Interaction between carbenoxolone and valproic acid on pentylenetetrazole kindling model of epilepsy.

Gap junctions play an important role in the synchronized neuronal discharges. The main reason of the epileptic seizures is disruption of this synchronization. Therefore, the aim of the present study is to explore the combination valproic acid with carbenoxolone in pentylenetetrazole-kindled rats. In the first set of experiments, pentylenetetrazole (35 mg/kg intraperitoneally was administered to the rats to produce the kindling and then permanent screw electrodes to record electroencephalographic signals. The kindled rats were divided into six groups. While electroencephalographic recordings received from animals, behavioral evaluation was done by an observer. The data analysis was performed using T test and Mann-Whitney U tests. The dose of 40 mg/kg carbenoxolone was the most effective in carbenoxolone treatment groups. It prevented generalized seizures by 50%, reduced seizure stage, seizure duration and spike frequency. There was no significant difference between carbenoxolone-valproic acid combination and valproic acid on any seizure parameters. The current study is the first study which shows the interaction of carbenoxolone with valproic acid in pentylenetetrazole kindling model. As a result, carbenoxolone-valproic acid combination was not more effective than the standalone use of these drugs.

Effect of clozapine on locomotor activity and anxiety-related behavior in the neonatal mice administered MK-801.

Atypical antipsychotics have been used to treat fear and anxiety disturbance that are highly common in schizophrenic patients. It is suggested that disruptions of N-methyl-d-aspartate (NMDA)-mediated transmission of glutamate may underlie the pathophysiology of schizophrenia. The present study was conducted to analyze the effectiveness of clozapine on the anxiety-related behavior and locomotor function of the adult brain, which had previously undergone NMDA receptor blockade during a developmental period. In order to block the NMDA receptor, male mice were administered 0.25 mg/kg of MK-801 on days 7 to 10 postnatal. In adulthood, they were administered intraperitoneally 0.5 mg/kg of clozapine and tested with open-field and elevated plus maze test, to assess their emotional behavior and locomotor activity. In the group receiving MK-801 in the early developmental period the elevated plus maze test revealed a reduction in the anxiety-related behavior (p<0.05), while the open-field test indicated a decrease in locomotor activity (p<0.01). Despite these reductions, clozapine could not reverse the NMDA receptor blockade. Also, as an atypical antipsychotic agent, clozapine could not reverse impairment in the locomotor activity and anxiety-related behavior, induced by administration of the MK-801 in neonatal period.

Systemic side effects of locally used oxymetazoline.

OBJECTIVES: The object of the study is to experimentally investigate the possible systemic side effects of Oxymetazoline including its nasal spray which has been in use for a long time both by the physicians and patients. There is no study in the literature to address the damages of oxymetazoline on the end organ. MATERIALS AND METHODS: The study conducted on 2 groups of rat. Group 1 (n = 8): Control; and Group 2 (n = 8): Oxymetazoline. During 4 week, the control group was applied with 2 drops of saline water on each nasal cavity 3 times a day and the other group was applied with 2 drops of oxymetazoline HCl 3 times a day. At the end of experiment, samples from mandible, parotid and tails of the rats were taken in 10% formalin for histopathological investigations. RESULTS: In histopathological experiments, when compared with the control group, the oxymetazoline group showed significant increase in many of the histopathological parameters (ischemic changes: P = 0.0001; congestion: P = 0.0006; arterial thrombosis: P = Ns; PNL accumulations: P = 0.001; necrosis: P = 0.0001; and ulceration: P = 0.014). The results of histopathologic tests on the samples taken from mandible and parotid gland, in comparison with the control group, showed no significant increase (focal inflammation: P = Ns; and lymphocyte aggregation: P = Ns). CONCLUSION: Due to the damage that the long-term use of nasal spray including oxymetazoline, it may cause injury on the end organ, which we revealed in our histopathological experiments. We believe that it's essential for the physicians to provide information on the side effects of the medicine to their patients who use for a long term.

Protective effects of caffeic acid phenethyl ester on the dose-dependent acute nephrotoxicity with paraquat in a rat model.

