Investigating the mechanism of action of ginkgolides and bilobalide on absence seizures in male WAG/Rij rats.

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6 mg/kg. In interaction groups, 6 µg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10 µg), CNQX (1 µg), and nicardipine (50 µg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p = .028), C (p = .046), and bilobalide (p = .043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p = .046), CNQX (p = .043), and nicardipine (p = .046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

Electroencephalographic investigation of the effects of Ginkgo biloba on spike-wave discharges in rats with genetic absence epilepsy.

OBJECTIVE: EGb 761, a plant extract obtained from the leaves of the Ginkgo biloba tree, is widely used in modern medicine and traditional medicine applications in the treatment of many diseases. However, in some clinical case reports, it has been suggested that G. biloba causes epileptic seizures. A limited number of experimental animal studies related to the effects of G. biloba on epileptic seizures do not provide sufficient information on the solution of a serious clinical problem with contrasting findings. We aimed to investigate the effects of EGb 761 administered in different doses to adult male Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is the genetic animal model of absence epilepsy, on absence seizures using in vivo electrophysiological method. In addition, the effects of EGb 761 doses on locomotor behavior of WAG/Rij rats were evaluated with open-field and rotarod behavioral tests. METHODS: 50, 100, 200, and 400 mg/kg doses of EGb 761 were administered to male WAG/Rij rats with implanted EEG electrodes by oral gavage for 28 days. Evaluation of absence seizures was performed on spike-wave discharges (SWDs) in EEG recorded for 4 h each week. The number of SWDs, the total duration of SWDs, and the mean duration of SWD were determined for the analysis. RESULTS: In the group treated with 400 mg/kg EGb 761, the number of SWDs and the mean duration of SWD at the 1st and 7th doses and the total duration of SWDs at the 1st, 7th and 14th doses were significantly increased (p < 0.05). In all experimental groups treated with EGb 761 doses, there was no significant change in locomotor activity in the open-field and the rotarod tests. CONCLUSION: Ginkgo biloba extract EGb 761 increased the epileptic SWD parameters of WAG/Rij rats at high doses (400 mg/kg), causing a pro-epileptic effect on absence seizures. It should be noted that in patients with epilepsy and in high-dose applications, G. biloba extract EGb 761 may lead to an increase in neuronal excitability.

The effects of a continuous 1-h a day 900-MHz electromagnetic field applied throughout early and mid-adolescence on hippocampus morphology and learning behavior in late adolescent male rats.

The purpose of this study was to investigate hippocampus morphology and changes in learning behavior in male rats in late adolescence exposed to the effect of a continuous 1-h a day 900-megahertz (MHz) electromagnetic field (EMF). Twenty-four male Sprague Dawley rats aged 3-weeks were divided equally into control, sham and EMF groups. EMF group rats were exposed to a 900-MHz EMF inside an EMF cage, while the sham group rats were placed in the same cage but were not exposed to such an effect. No procedure was performed on the control group. Following 25-day application of EMF, passive avoidance, 8-arm radial maze and Y-maze tests were applied to determine rats' learning and memory performances. Open field and rotarod tests were applied to assess locomotor activity. At the end of the tests, the animals' brains were removed. Sections were taken and stained with toluidine blue. The regions of the hippocampus were subjected to histopathological evaluation. At histopathological examination, impairments of pyramidal and granular cell structures were observed in the EMF group hippocampus. No significant change was observed in learning, memory or locomotor behavior in any group. In conclusion, 900-MHz EMF applied in early and mid-adolescence causes no changes in learning, memory or locomotor behavior.

Does pain sensitivity increase during ictal period? Evidence from absence epileptic WAG/Rij rats.

