Attenuation of oxidative stress and neurotoxicity involved in the antidepressant-like effect of the MK-801(dizocilpine) in Bacillus Calmette-Guerin-induced depression in mice.

Background The emerging line of research suggests that neuro-inflammation and oxidative stress are linked to the development of depression-like behavior. The tryptophan metabolizing enzyme, indolamine 2,3-dioxygenase (IDO), serves as an important interface between chronic inflammation and depression. IDO is induced by pro-inflammatory cytokines and diverts tryptophan towards the kynurenine pathway, decreasing serotonin synthesis. Further, the metabolites of kynurenine pathway increase brain oxidative stress and also cause N-methyl-D-aspartate (NMDA) receptor-mediated exitotoxicity. The resulting oxidative damage and dysfunction in glutamatergic neurotransmission alters the network connectivity of the brain, which may be the further mechanism for emergence of depression-like symptoms. Methods A depression-like illness was induced in mice by injecting Bacillus Calmette-Guerin (BCG) suspended in isotonic saline at a dose of 107 CFU I.P. The mice were then divided into different groups and were administered MK-801 or normal saline for the next 21 days, after which a battery of behavior and biochemical tests were conducted to assess them. Results The BCG group had significantly reduced sucrose preference index and an increase in immobility time in forced swim test (FST) and Tail Suspension Test (TST) as compared to the saline group. There was also a significant increase in the brain MDA levels and a decline in the brain GSH levels. The hippocampal tissue from the BCG group had significantly more comet cells than the saline group. The NMDA receptor antagonist, MK-801, was able to reverse the BCG-induced depression-like behaviour. MK-801 also showed significant decrease in brain oxidative stress but failed to show significant protection against BCG-induced neurotoxicity observed in comet assay. Conclusions The NMDA receptor antagonist, MK-801, mitigated BCG-induced, depressive-like behavior in mice by improving the sucrose preference and decreasing the duration of immobility time in TST and FST. The overall improvement in depression-like behavior was accompanied by a reduction in brain oxidative stress and comet cells, thus suggesting the antioxidant and neuroprotective action of MK-801.

Effects of Musa sapientum stem extract on experimental models of anxiety.

OBJECTIVE: The Musa sapientum (banana) plant extract has shown antioxidant activity in previous studies. Oxidative stress is one of the important factors implicated in the pathogenesis of anxiety disorders. The present study aimed to evaluate the anxiolytic activity of aqueous extract of M. sapientum stem (MSSE) in experimental models in mice. MATERIAL AND METHODS: Elevated Plus Maze method and locomotor monitoring by photoactometer were used. Animals were divided into five different groups (n=6/group). The vehicle, standard and the experimental groups were given distilled water (10 ml/kg), diazepam (1 mg /kg intraperitoneally) and incremental doses of 25, 50 and 100 mg/kg of MSSE, respectively, prior to the experiment. The standard group received diazepam. RESULTS: The number of open arm entries and the duration of time spent in the open arms in the MSSE-treated groups increased significantly in a dose-dependent manner as compared to that of control group. The duration of time spent in closed arms in the MSSE-treated groups decreased significantly in a dose-dependent manner as compared to that of the control group. MSSE also decreased the locomotor activity significantly at all three test doses. CONCLUSION: The results of this study suggest an anxiolytic activity for MSSE, which make it a potential natural compound for treatment of anxiety disorders.

Effect of Musa sapientum Stem Extract on Animal Models of Depression.