Paraquat (PQ), which is used extensively as a potent herbicide throughout the world, is highly toxic in humans. We aimed to determine PQ-induced biochemical and histologic changes in the kidneys, and to evaluate the ability of the protective effects of caffeic acid phenethyl ester (CAPE) against PQ-induced injury in rats. Forty-eight rats were divided into eight groups of six: Group 1: Control; Group 2: 10 µmol/kg CAPE; Group 3: 15 mg/kg PQ; Group 4: 30 mg/kg PQ; Group 5: 45 mg/kg PQ; Group 6: 15 mg/kg PQ+CAPE; Group 7: 30 mg/kg PQ+CAPE; Group 8: 45 mg/kg PQ+CAPE. PQ and CAPE were injected intraperitoneally. The levels of the total oxidant status (TOS) and total antioxidant status (TAS) were determined in the supernatants of the excised left kidney. Right kidney tissue of each rat was removed to obtain a histologic score. When PQ-administrated (15, 30, 45) groups compared with other groups, TOS values were found to be significantly higher (p < 0.01). PQ (15, 30, 45) groups had significantly diminished values of TAS than the other groups (p < 0.001). Of histologic score evaluation, only the PQ45 group had a significantly higher value than the sham, and CAPE groups (p < 0.05). Moreover, in CAPE+PQ45 group, the level of histologic score was decreased compared to PQ45 group (p < 0.001). In conclusion, the evaluation of the data suggests that CAPE can be used to prevent the acute effects of PQ nephrotoxicity.

Efficacy of resuscitation with Intralipid in a levobupivacaine-induced cardiac arrest model.

AIM: Cardiac toxicity due to the administration of local anesthetics may be fatal. In this study, we evaluated the efficacy of a 20% lipid solution combined with epinephrine in a levobupivacaine-induced cardiac arrest model. MATERIALS AND METHODS: A total of 14 New Zealand rabbits were sedated and mechanically ventilated. Asystole was induced with intravenous levobupivacaine injection. The rabbits were randomized into groups receiving the same volume of either 0.9% saline (CR group) or a 20% lipid solution (LE group) along with a 100 µg/kg epinephrine bolus, which were administered immediately upon asystole. Standard advanced cardiac life support protocols were performed. RESULTS: Four subjects in the LE group as well as 3 subjects in the CR group had a spontaneous recovery (P = 0.592). In the 20th minute after arrest, 3 subjects in the LE group had maintained spontaneous circulation, while there was only 1 subject from the CR group with the same outcome. CONCLUSION: We found that adding a lipid solution to epinephrine for the resuscitation of rabbits that underwent levobupivacaine- induced cardiac arrest increased recovery rates of circulation and therefore the likelihood of survival. Further studies are needed to develop clinical therapies for the systemic toxicity of local anesthetics.

Thymoquinone attenuates trauma induced spinal cord damage in an animal model.

BACKGROUND: Spinal cord injury (SCI) is one of the most devastating conditions leading to neurological impairment and disabilities. The aim of the study was to investigate the potential neuroprotective effect of thymoquinone (TQ) histopathologically in an experimental model of traumatic spinal cord injury (SCI). METHODS: Twenty-four male Wistar albino rats were randomly divided into 4 groups: control group; SCI group; SCI-induced and 10 mg/kg/day TQ administered group; SCI-induced and 30 mg/kg/day TQ administered group. TQ was given as intraperitoneal for three days prior to injury and four days following injury. Spinal cord segment between T8 and T10 were taken for histopathologic examination. Hemorrhage, spongiosis and liquefactive necrosis were analyzed semiquantatively for histopathological changes. RESULTS: Administration of TQ at a dose of 10 mg/kg did not cause any significant change on the histological features of neuronal degeneration as compared to the SCI group (p=0.269); however, 30 mg/kg TQ significantly decreased the histological features of spinal cord damage below that of the SCI group (p=0.011). CONCLUSION: Data from this study suggest that TQ supplementation attenuates trauma induced spinal cord damage. Thus, TQ needs to be taken into consideration, for it may have a neuroprotective effect in trauma induced spinal cord damage.

Ameliorating effect of quercetin on acute pentylenetetrazole induced seizures in rats.

OBJECTIVE: The aim of the study to elicit effects of pure quercetin in pentylenetetrazole (PTZ) and picrotoxin induced seizures. MATERIALS AND METHODS: Each animal group was divided into six groups and composed of six rats. Rats were assigned to the following experiments and groups (G): (G1) PTZ 45 mg/kg + DMSO; (G2) PTZ 45 mg/kg + 5 mg/kg quercetin; (G3) PTZ 45 mg/kg + 10 mg/kg quercetin; (G4) PTZ 45 mg/kg + 20 mg/kg quercetin; (G5) PTZ 45 mg/kg + 40 mg/kg quercetin; (G6) Picrotoxin 5 mg/kg + DMSO; (G7) Picrotoxin 5 mg/kg + 10 mg/kg quercetin; (G8) Picrotoxin 5 mg/kg + 20 mg/kg quercetin. In all groups quercetin were injected 30 min before PTZ and picrotoxin applications. RESULTS: Compared to PTZ, quercetin significantly prolonged onset of the seizure in 10 mg/kg (P < 0.05) and reduced the seizure stage in 10 mg/kg quercetin injected group (P < 0.01). Compared to PTZ, quercetin also declined the generalized seizure duration at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.05) doses. At the doses of 5 mg/kg and 40 mg/kg quercetin there were no significant changes in seizure parameters. Development of picrotoxin induced seizures is slower than in PTZ. Quercetin was found to be unable to prevent seizure in picrotoxin induced seizures. Surprisingly, quercetin also significantly reduced the onset of seizures at the dose of 20 mg/kg (P < 0.05). CONCLUSION: quercetin (at doses of 10 and 20 mg/kg i.p) prevented seizures in PTZ (45 mg/kg i.p) induced seizures. Especially, 10 mg/kg PTZ prolonged onset of seizures, reduced the seizure duration and seizure severity score in comparison with control group. At a higher (40 mg/kg) dose quercetin failed to prevent PTZ induced seizures. In addition 20 mg/kg quercetin significantly reduced the onset of seizures that suggest a preconvulsive effect. 20 mg/kg quercetin reduced the onset of picrotoxin induced seizures. In picrotoxin model, it may be claimed that quercetin at higher doses accelerate the epileptic activity owing to its antagonistic effect on GABAA. Further investigations are needed to explore the mechanisms of the antiepileptic and preconvulsant effects of quercetin.

Effect of levetiracetam on penicillin induced epileptic activity in rats.

The aim of this study was to investigate the effects of levetiracetam (LEV) on penicillin-induced epileptiform activity in rats. Penicillin was applied intracerebroventricularly (icv) at a dose of 500 IU to induce epileptiform activity. LEV was given intraperitoneally (ip) at doses of 20, 40, 80 mg/kg before penicillin injection. This agent reduced epileptiform activity by decreasing spike frequencies. The mean spike frequencies decreased significantly in all the LEV treated groups. There was no significant change in the spike amplitudes of the LEV groups compared with the control group. 40 mg/kg of LEV was determined as the most effective dose on reducing epileptiform activity. The results of this study suggest that LEV is an effective antiepileptic agent in penicillin-induced epilepsy.

Determination of oxidative stress and effect of erdosteine on rhinitis medicamentosa in a rat model.

We aimed to determine the presence of oxidative stress in rhinitis medicamentosa (RM) and to evaluate the effect of erdosteine (ED) on mucosal changes in a rat model. Twenty-four male rats were used in this experimental study. Three groups were created. Group 1 (n=8) was the control group. Two puffs of 0.05% oxymetazolin were sprayed into the nasal cavities of the remaining rats (n=16) three times daily for eight weeks. One of these 16 rats was scarified at the end of the eight weeks and examined to confirm the presence of RM. Seven of the remaining 16 rats were killed, and venous blood samples were taken (Group 2). Group 3 (n=8) received 10mg/kg of an ED suspension orally for seven days. All rats were put on formalin for light microscopy. The total antioxidant status (TAS) was similar in all groups (p=0.073). The total oxidative status (TOS) of the RM group was significantly higher than that of the control group and RM+ED group (Group 3) (p=0.003 and p=0.011, respectively). The pathological recovery of the nasal mucosa of the rats was similar in the RM+ED and control groups. The TOS was high in this RM rat model, and oxidative stress was associated with RM. ED significantly ameliorated nasal mucosal changes induced by RM, suggesting that oxidative stress may play an important role in the pathophysiology of this condition.

Evaluation of mean platelet volume in patients with type 2 diabetes mellitus and blood glucose regulation: a marker for atherosclerosis?

OBJECTIVE: Platelets have an important role in atherosclerosis and arterial thrombosis. Cardiovascular complication prevalence of type 2 diabetes mellitus (type 2 DM) may be associated with glycosylated hemoglobin (HbA1c) and mean platelet volume (MPV). The aim of the study was to investigate if platelets were activated in diabetes and its associated vascular complications by measuring the MPV in the diabetics compared to the non-diabetics, and to determine the correlation of MPV with fasting serum glucose (FSG), HbA1c and duration of diabetes in the diabetic patients, respectively. MATERIALS AND METHODS: The study carried out in 65 patients with type 2 DM and 40 non-diabetic subjects. In addition to non-diabetic patients, all diabetic patients were divided into two groups according to their HbA1c levels: group A consisted of patients with HbA1c levels ≤7% and group B consisted of patients with HbA1c levels >7%. RESULTS: MPV was significantly higher in Group B as compared to both non-diabetics and Group A. MPV had a high positive correlation with HbA1c and FSG, as with diabetes duration. It is found that MPV was increased in type 2 DM. CONCLUSION: Our findings suggested an association between MPV and HbA1c. Therefore, MPV would be a beneficial prognostic marker of cardio-vascular complications in patients with type 2 DM.