OBJECTIVE: The hyperexcitable brain provides a common ground for comorbidity of pain syndromes and epilepsy. There are controversial reports about pain sensitivity during the ictal period. We analyzed the pain sensitivity during the ictal period in the genetic absence epilepsy animal model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. METHODS: The ictal and interictal pain sensitivities of symptomatic WAG/Rij rats (8 months old, n = 19) were determined and compared with those of age-matched control Wistar rats (n = 19). Pain sensitivity was assessed by applying heat stimulation to hind paws and measuring the paw-withdrawal latency using a thermal plantar analgesia meter in awake and freely moving animals. All measurements were made during the interictal and ictal periods and confirmed by simultaneous electroencephalography (EEG) through intracranially implanted electrodes. RESULTS: The nociceptive stimulus-induced withdrawal latency during the ictal period in absence epilepsy WAG/Rij rats was significantly shorter when compared with that during the interictal period (p = 0.007) and when compared with that in the control Wistar rats (p = 0.001). CONCLUSION: Our data indicate higher pain sensitivity during the ictal period in absence epilepsy rats. Considering the fact that subjects are less responsive during spike-wave discharges, there is a decrease in the level of consciousness and/or responsiveness ictally during all generalized genetic seizures, this increased pain sensitivity is rather surprising during the ictal period. Although the mechanism remains unknown, this novel finding deserves further investigation.

Epilepsy may cause increased pain sensitivity: Evidence from absence epileptic WAG/Rij rats.

OBJECTIVE: The comorbidity of epilepsy and pain disorders as well as effectiveness of certain therapeutic approaches in both conditions attracted attention to epilepsy-pain interactions. This lead to the discovery of significantly shared pathophysiological mechanisms although many aspects remain largely unknown. To test the hypothesis that epilepsy may be associated with altered pain sensitivity, we analyzed interictal pain sensitivity using epilepsy prone WAG/Rij rats, a genetic model exhibiting age-related-onset absence epilepsy. METHODS: Two series of experiments were conducted. In experiment I, pain sensitivity of symptomatic WAG/Rij rats were compared with age-matched control Wistar rats. In experiment II, pain sensitivity of WAG/Rij rats were monitored longitudinally when they were presymptomatic (at 2months) and symptomatic (after maturation, at 8months), and compared with age-matched control Wistar rats. Pain sensitivity was assessed by applying heat stimuli to hind paws and measuring the paw-withdrawal latency using thermal plantar analgesia meter in awake and freely moving animals. All pain measurements were made during the interictal period, confirmed by simultaneous electroencephalography through intracranially implanted electrodes. RESULTS: In experiment I, the interictal pain withdrawal latency of symptomatic WAG/Rij rats was significantly shorter than control Wistar rats (P<0.01). In experiment II, WAG/Rij rats had significantly shorter latency of withdrawal response than control Wistar rats, both at presymptomatic (P<0.05) and symptomatic stage (P<0.0001). Matured (8months old) control Wistar rats demonstrated significantly increased withdrawal latency compared to the 2months animals (P<0.01), but the WAG/Rij rats did not (P>0.5). CONCLUSION: Epileptic WAG/Rij rats present significantly increased pain sensitivity when compared to control Wistar rats, suggesting comorbidity of epilepsy and pain.

The effects of edaravone in ketamine-induced model of mania in rats.

Bipolar disorder is a chronic disease characterized by recurring episodes of mania and depression that can lead to disability. This study investigates the protective effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a drug with well-known antioxidant properties, in a model of mania induced by ketamine in rats. Locomotor activity was assessed in the open-field test. Superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) levels were measured in order to evaluate oxidative damage in the rat hippocampus and prefrontal cortex. Increased locomotor activity (hyperlocomotion) was observed at the open-field test with ketamine treatment (25 mg/kg, i.p., 8 days). Edaravone (18 mg/kg) treatment did not prevent hyperlocomotion in the mania model induced with ketamine in rats, but lithium chloride (47.5 mg/kg, i.p., positive control) did prevent hyperlocomotion. Edaravone and lithium chloride treatments were found to reduce the increase in SOD and CAT activity following ketamine administration in a non-significant manner but caused no change in TBARS levels.

Evaluation of spatial memory and locomotor activity during hypercortisolism induced by the administration of dexamethasone in adult male rats.

In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid-induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory.