Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in-food protocols

PURPOSE: The present study evaluated the effectiveness of intraperitoneal (IP) injections and oral administration of carbamazepine (CBZ) in food on the frequency of spontaneous motor seizures in rats with kainate-induced epilepsy. The purpose was to develop a convenient drug-in-food approach for continuous, long-term administration of potential antiepileptic drugs (AEDs). METHODS: Single IP injections of CBZ (10-100 mg/kg) were compared to vehicle injections via six AED-versus-vehicle tests using a repeated-measures, crossover protocol. Similar protocols were used with CBZ-containing or control food pellets. RESULTS: CBZ significantly reduced motor seizure frequency at 30 and 100 mg/kg after single IP injections, and these doses completely blocked motor seizures during a 6-h postdrug epoch in 25% and 70% of the animals, respectively. Single administrations of 30 mg/kg and 100 mg/kg CBZ in food also significantly reduced motor seizures, and blocked seizures in 33% and 89% of the rats, respectively. CBZ administered in food three times per day (100 mg/kg x3 CBZ in food) continuously blocked nearly all motor seizures over a 5-day period, and completely suppressed motor seizures in 50% of the animals tested. CONCLUSIONS: CBZ strongly suppresses spontaneous motor seizures, and single doses of CBZ in food are as effective as IP injections in rats with kainate-induced epilepsy. CBZ administered regularly in food continuously blocks nearly all motor seizures, and may provide a relatively simple method to test AEDs in chronic models of epilepsy.     

Opiate and non-opiate aspects of morphine induced seizures

The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.     

Pyrrolidone-carboxylic acid magnesium salt (PCA-Mg2+) protects against seizures induced by excitatory amino acids

Single administration of PCA-Mg2+ (200 mg/kg, s.c.) increased the latency and shortened the duration of seizures produced by systemic injection of N-methyl-D-aspartate (NMDA) in mice. Mortality was reduced in mice pretreated with PCA-Mg2+. Single or repeated (twice a day for 5 days) injections of PCA-Mg2+ (250 mg/kg, i.p.) also attenuated kainate-induced seizures in rats. However, PCA-Mg2+ had no effect on kainate-induced automatisms but reduced the frequency of generalized seizures. These results indicate that pharmacological doses of Mg2+ protect experimental animals against excitatory amino acid-induced seizures.     

The acute effects of estradiol benzoate on amygdala-kindled seizures in male rats

Using amygdaloid-kindling model of epilepsy, effects of acute estradiol treatment on seizure parameters were investigated in male rats. Fully kindled male rats were treated with various doses of estradiol benzoate (EB, 10, 30 and 50 microg/kg, i.p.) and kindling parameters such as seizure stage (SS), afterdischarge duration (ADD) and stage 5 duration (S5D) were elicited at various times (0.25, 1.5, 3 h and every 24 h for 96 h) post-drug administration. While the 10-microg/kg dose of EB failed to change seizure parameters, administration of the 30- and 50-microg/kg doses caused significant prolongation of ADD and S5D (was not changed significantly by the latter dose) at various time intervals post-drug administration. Pretreatment with the 3 mg/kg dose of tamoxifen citrate (TAM) inhibited the EB (30 microg/kg) effect, while pretreatment with the 10-mg/kg dose produced significant prolongation of ADD and S5D. These results suggest that in male amygdaloid kindled rats, acute estradiol treatment leads to an intensification of seizure that is manifested by increases in ADD and S5D. As the effect is evident 0.25 h post-EB administration and duel action of TAM in opposing the EB effect at low doses and potentiating it at the higher doses, the possibility of a genomic effect may be ruled out. The variable effects of TAM might be explained by its partial agonistic property on estrogen receptors     

Gender difference in susceptibility to picrotoxin-induced seizures is seizure- and stimulation-dependent

In a dose-response study, the pattern of sex-associated susceptibility to picrotoxin-induced myoclonic, focal, akinetic, and generalized tonic-clonic (GTC) seizures was investigated in rats to determine whether the reported heightened susceptibility of females to seizures was a general phenomenon in rats or whether it was limited to specific types of seizures. The latency to and incidence of specifically categorized seizures were used as indices of susceptibility after male and female rats had been injected with picrotoxin (3-10 mg/kg). The results revealed that at low doses of picrotoxin (4 mg/kg), female rats had significantly shorter latencies to myoclonic seizures and significantly shorter latencies and higher incidences of GTC seizures. At higher doses of picrotoxin (8 and 10 mg/kg), the pattern of relative susceptibility of males and females to myoclonic seizures was reversed, with males having shorter latencies than females. There were no significant sex differences in the incidence of or latency to focal or akinetic seizures at any of the doses tested. These findings indicate 1) that there are significant sex differences in seizure susceptibility only for specific seizure categories in rats; and 2) that for seizure categories where significant sex differences were identified, the observed pattern of relative susceptibility of males and females depends on the dose of picrotoxin tested. Thus, patterns of sex-associated seizure susceptibility favoring either males or females are both seizure- and stimulation-limited and do not reflect general dispositions to seizures in either sex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Chronic Oestradiol,Progesterone and Medroxyprogesterone Acetate on Hippocampal Neurogenesis and Adrenal Mass in Adult Female Rats

Both natural oestrogens and progesterone influence synaptic plasticity and neurogenesis within the female hippocampus. However, less is known of the impact of synthetic hormones on hippocampal structure and function. There is some evidence that the administration of the synthetic progestin, medroxyprogesterone acetate (MPA) is not as beneficial as natural progesterone and can attenuate oestrogen‐induced neuroprotection. Although the effects of oestradiol have been well studied, little is known about the effects of natural and synthetic progestins alone and in combination with oestradiol on adult neurogenesis in females. In the present study, we investigated the effects of chronic oestradiol, progesterone, MPA and the co‐administration of each progestin with oestradiol on neurogenesis within the dentate gyrus of adult ovariectomised female rats. Twenty‐four hours after a bromodeoxyuridine (BrdU; 200 mg/kg) injection, female rats were repeatedly administered either progesterone (1 or 4 mg), MPA (1 or 4 mg), oestradiol benzoate (EB), progesterone or MPA in combination with EB (10 μg), or vehicle for 21 days. Rats were perfused on day 22 and brain tissue was analysed for the number of BrdU‐labelled and Ki67 (an endogenous marker of cell proliferation)‐expressing cells. EB alone and MPA + EB significantly decreased neurogenesis and the number of surviving BrdU‐labelled cells in the dorsal region of the dentate gyrus, independent of any effects on cell proliferation. Furthermore, MPA (1 and 4 mg) and MPA + EB treated animals had significantly lower adrenal/body mass ratios and reduced serum corticosterone (CORT) levels. By contrast, progesterone + EB treated animals had significantly higher adrenal/body mass ratios and 1 mg of progesterone, progesterone + EB, and EB significantly increased CORT levels. The results of the present study demonstrate that different progestins alone and in combination with oestradiol can differentially affect neurogenesis (via cell survival) and regulation of the hypothalamic‐pituitary‐adrenal axis. These findings have implications for women using hormone replacement therapies with MPA for both neuroprotection and stress‐related disorders.     

The Ontogeny of GABAergic Enhancement of the γ-Hydroxybutyrate Model of Generalized Absence Seizures

The ontogeny of GABAergic enhancement of generalized absence seizures was examined in the gamma-hydroxybutyrate (GHB) model of generalized absence seizures. The GHB seizure was quantitated in developing and adult rats in the presence of varying doses of the GABAa agonist muscimol or intracerebroventricularly (i.c.v.) administered GABA. Both GABA and muscimol potentiated GHB-induced seizures in an age-dependent fashion. The adult dose of 1 mg/kg muscimol was extremely potent in rats less than 28 days of age and resulted in the death of all younger animals tested secondary to profound hypothermia. A dose of 0.1 mg/kg muscimol was associated with a significant prolongation of GHB seizure in rats less than 35 days of age, but had no effect on older animals. The response to GHB was also age dependent, with the greatest sensitivity occurring during the fourth and fifth week of life. The developmental sensitivity of the rat to GHB seizure correlated with enhancement of the seizure by muscimol and GABA, and both phenomena parallel the maturation of thalamocortical recruiting mechanisms thought to play a role in the pathogenesis of the bilaterally synchronous spike wave discharges that characterize generalized absence seizures.     