Effects of paliperidone palmitate on coagulation: an experimental study.

OBJECTIVE: The aim of the present study was to examine the effects of a new antipsychotic drug paliperidone palmitate on hemogram and coagulation parameters in rats. MATERIALS AND METHODS: Experiments were performed on 22 female albino Wistar rats (8-12 weeks old). Control group was given drinking water as vehicle (0.3 mL). PAL-1 rats were given 1 mg/kg paliperidone palmitate (in 0.3 mL drinking water) by oral gavage once a day for ten days and PAL-3 rats received 3 mg/kg paliperidone palmitate (in 0.3 mL drinking water) by oral gavage for ten days. Blood samples were drawn from the heart 24 hours after the last drug dose, and hemogram and coagulation parameters were measured with automated analyzers. RESULTS: Hemogram did not change in the paliperidone treated groups compared to the controls. Factor VIII levels decreased in the PAL-1 and PAL-3 groups; and this decrease was significantly greater in the PAL-3. Factor IX levels decreased in PAL-3 rats, but its levels also increased in PAL-1 rats compared to the control. DISCUSSION: Paliperidone has led to changes in the serum levels of coagulation factors VIII and IX in rats. As a result, paliperidone may be causing thromboembolism or bleeding in a dose-independent manner.

Investigation of neutrophil lymphocyte ratio and blood glucose regulation in patients with type 2 diabetes mellitus.

OBJECTIVE: Leukocytosis is thought to be directly associated with the pathogenesis of atherosclerosis and metabolic syndrome. Increased white blood cell (WBC) count is related to cardiovascular disease in patients with type 2 diabetes mellitus; raised neutrophil lymphocyte ratio (NLR) is associated with metabolic syndrome. There is little information, however, concerning a correlation between glycosylated haemoglobin (HbA1c) and NLR. The aim of the present study was to investigate the relationship between NLR and blood glucose regulation. METHODS: This retrospective study was conducted in patients with type 2 diabetes mellitus, divided into two groups according to HbA1c levels: group 1, HbA1c levels ≤ 7%; group 2, HbA1c levels > 7%. Venous WBC, neutrophil and lymphocyte counts were determined. RESULTS: Of 71 patients included, fasting serum glucose, neutrophil and WBC counts were significantly higher in group 2 compared with group 1. NLR had a positive correlation with HbA1c. CONCLUSION: There may be a significant relationship between NLR and blood glucose regulation. The authors propose that increased NLR may be associated with elevated HbA1c in patients with type 2 diabetes mellitus.

The effect of blood glucose regulation on the presence of opportunistic Demodex folliculorum mites in patients with type 2 diabetes mellitus.

OBJECTIVES: To measure the rate of Demodex folliculorum mite infestation in patients with type 2 diabetes mellitus and to investigate if it was related to blood glucose control. METHODS: Patients with type 2 diabetes were classified according to their glycosylated haemoglobin (HbA(1c)) level into two groups: a well controlled blood glucose group (HbA(1c) ≤ 7%) and a poorly controlled blood glucose group (HbA(1c) > 7%). A standardized skin surface biopsy method was used to determine if the patients had D. folliculorum infestation (>5 mites/cm² of skin). RESULTS: A total of 69 patients (38 female) were enrolled in the study. Seventeen (24.6%) patients had D. folliculorum infestation. There were no significant differences in age, sex or body mass index between patients with and without D. folliculorum infestations. A significantly higher proportion of patients with poor blood glucose control had D. folliculorum infestation compared with patients with well controlled blood glucose. CONCLUSIONS: These current findings suggest that poor blood glucose regulation increases the susceptibility to D. folliculorum mite infestation in patients with type 2 diabetes.

Pituitary apoplexy due to thyroxine therapy in a patient with congenital hypothyroidism.

A 24-year-old woman was admitted with general weakness, umbilical swelling, developmental delay, speech disorder, constipation, gait problem. Her findings were umbilical hernia, xerosis, dry hair, and short stature. After thyroxine treatment, she also had headache, vomiting, and palpitation, lack of appetite, and sleep disturbance. Pituitary magnetic resonance imaging revealed a heterogeneous mass at the central part of the gland on coronal section and it was interpreted as pituitary apoplexy. In the current case, the patient with congenital hypothyroidism (CH) developed pituitary apoplexy (PA) after thyroxine therapy. Therefore, it is suggested that the complaints were related to PA rather than adrenal insufficiency. Here we describe a case report evaluating PA in a patient with thyrotrophic pituitary adenoma due to CH. To the best of our knowledge, this is the first case in terms of PA associated with CH after thyroxine therapy in the literature.