BACKGROUND: Musa sapientum, the banana plant, has shown to possess antioxidant activity in previous studies. Oxidative stress has been linked to the pathogenesis of major depressive disorder (MDD) with evidence of increased serum levels of oxidative stress biomarkers in MDD patients. OBJECTIVE: The present study aimed to evaluate the antidepressant activity of M. sapientum stem extract (MSSE) in experimental models in mice. MATERIALS AND METHODS: Forced swim test (FST) and tail suspension test (TST) were carried out in five different groups (n = 6/group) of mice. The vehicle, standard drug, and the three test groups were orally administered distilled water (10 mL/kg), fluoxetine (25 mg/kg), and incremental doses of 25, 50, and 100 mg of MSSE, respectively, 45 min prior to the experiment. RESULTS: On FST, the duration of immobility in control group, which was 161.5 ± 6.78 (in seconds, mean ± standard error of mean [SEM]), decreased to 149.33 ± 2.70 (25 mg/kg MSSE), 120.17 ± 8.35 (50 mg/kg MSSE), and 45.17 ± 4.11 (100 mg/kg MSSE) in the treated groups. On TST, the duration of immobility in control group, which was 173.83 ± 12.65 (mean ± SEM), decreased to 163.17 ± 6.91 (25 mg/kg MSSE), 139.0 ± 5.9 (50 mg/kg MSSE), and 124.0 ± 4.42 (100 mg/kg MSSE) in the treated groups. The difference in the duration of immobility was statistically significant at middle and higher doses, i.e. 50 and 100 mg/kg MSSE (P < 0.05) respectively, when compared with the control group in both the tests. CONCLUSION: A significant antidepressant-like activity was found in MSSE, which could be a potential natural compound for use in depression. SUMMARY: The five groups - vehicle, standard drug, and the three test groups were administered distilled water (10 mL/kg), fluoxetine (25 mg/kg), and incremental doses of 25, 50, and 100 mg of Musa sapientum stem extract (MSSE), respectivelyThe duration of immobility decreased in the treated groups as compared to the control group on both, forced swim and tail suspension, testsThe difference in the duration of immobility was statistically significant at middle and higher doses, i.e., 50 and 100 mg/kg MSSE (P < 0.05), when compared with the control group in both the tests. Abbreviations Used: MDD: Major depressive disorder; MSSE: Musa sapientum stem extract; FST: Forced swim test; TST: Tail suspension test; GSH: Glutathione, MDA: Malondialdehyde; SOD: Superoxide dismutase.

Effect of Low Level Subchronic Microwave Radiation on Rat Brain.

OBJECTIVE: The present study was designed to investigate the effects of subchronic low level microwave radiation (MWR) on cognitive function, heat shock protein 70 (HSP70) level and DNA damage in brain of Fischer rats. METHODS: Experiments were performed on male Fischer rats exposed to microwave radiation for 90 days at three different frequencies: 900, 1800, and 2450 MHz. Animals were divided into 4 groups: Group I: Sham exposed, Group II: animals exposed to microwave radiation at 900 MHz and specific absorption rate (SAR) 5.953 × 10-4 W/kg, Group III: animals exposed to 1800 MHz at SAR 5.835 × 10-4 W/kg and Group IV: animals exposed to 2450 MHz at SAR 6.672 × 10-4 W/kg. All the animals were tested for cognitive function using elevated plus maze and Morris water maze at the end of the exposure period and subsequently sacrificed to collect brain tissues. HSP70 levels were estimated by ELISA and DNA damage was assessed using alkaline comet assay. RESULTS: Microwave exposure at 900-2450 MHz with SAR values as mentioned above lead to decline in cognitive function, increase in HSP70 level and DNA damage in brain. CONCLUSION: The results of the present study suggest that low level microwave exposure at frequencies 900, 1800, and 2450 MHz may lead to hazardous effects on brain.

CYP2D6*2 Polymorphism as a Predictor of Failed Outpatient Tramadol Therapy in Postherpetic Neuralgia Patients.

Human cytochrome P4502D6 (CYP2D6) gene is highly polymorphic, leading to wide interindividual ethnic differences in CYP2D6-mediated drug metabolism. Its activity ranges from complete deficiency to excessive activity, potentially causing toxicity of the medication or therapeutic failure with recommended drug dosages. The aim of the study was to find the association of CYP2D6*2 polymorphisms with demographic characters (age, sex, and weight), pain intensity scales [numerical rating scale (NRS) sleep, global perceived effect (GPE)], and adverse drug effects in postherpetic neuralgia (PHN) patients receiving tramadol. The study comprised 246 patients [including 123 nonresponders (NRs) and 123 responders (Rs)] with PHN undergoing analgesic treatment at the pain clinic, Out Patient Department, University College of Medical Sciences, Guru Teg Bahadur Hospital, Delhi, India. Patients with any history of diabetes mellitus, human immunodeficiency virus, malignancy, hematological or liver disease, psychiatric illness, alcohol abuse, and tramadol sensitivity were excluded from the study. The NRSs of (resting and movement), NRS-sleep, and GPE were evaluated by the treating physician. Adverse drug effects during the time of the study were recorded. All samples were analyzed for CYP2D6*2 polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. The genotype distribution did not vary significantly among genders [NR (P = 0.723); R (P = 0.947)] and different age groups in NRs (P = 0.763) and Rs (P = 0.268). Clinically, statistically significant (P < 0.001) results were obtained in both the groups when compared with baseline in the NRS-sleep and GPE scores, whereas no association was found between NRS-sleep and GPE scores when compared with CYP2D6*2 genotype (P > 0.05). In addition, CYP2D6*2 genotype was not related to the adverse effects of analgesic therapy. The overall results suggested that CYP2D6*2 polymorphism plays no role in the PHN patients receiving tramadol treatment. The CYP2D6*2 polymorphism may not be a predictor of treatment outcome of patients with respect to PHN-receiving tramadol.

Cognitive impairment and neurogenotoxic effects in rats exposed to low-intensity microwave radiation.

The health hazard of microwave radiation (MWR) has become a recent subject of interest as a result of the enormous increase in mobile phone usage. The present study aimed to investigate the effects of chronic low-intensity microwave exposure on cognitive function, heat shock protein 70 (HSP70), and DNA damage in rat brain. Experiments were performed on male Fischer rats exposed to MWR for 180 days at 3 different frequencies, namely, 900, 1800 MHz, and 2450 MHz. Animals were divided into 4 groups: group I: sham exposed; group II: exposed to MWR at 900 MHz, specific absorption rate (SAR) 5.953 × 10(-4) W/kg; group III: exposed to 1800 MHz, SAR 5.835 × 10(-4) W/kg; and group IV: exposed to 2450 MHz, SAR 6.672 × 10(-4) W/kg. All the rats were tested for cognitive function at the end of the exposure period and were subsequently sacrificed to collect brain. Level of HSP70 was estimated by enzyme-linked immunotarget assay and DNA damage was assessed using alkaline comet assay in all the groups. The results showed declined cognitive function, elevated HSP70 level, and DNA damage in the brain of microwave-exposed animals. The results indicated that, chronic low-intensity microwave exposure in the frequency range of 900 to 2450 MHz may cause hazardous effects on the brain.

Effect of Cinnamomum zeylanicum extract on scopolamine-induced cognitive impairment and oxidative stress in rats.

OBJECTIVE: Cinnamomum zeylanicum (CZ) is commonly known as cinnamon in traditional system of medicine having antibacterial, antioxidant, antidiabetic, hypolipidemic, and other activities. The present study was designed to assess the effect of extract of CZ bark on cognitive performance of scopolamine (SCOP)-treated rats and on associated altered oxidative stress markers in the brain of rats. METHODS: The extract was administered orally in three doses (100, 200, and 400 mg/kg) for a period of 21 days. SCOP was administered in the dose of 1.0 mg/kg intraperitoneally. The Morris water maze and passive avoidance step-down tasks were performed to assess cognitive functions. At the end of the study, oxidative stress parameters namely, malondialdehyde (MDA) and reduced glutathione (GSH) were also analyzed in the brain tissue of rats. RESULTS: SCOP-treated group showed significantly impaired acquisition and retention of memory as compared to the saline- and vehicle-treated groups. Pretreatment with CZ extract (200 and 400 mg/kg) for 21 days significantly reversed SCOP-induced amnesia as evidenced by increased step-down latency in passive avoidance and decreased latency in Morris water maze test compared to the SCOP-treated group. SCOP administration also caused the increase of MDA and reduction of GSH levels. Pretreatment with CZ extract (200 and 400 mg/kg) resulted in a significant decrease in MDA levels and increase in GSH levels as compared to the SCOP-treated animals. DISCUSSION: The results suggest that CZ can induce cognitive improvement in SCOP-treated rats and this effect can be attributed to a certain extent to decreased oxidative stress.

