoaminergic system in mice is affected by EP-MRI. The short- and long-term effects of EP-MRI on immobility time in the FST and motor activity within a locomotor activity cage were examined. Two groups of mice underwent 20 min of EP-MRI in an MR scanner (Siemens, 1.5 T Symphony) either 23.5 or 1 h before the start of the second session of the FST. In both groups, the immobility duration in the FST was reduced, similar to effective antidepressant drug treatments. Climbing behavior in the 1-h group and swimming behavior in the 23.5-h group increased significantly, similar to that seen after the administration of desipramine (a noradrenaline reuptake inhibitor) and sertraline (a selective serotonin reuptake inhibitor), respectively. The findings support the hypothesis that EP-MRI has an antidepressant-like effect. We suggest that the antidepressant-like effect begins in the early period with noradrenaline systems and is maintained in the late period with serotonin systems.

The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: The role of 5-HT3 Receptors.

Tianeptine is an unusual tricyclic antidepressant drug. In this study, we aimed to investigate the antinociceptive effect of tianeptine on visceral pain in rats and to determine whether possible antinociceptive effect of tianeptine is mediated by serotonergic (5-HT(2,3)) and noradrenergic (α(1,2)) receptor subtypes. Male Sprague Dawley rats (250-300 g) were supplied with a venous catheter, for drug administrations, and enameled nichrome electrodes, for electromyography, at external oblique musculature. Colorectal distension (CRD) was employed as the noxious visceral stimulus and the visceromotor response (VMR) to CRD was quantified electromyographically before and 5, 15, 30, 60, 90 and 120 min after tianeptine administration. Antagonists were administered 10 min before tianeptine for their ability to change tianeptine antinociception. Intravenous administration of tianeptine (2.5-20 mg/kg) produced a dose-dependent reduction in VMR. Administration of 5-HT(3) receptor antagonist ondansetron (0.5, 1 and 2 mg/kg), but not 5-HT(2) receptor antagonist ketanserine (0.5, 1 and 2 mg/kg), reduced the antinociceptive effect of tianeptine (10mg/kg). In addition, administration of α(1)-adrenoceptor antagonist prazosin (1 mg/kg) or α(2)-adrenoceptor antagonist yohimbine (1 mg/kg) did not cause any significant effect on the tianeptine-induced antinociception. Our data indicate that intravenous tianeptine exerts a pronounced antinociception against CRD-induced visceral pain in rats, and suggests that the antinociceptive effect of tianeptine appears to be mediated in part by 5-HT(3) receptors, but does not involve 5-HT(2) receptors or α-adrenoceptors.

Possible role of sildenafil in inhibiting rat vas deferens contractions by influencing the purinergic system

Abstract

The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: The role of serotonergic and noradrenergic receptors☆ , ☆☆

It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α₂-adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an α(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300 μg/kg) but not imiloxan (an α(2B)-adrenoceptor antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally, ketanserin (a 5-HT₂ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HT₄ receptor antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HT₃ receptor antagonist, 0.5, 1, and 2 mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α(2A)-/α(2C)-adrenoceptors and 5-HT₂/5-HT₄ receptors may be responsible for the antinociceptive effect of imipramine on visceral pain in rats.

Evaluation of antinociceptive and neurotoxic effects of intrathecal dexmedetomidine in rats.

OBJECTIVE Dexmedetomidine has been reported to produce analgesia after intrathecal administration. In the present study the α2-adrenoceptor agonist dexmedetomidine was evaluated for its potential spinal neurotoxic effects. MATERIAL AND METHODS Three days after intrathecal cannulation, rats were administered either dexmedetomidine (3 μg/30 μL, i.t.) or saline (30 μL, i.t.). Antinociceptive, sedative and motor effects of intrathecal administrations of dexmedetomidine or saline were evaluated during 90 min. The tail-flick and hot plate tests were used to assess the thermal nociceptive threshold. Seven days after drug administration, animals were sacrified and spinal cords were evaluated for histopathological changes by light microscopy. RESULTS Dexmedetomidine administered intrathecally produced antinociception. Antinociception was accompanied by immediate sedation and loss of placing-stepping reflexes that lasted over 40 min in all dexmedetomidine administered rats. In all rats, microscopic examination revealed mild gliosis and minimal infiltration of inflamatory r cells in posterior white matter. Mild (total score 4-6) histopathologic lesions were seen in four animals in dexmedetomidine adminisered rats, but there was no statistically significant difference when compared with the saline administered rats. CONCLUSION We observed that intrathecal injections of dexmedetomidine at the dose of 3 μg/30 μL produce antinociception but did not cause any histopathological sign of injury in the spinal cord.

The role of heart-type fatty acid-binding protein in the evaluation of carbon monoxide poisoning in rats

Acute carbon monoxide (CO) poisoning can cause early and persistent damages in tissues sensitive to hypoxia. This study investigated serum heart-type fatty acid-binding protein (H-FABP) levels as a biomarker of acute CO poisoning in rats. The rats were exposed to a mixture of either 3000 (group A) or 5000 (group B) parts per million (ppm) CO in air, or to ambient air (group C, control group). Blood samples were taken just before, immediately after and 6 hours after the exposure, and serum H-FABP and troponin-I levels were measured. The consciousness level was evaluated just after the exposure. The survival rate was monitored for 7 days. Serum H-FABP levels increased just after the CO exposure in both groups A and B. Additionally, H-FABP level was higher in group B than in group A, immediately after the exposure. However, serum troponin-I levels only increased at 6 hours after the CO exposure in groups A and B. Consciousness and survival rates in group B were lower than that in group A. Our results suggest that H-FABP might have potential to be an early and quantitative parameter of clinical severity and prognosis in CO poisoning.

Time course of serum S100B protein and neuron-specific enolase levels of a single dose of chlorpyrifos in rats.

Organophosphate (OP) compounds are a large class of chemicals, many of which are used as pesticides. It is suggested that OPs specifically affect glia and neurons. Effects of acute exposure to chlorpyrifos (CPF), which is a common organophosphorus pesticide used worldwide, on neuron-specific enolase (NSE) and S100B levels in rat blood during 7 days were assessed. Rats were evaluated either before (0 hr) or 2, 12, 24, 48 and 168 hr (7 days) after injection of CPF (279 mg/kg, s.c.) or vehicle (peanut oil, 2 ml/kg, s.c.) for clinical signs of toxicity. Immediately after the evaluation of toxicity, blood samples were taken for biochemical assays. CPF administration produced decreases in body-weight and temperature, which were observed for first time at 12 hr after CPF administration and continued for 168 hr (p < 0.05-0.001). Serum S100B and NSE levels were acutely increased 2 hr after CPF administration and remained high at 12 hr (p < 0.01-0.001). NSE and S100B levels were not different in either CPF or vehicle groups at following time points. Serum butyrylcholinesterase (EC 3.1.1.8; BuChE) activity was dramatically reduced at 2 hr after CPF and remained low at each time points during 7 days (p < 0.01-0.001). Our results suggest that the usefulness of serum levels of these glia- and neuron-specific marker proteins in assessing OP toxicity, specifically CPF-induced toxicity.

Synthesis, characterization and anti-inflammatory activity of new 5-(3,4-dichlorophenyl)-2-(aroylmethyl) thio-1,3,4-oxadiaxoles.

Several 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiazoles were synthesized and characterized by elemental analyses, IR and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carregeenan-induced edema in rat paw. In addition, ulcerogenic activity was determined. The anti-inflammatory data scoring showed that compounds 5e, 5f and 5g, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5f was comparable to that of the reference drug indometacin (CAS 53-86-1).