Domoic acid preconditioning and seizure induction in young and aged rats

Clinical reports suggest that the elderly are hypersensitive to the neurological effects of domoic acid (DOM). In the present study we assessed DOM-induced seizures in young and aged rats, and seizure attenuation following low-dose DOM pretreatment (i.e. preconditioning). Seizure behaviours following saline or DOM administration (0.5-2mg/kg i.p.) were continuously monitored for 2.5h in na?ve and DOM preconditioned rats. Competitive ELISA was used to determine serum and brain DOM concentrations. Dose- and age-dependent increases in seizure activity were evident in response to DOM. Lower doses of DOM in young and aged rats promoted low level seizure behaviours. Animals administered high doses (2mg/kg in young; 1mg/kg in aged) progressed through various stages of stereotypical behaviour (e.g., head tics, scratching, wet dog shakes) before ultimately exhibiting tonic-clonic convulsions. Serum and brain DOM analysis indicated impaired renal clearance as contributory to increased DOM sensitivity in aged animals, and this was supported by seizure analysis following direct intrahippocampal administration of DOM. Preconditioning young and aged animals with low-dose DOM 45-90 min before high-dose DOM significantly reduced seizure intensity. We conclude that age-related supersensitivity to DOM is related to reduced clearance rather than increased neuronal sensitivity, and that preconditioning mechanisms underlying an inducible tolerance to excitotoxins are robustly expressed in both young and aged CNS.     

Nature and the time course of seizures associated with surgical removal of the pineal gland from parathyroidectomized rats

About 80% of male rats that are parathyroidectomized at 23 days of age and are pinealectomized a week later exhibit intermittent seizures and frequently death. Characteristically, the seizures are violent and death is probably a result of asphyxiation. The peak incidence of seizures in these rats occurs within 8 hr after pinealectomy and approximately 50% of the animals die within 48 hr of the operation. Chlordiazepoxide (18–20 mg/kg), diazepam (18–20 mg/kg) or chlorpromazine (20 mg/kg), given as single subcutaneous doses at the time of pinealectomy, delayed the onset of the seizures. Haloperidol (20 mg/kg) had a modest suppressive effect on the seizure activity. Diphenylhydantoin (20 mg/kg) did not affect the percentage of rats that convulsed, the onset of the seizures, the frequency of the seizures, or the 48 hr mortality.     

Sex differences in models of temporal lobe epilepsy: role of testosterone

Kainic acid and pilocarpine were used to assess sex differences in temporal lobe seizures. Adult Sprague-Dawley rats were injected with kainic acid (10-12 mg/kg) or with pilocarpine (380 mg/kg) and behavior was recorded for the next 3 h. Trunk blood was collected for hormonal measurements. Our data indicate that the male is more susceptible to the convulsant effects of agents that produce temporal lobe-like seizures. Males presented a higher amount of full limbic convulsions than females. To assess the role of plasma testosterone levels in kainate-induced seizures, a group of males was gonadectomized and half received testosterone replacement. The presence of testosterone, in intact and in gonadectomized males with testosterone replacement, increased the susceptibility to seizure. Seizures were either stronger (full limbic) or more frequent in animals with testosterone compared to animals devoid of testosterone. These results suggest that differences in plasma levels of testosterone may be partially responsible for the observed gender differences in seizure susceptibility. Our data reveal a reciprocal relationship between kainic acid-induced temporal lobe seizures and plasma testosterone. Testosterone enhances the occurrence and the severity of seizures. Conversely, kainic-acid-induced seizures decrease plasma testosterone. The higher plasma corticosterone levels found in these males suggest that kainic acid-induced seizures activate the hypothalamic-pituitary-adrenal axis which may induce alterations in plasma levels of male reproductive hormones.