Possible role of oxidative stress and brain derived neurotrophic factor in triazophos induced cognitive impairment in rats.

Triazophos, O,O-diethyl-1-H-1,2,4-triazol-3-yl phosphorothioate, (TZ) is an organophosphate pesticide widely used as an insecticide in agriculture fields, however, its adverse effects on cognitive function remain unknown till date. The present study was designed to identify the effect of TZ on cognitive function in order to gain an insight into the molecular mechanism(s) probably involved in TZ induced toxicity. Wistar male albino rats were orally administered with TZ at 8.2 mg/kg bw daily for 30 days. Cognitive function was assessed by evaluating step down latency (SDL) in passive avoidance apparatus, transfer latency (TL) on elevated plus maze and escape latency (EL) using morris water maze. The biochemical changes, in terms of malondialdehyde (MDA), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were evaluated in hippocampi regions. Relative mRNA expression and protein expression of BDNF were also evaluated. The results demonstrated that rats treated with TZ showed significantly (p < 0.01) reduced SDL and prolonged TL and EL as compared to control group rats. Moreover, significantly low (p < 0.01) mRNA expression and protein levels (p < 0.001) of BDNF, increased MDA and reduced GSH levels were observed in TZ treated rats. The study concludes that chronic exposure to TZ significantly impairs the learning and memory which may be attributed to the significantly reduced mRNA and protein expression of BDNF in hippocampus. Moreover, BDNF is negatively correlated to MDA levels and positively correlated to GSH levels. Hence, it can be suggested that interplay between BDNF and oxidative stress plays an important role in mediating the toxic effects of TZ.

Effect of low level microwave radiation exposure on cognitive function and oxidative stress in rats.

Use of wireless communicating devices is increasing at an exponential rate in present time and is raising serious concerns about possible adverse effects of microwave (MW) radiation emitted from these devices on human health. The present study aimed to evaluate the effects of 900 MHz MW radiation exposure on cognitive function and oxidative stress in blood of Fischer rats. Animals were divided into two groups (6 animals/group): Group I (MW-exposed) and Group II (Sham-exposed). Animals were subjected to MW exposure (Frequency 900 MHz; specific absorption rate 8.4738 x 10(-5) W/kg) in Gigahertz transverse electromagnetic cell (GTEM) for 30 days (2 h/day, 5 days/week). Subsequently, cognitive function and oxidative stress parameters were examined for each group. Results showed significant impairment in cognitive function and increase in oxidative stress, as evidenced by the increase in levels of MDA (a marker of lipid peroxidation) and protein carbonyl (a marker of protein oxidation) and unaltered GSH content in blood. Thus, the study demonstrated that low level MW radiation had significant effect on cognitive function and was also capable of leading to oxidative stress.

CYP2D6*4 polymorphism, tramadol treatment and its clinical impact in patients with postherpetic neuralgia.

AIM: The aim of this study was to investigate the associations between the CYP2D6*4 polymorphism, interindividual differences in CYP2D6 activity and adverse drug effects in postherpetic neuralgia (PHN) patients receiving tramadol. PATIENTS & METHODS: The study comprised 158 patients (including 78 nonresponders and 80 responders) with PHN who were undergoing analgesic treatment at the Pain Clinic in the Out Patient Department of the University College of Medical Sciences, Guru Teg Bahadur Hospital (New Delhi, India). The numerical rating scale scores were measured at the resting and movement stages; Neuropathic Pain Symptom Inventory scores were evaluated by the treating physician. WHO-brief questionnaire scores for quality of life and adverse drug effects during the time of study were recorded. All samples were analyzed for the CYP2D6*4 polymorphism using the PCR-restriction fragmentation length polymorphism method. RESULTS: The genotype distribution did not vary significantly among different age groups in nonresponders and responders. The CYP2D6*4 polymorphism was significantly associated with lower Neuropathic Pain Symptom Inventory (burning, squeezing stabbing and pressure) scores. The quality-of-life (sociological, psychological and environmental domains) scores correlated with CYP2D6*4 and showed significant results (p < 0.05) using a generalized linear model. No association was found between the physiological domain compared with the CYP2D6*4 allele (p > 0.05). In addition, the homozygous mutated CYP2D6*4 allele was not related to adverse effects of analgesic therapy. CONCLUSION: The CYP2D6*4 polymorphism may not be a predictor for treatment outcome of patients with PHN receiving tramadol. However, further investigation is required to confirm these findings in a larger sample size.

Protective effect of N-acetylcysteine on bisphenol A-induced cognitive dysfunction and oxidative stress in rats.

Bisphenol A (BPA) is commonly used as a monomer in polycarbonate plastics. The present study was designed to investigate the effect of BPA on cognitive functions and oxidative stress in the brain tissue of rats and if co-administration of N-acetylcysteine (NAC), an antioxidant, can modulate the effect of BPA on cognitive functions and prevent any possible oxidative stress. The BPA was administered per orally (p.o) in two doses 2 and 20 µg/kg for 28 days. Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and spatial navigation task on Morris water maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and reduced glutathione (GSH) levels. A significant reduction in SDL, and prolongation of latency in spatial navigation task were observed in BPA (2 and 20 µg/kg) treated group as compared to control group. The co-administration of NAC (100 mg/kg, p.o) antagonized the effect of BPA on SDL and spatial navigation test. NAC treatment also attenuated the BPA-induced increased MDA levels and decreased GSH levels in brain. Results of the present study show that NAC has potential to reverse cognitive dysfunction and oxidative stress induced by BPA exposure in rats.

Anticonvulsant and antioxidant actions of trimetazidine in pentylenetetrazole-induced kindling model in mice.

The present study was carried out to investigate the effect of trimetazidine on the course of pentylenetetrazole (PTZ)-induced chemical kindling and oxidative stress markers in PTZ-kindled mice. Kindling was induced by repeated injections of a subconvulsive dose of PTZ (30 mg/kg, i.p.) on alternate days for 5 weeks or until stage 4 of the seizure score was evoked on three consecutive administrations. Trimetazidine was administered daily in three doses (5, 10 and 20 mg/kg) per orally (p.o.) along with alternate-day PTZ. Following PTZ kindling, oxidative stress parameters, i.e. levels of malondialdehyde (MDA) and reduced glutathione (GSH), were assessed in isolated homogenized whole brain tissue. The results showed that PTZ treatment progressively increased the seizure score in control mice. Biochemical analysis revealed a significant increase in MDA levels and decreased GSH levels in the brain homogenate of PTZ-kindled mice. Daily treatment with trimetazidine in doses of 10 and 20 mg/kg significantly decreased the PTZ-induced seizure score. However, a low dose of trimetazidine (5 mg/kg) failed to improve the seizure score. Pretreatment of trimetazidine in all doses showed an ameliorating effect on biochemical alteration induced by PTZ treatment. The results of the present study indicate the potential anticonvulsant activity of trimetazidine against PTZ-induced kindling in mice.

Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice.

Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer.

Protective role of melatonin in myocardial oxidative damage induced by mercury in murine model.

This study was designed to investigate the electrophysiological, hemodynamic and biochemical parameters of mercuric chloride and methylmercury exposure on cardiovascular functions and its modulation by melatonin in vivo. Wistar albino rats were divided into six group containing 10 animals each. Mercuric chloride (3.75 µM/L) in drinking water and methylmercury (0.5 mg/kg/day) through gavage, given for 1 month, induced a statistically significant increase (p < 0.001) in left ventricular end diastolic pressure, blood and cardiac tissue mercury content and myocardial lipid peroxides compared to control. Significant attenuation (p < 0.05) of baroreflex sensitivity and depletion of myocardial endogenous antioxidants (p < 0.001) viz. Reduced glutathione (GSH) and superoxide dismutase (SOD) were also found in the mercury-exposed groups as compared to control group. Mercury exposure followed by subacute treatment with melatonin (4 µg/mL/day) in drinking water for 1 month significantly lowered (p < 0.01) left ventricular end diastolic pressure and lipid peroxide levels and increased baroreceptor sensitivity (p < 0.001) and also levels of GSH and SOD (p < 0.001) as compared to mercury-exposed rats. The results of our study provide clear evidence that elevated oxidative stress and altered baroreflex mechanisms caused by mercury intoxication may be the contributing factors responsible for impairment of cardiovascular functions and melatonin may exhibit cardioprotective property against subacute heavy metal intoxication and enhance the antioxidant defense against mercury-induced oxidative myocardial injury in rats.

Clove oil reverses learning and memory deficits in scopolamine-treated mice.

The present study was performed to examine the effect of Eugenia caryophyllata (Myrtaceae) on learning and memory, and also evaluate whether it can modulate oxidative stress in mice. Passive avoidance step-down task and elevated plus-maze were used to assess learning and memory in scopolamine-treated mice. Oxidative stress parameters were also assessed in brain samples by estimating the malondialdehyde (MDA) and reduced glutathione (GSH) levels at the end of the study. Scopolamine (0.3 mg/kg, i. p.) produced impairment of acquisition memory as evidenced by a decrease in step-down latency and an increase in transfer latency on day 1, and also impairment of retention of memory on day 2. Pretreatment with clove oil (0.05 mL/kg and 0.1 mL/kg) for 3 weeks significantly reversed the increase in acquisition latency and all the doses (0.025, 0.05, 0.1 mL/kg, i. p.) reversed the increase in retention latency induced by scopolamine (0.3 mg/kg, i. p.) in elevated plus-maze. However, 0.05 mL/kg clove oil attenuated memory deficits in the passive avoidance step-down task. Brain samples showed a significant decrease in MDA levels in the group treated with clove oil (0.05 and 0.025 mL/kg). GSH levels were also increased in clove oil-treated mice though the results were not significant. Thus, it can be concluded that clove oil can reverse the short-term and long-term memory deficits induced by scopolamine (0.3 mg/kg, i. p.) and this effect can, to some extent, be attributed to decreased oxidative stress.

Trimetazidine exerts protection against increasing current electroshock seizure test in mice.

Trimetazidine, a novel anti-ischemic agent, is used in the therapy of angina, vertigo and chorioretinal diseases. It has also been examined for its effect on nociception, inflammation and neuroprotection in various animal models. The present study was designed to investigate the effect of trimetazidine on electrically induced seizures in mice. Trimetazidine was administered orally in doses of 5, 10 and 20mg/kg (single dose) to observe its effect on the increasing current electroshock seizure (ICES) test in mice. Trimetazidine in 10 and 20mg/kg doses significantly raised the seizure-threshold current in the ICES test. Further, co-administration of per se ineffective dose of trimetazidine (5mg/kg, p.o.) with sub-anticonvulsant dose of nimodipine (10mg/kg, p.o.) and phenytoin (12.5mg/kg, p.o.) offered significant protection in the ICES test. These results indicate that trimetazidine possesses significant anticonvulsant activity against electro-convulsions in the mice.