Influence of carbenoxolone on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats.

Abnormal synchronized neuronal discharges mediated by gap junctions have an important role in epileptic seizures. The analysis of anticonvulsant drugs acting on gap junctions is still a priority in epilepsy research. Therefore, the present study was designed to investigate the effect of carbenoxolone, a gap junction blocker, on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats. Male Wistar albino rats, 14 weeks of age, were used. In the first step of the study, animals were given PTZ 35 mg/kg intraperitoneally (i.p.) three times a week until kindling was produced. Then, indwelling screw electrodes - allowing EEG monitoring of conscious rats - were implanted into the crania of the kindled rats. In this way, we were able to record EEG activity and evaluate seizure stage at the same time. In the second step of the study, the interaction between carbenoxolone (40 mg/kg i.p.) and phenytoin (60 mg/kg, i.p.) was investigated. The data analysis was performed using a one-way ANOVA with LSD post-hoc test. Total spike number and the generalized seizure duration were reduced in the carbenoxolone treated group compared to the PTZ group. Phenytoin decreased generalized seizure duration, total spike number and seizure severity score. Carbenoxolone and phenytoin have anti-seizure effects in PTZ kindled rats. There was no significant difference between the carbenoxolone + phenytoin combination and phenytoin in terms of generalized seizure duration, total spike number and seizure stage. The results indicate that carbenoxolone combined with phenytoin is not more effective than the use of these drugs alone.

Anticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats.

Carnosine is a compound of naturally-occurring dipeptide that synthesized by the carnosine synthetase from beta-alanine and l-histidine. Recent reports claim that carnosine plays an important role in the control of epilepsy but its involvement in anticonvulsant functions remains unknown. In this study, we investigated the effects of carnosine in a rat model of epilepsy using the intracortical penicillin injection method. Thirty minutes after penicillin injection, the doses of 125, 250, 500, 1000 mg/kg carnosine and 90 min before penicillin injection the dose of 500 mg/kg carnosine were administered intraperitoneally. The epileptiform activity was verified by electrocorticographic (ECoG) recordings. The mean spike frequency of penicillin-induced epileptiform activity was significantly decreased in all carnosine-treated rats when compared with those of penicillin-injected. The dose of 500 mg/kg for carnosine treated and pretreated rats was found to be the most effective dose in reducing the frequency of penicillin-induced epileptiform activity. There was no significant difference in the mean onset of epileptiform activity between penicillin and 500 mg/kg carnosine pretreated groups. These findings indicate that carnosine has an anticonvulsant effect on penicillin-induced epilepsy in rats. Thus, our data support the hypothesis that carnosine may be a potential anticonvulsant drug for clinical therapy of epilepsy in the future.

Inhibition of neuronal nitric oxide synthase prevents iron-induced cerebellar Purkinje cell loss in the rat.

Iron plays an important role in maintaining normal brain function. However, in many neurodegenerative diseases abnormal iron accumulation in specific brain regions has been consistently reported. In this study, we investigated the neurotoxic effect of the intracerebroventricularly injected iron on the cerebellar Purkinje cells in the rat and the role of nitric oxide (NO) in this process. The role of NO in rats administered iron (FeCl36H2O) was examined with the use of a donor of NO, L-arginine (L-Arg) and a central selective inhibitor of NO synthase, 7-nitroindazole (7-NI). For this reason, rats were divided into 5 groups: control, iron-injected, iron plus L-Arg, iron plus 7-NI, and iron plus L-Arg plus 7-NI. Means (value +/- standard deviation) of the total numbers of Purkinje cells in the cerebellum were estimated as 337 +/- 23, 209 +/- 16, 167 +/- 19, 305 +/- 26, and 265 +/- 14 thousands in the control, iron, iron plus L-Arg, iron plus 7-NI, and iron plus L-Arg plus 7-NI groups, respectively. Iron treatment alone and the combination of iron and L-Arg caused a significant reduction in the total number of cerebellar Purkinje cells. Therefore, L-Arg increased the Purkinje cell loss induced by treatment with iron. These data show that inhibition of the neuronal NOS by 7-NI can prevent some of the deleterious effects of iron on cerebellar Purkinje cells. Presence of L-arginine decreased the neuroprotective effect of 7-NI.