Anxiogenic and proconvulsant effect of gatifloxacin in mice.

The present study was performed to assess the neurological and neurobehavioural effects of gatifloxacin after its oral administration in two doses: 25 and 50 mg/kg for 7 days and 14 days in mice. The neurobehavioural parameters used for the short-term study (x 7 days) were pentylenetetrazole-induced seizure, forced swim test, elevated plus-maze, spontaneous alternation behaviour and rota-rod tests. However, only pentylenetetrazole-induced seizure and rota-rod tests were performed in long term (x 14 days) study. The results showed proconvulsant effect of gatifloxacin (50 mg/kg) in pentylenetetrazole-induced seizure test after both short- and long-term administration studies. Gatifloxacin in both doses showed an anxiogenic effect. However, in both doses, it did not show any effect on memory and mood as the drug did not show any effect in alternation behaviour and forced swim tests. In the long term study, gatifloxacin in 50 mg/kg, p.o. produced grip impairing effect only after 14 days of administration. These results reveal that gatifloxacin possesses proconvulsant and anxiogenic effects but it does not have an effect on mood and memory. Besides, long term administration of gatifloxacin for 14 days was found to reduce grip strength indicating its movement impairing effect in mice.

On the mechanism of anticonvulsant effect of tramadol in mice.

The present study was conducted to examine the effects of tramadol, an atypical opioid on convulsive behaviour in maximal electroshock (MES) seizure test on mice. Moreover, an attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 sec). Seizure severity was determined by (1) the duration of tonic hindlimb extensor (THE) phase and by (2) mortality due to electroconvulsions. Intraperitoneal (i.p.) administration of tramadol dose-dependently (10-50 mg/kg) decreased the duration of THE phase of MES. The anticonvulsant effect of tramadol was antagonized by the opioid antagonists, naloxone in high dose, and MR2266, a selective kappa antagonist but not by naltrindole, a delta opioid antagonist. Coadministration of either gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol and baclofen) or N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 with tramadol augmented the anticonvulsant effect of the latter drug. By contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, counteracted the diazepam-induced facilitation of anti-MES effect of tramadol. Similarly, delta-aminovaleric acid (DAVA), a GABAB receptor antagonist, abolished the facilitatory effect of baclofen, a GABAB agonist on anti-MES action of tramadol. These BZD-GABAergic antagonists, flumazenil or DAVA, on their own also antagonized the anti-MES effect of tramadol administered alone. No significant effect on mortality was observed in any of the studied groups. Taken together, the current results have demonstrated a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), GABAA-BZD receptors system, GABAB receptors and NMDA channel involvement in the antielectroshock effect of tramadol in mice.

Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice.

The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.

Possible mechanism involved in the anticonvulsant action of butorphanol in mice.

The study was designed to examine the effect of butorphanol, a classical opioid on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2 s). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of butorphanol produced a dose-dependent (0.25-2 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of butorphanol was antagonized by all the three opioid receptor antagonists (i.e., naloxone [mu], MR2266 [kappa], and naltrindole [delta], respectively). Coadministration of gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol, and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with butorphanol augmented the anticonvulsant action of the latter drug. In contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of butorphanol. Similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, antagonized the facilitatory effect of baclofen, a GABA(B) agonist on anti-MES action of butorphanol. These BZD-GABAergic antagonists, flumazenil or DAVA, per se also counteracted the anti-MES effect of butorphanol given alone. These data exemplify the benefits of using the MES test, which is sensitive to opioidergic compounds and distinguished convulsive behavioural changes associated with GABAergic and NMDAergic effects. Taken together, the results implicate a role for multitude of neurotransmitter systems, i.e., opioid (mu, kappa, delta), NMDA channel, BZD-GABA(A) chloride channel complex, and GABA(B) receptors in the anti-MES action of butorphanol.