Duration Of Tonic Hind Limb Extension Research Articles

Acute and Sub-chronic Anticonvulsant Effects of Edaravone on Seizure Induced by Pentylenetetrazole or Electroshock in Mice, Nitric Oxide Involvement.

Edaravone is an anti-stroke medication that may have nitric oxide (NO) modulating properties. This study evaluated the role of NO in the acute and sub-chronic anticonvulsant effects of edaravone in murine models of seizures induced by intraperitoneal (IP) or intravenous (IV) injections of pentylenetetrazole (PTZ) or electroshock (maximal electroshock seizure [MES]). 132 male albino mice were randomly divided into 22 groups (n=6) and given IP injections of vehicle or edaravone either acutely or for eight days (sub-chronically). The seizure was induced by electroshock or PTZ (IP or IV). The following edaravone doses were used: 7.5, 10, 12.5 (acute); 5, 7.5, 10 (sub-chronic) in IP PTZ model; 5, 7.5, 10 in IV PTZ model; and 5, 10 mg/Kg in the MES. To evaluate NO involvement, 216 mice were randomly divided into 36 groups (n=6) and pretreated with vehicle, edaravone, a non-specific nitric oxide synthase (NOS) inhibitor: N(ω)-nitro-L-arginine methyl ester (L-NAME) (5 mg/Kg), a specific nNOS inhibitor: 7-nitroindazole (7-NI) (60 mg/Kg), or a combination of edaravone plus L-NAME or 7-NI, either acutely or for eight days before seizure induction. Doses of edaravone were as follows: in IP PTZ model: 12.5 (acute) and 10 (sub-chronic); in IV PTZ model: 10; and in the MES: 5 mg/Kg. Data were analyzed using the one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS 18). P≤0.05 was considered statistically significant. In the IP PTZ model, edaravone increased time latencies to seizures (P<0.001), prevented tonic seizures, and death. Edaravone increased the seizure threshold (P<0.001) in the IV PTZ model and shortened the duration of tonic hind-limb extension (THE) in the MES model (P<0.001). In comparison to mice treated with edaravone alone, adding L-NAME or 7-NI reduced seizure time latencies (P<0.001), reduced seizure threshold (P<0.001), and increased THE duration (P<0.001). Edaravone (acute or sub-chronic) could prevent seizures by modulating NO signaling pathways.

Anticonvulsant Effect of Nebivolol alone and in Combination with Phenytoin against Maximal Electroshock-Induced Seizures in Mice

Introduction: Phenytoin is widely used in treatment of generalised tonic clonic seizures but its adverse effects make its usage limited. Hence forth, there is a need for newer antiepileptics. Studies have shown antiepileptic property for nebivolol in combination with phenytoin hence, reducing the dosage of phenytoin and its adverse effects and toxicities. Aim: To evaluate the anticonvulsant property of nebivolol alone and in combination with phenytoin against Maximal Electroshock Seizures (MES) in a mouse model. Materials and Methods: This was an experimental animal study on total of 36 swiss albino male mice were randomly assigned to six groups with six animals in each group in December 2019 at Sri Manakula Vinayagar Medical College and Hospital. Group 1 was considered as normal control, Group 2 received Phenytoin 25 mg/kg Intraperitoneal (IP); Group 3 &amp; 4 received Nebivolol 0.25 mg/kg oral &amp; 0.50 mg/kg oral, respectively; Group 5 received 12.5 mg/kg IP and nebivolol 0.25 mg/kg oral; Group 6 received Phenytoin 12.5 mg/kg IP and nebivolol 0.50 mg/kg oral. Anticonvulsant effect of the drugs nebivolol and phenytoin was elicited in mice by MES test. After induction following parameters were recorded for onset of Tonic Hind Limb Extension (THLE), duration of clonus, duration of THLE, number of jerks, recovery time. Statistical analysis was done by ANOVA followed by post-hoc Dunnett t-test. Results: Significant reduction in duration of THLE (p&lt;0.01) and clonus (p&lt;0.001) was observed in the group treated with phenytoin (12.5 mg/kg) and nebivolol (0.50 mg/kg). Conclusion: The present study concludes that the lower dose of phenytoin in combination with nebivolol can reduce seizures induced by MES in mice model.

Potentiation of anticonvulsant effect of phenytoin by celecoxib against maximum electroshock induced convulsions in albino rats

Background: Epilepsy, a chronic neurological disorder affects more than 1% of world population. Despite the availability of a number of antiepileptics, refractoriness to them exists in approximately one third of cases worldwide. Induction of cycloxygenase and increased levels of proinflammatory meditators are seen in epilepsy. P-glycoprotein upregulation due to phenytoin was found to contribute to its pumping out of cell, leading to refractoriness to phenytoin therapy. Also, cycloxygenase-2 inhibitors were found to prevent P-glycoprotein upregulation. Since cycloxygenase-2 inhibition decreases levels of proinflammatory cytokines responsible for neuroinflammation, this study aims to evaluate anticonvulsant effect of celecoxib and also to investigate whether it potentiates the anticonvulsant effect of phenytoin.Methods: Maximum electroshock seizures (MES) were induced in Albino rats using electroconvulsiometer to evaluate tonic convulsions, identified by tonic hind limb extension (THLE) in rats. A delay in onset of THLE and a reduction in duration of THLE were taken as deciding parameters to ascertain anticonvulsive activity. Rats randomly divided into groups, received pretreatment with celecoxib at 3 doses (10, 20, 40 mg/kg), phenytoin (6.25 mg/kg), phenytoin (12.5 mg/kg) and combination of phenytoin (6.25 mg/kg) with celecoxib (ED50, i.e. 20 mg/kg), before inducing MES seizures and findings compared to control group.Results: Celecoxib (20 and 40 mg/kg) showed significant anticonvulsant effect by MES test. Also, its combination with phenytoin caused significant decrease in the duration of THLE when compared to phenytoin alone at the same dose.Conclusions: The results of this study indicate that celecoxib potentiates the anticonvulsant effect of phenytoin.

Amelioration of Oxidative Stress and Neuroinflammation by Saroglitazar, A Dual PPARα/γ Agonist in MES Induced Epileptic Rats

Oxidative stress and neuroinflammatory process are implicated in pathophysiology of epilepsy as well as epileptogenesis. The α and γ isoform of peroxisome proliferator-activated receptors (PPAR) agonist has been reported to have antioxidant and anti-inflammatory functions. We hypothesized that saroglitazar, a dual PPAR-α and PPAR-γ agonist may ameliorate oxidative stress and neuroinflammatory process in MES induced epileptic rats. A total of 36 rats were randomized to different groups (n=6). Group I served as normal control, while in the remaining groups (group IV, V and VI) animals were pre-treated with saroglitazar for 15 days prior to inducing MES. Group I animals were pre-treated with vehicle and group-III with diazepam (2mg/kg). Epilepsy was induced in rats and time taken for onset of tonic hind limb extension (THLE), duration of THLE, duration of clonic phase and recovery time in seconds were noted. Brain SOD and MDA levels were assessed and immunohistochemical analysis was done to evaluate the expression of inflammatory marker COX-2. Pre-treatment with saroglitazar was effective against tonic clonic seizure in MES treated rats. SOD levels significantly increased and a significant reduction in MDA levels with a remarkable decrease in the uptake of COX-2 antibody were reported. Saroglitazar attenuated MES induced epilepsy and the probable underlying mechanisms are due to the inhibition of oxidative stress and neuroinflammation.

Combined Anticonvulsant Effect of Nifedipine and Pentazocine in Experimentally Induced Seizures by Maximal Electro Shock Method in Mice

Objective: The aim of the study was to determine the combined anticonvulsant effect of nifedipine (calcium channel blocker) and pentazocine (opioid analgesic) in experimentally induced seizures by Maximal Electro-Shock (MES) method in mice. Methodology: The swiss albino mice weighing 20-40g of either sex were obtained from National Institute of Nutrition, Hyderabad after obtaining ethical approval. The pretreated mice are subjected to MES stimulation by electro convulsometer with alternate current at intensity required to produce tonic hind limb extension response. The animals showing positive response are divided into four groups (6 animals per group). Group I received distilled water, group II treated with nifidipine (10mg/kg/bw), group III pentazocine (30mg/kg/bw) and group IV combination of nifidipine (10mg/kg/bw) and pentazocine (30mg/kg/bw). Intraperitoneal is the route of administration. The parameters like duration of convulsions, Tonic Hind Limb Extension (THLE) and duration of recovery recorded. P&lt;0.05 was considered as significant and P&lt;0.001 was considered as highly significant. Results: The duration of convulsions, duration of THLE and duration of recovery has been significantly reduced in combination treatment wih nifedipine 10mg/kg and pentazocine 30mg/kg compared to nifedipine 10mg/kg and pentazocine 30mg/kg individually. Conclusion: The results obtained in this study provide supporting pharmacological evidence of efficacy, possible potential benefit of combining nifedipine with pentazocine in the treatment of epilepsy. Keywords: Seizures, Maximal electroshock, Electroconvulsometer, anticonvulsant, Nifedipine, Pentazocine.

Acute Boldine Treatment Induces Anti-convulsant Effects in Mice through its Antioxidant Activity.

Boldine is a natural antioxidant that exhibits some important pharmacological properties, which is due to its free radical scavenging effects. And at the same time, reactive oxygen species (ROS) has an important role in pathogenesis of seizure; hence, reducing it via antioxidants like boldine seems to be effective in treating seizure. This study was designed to investigate whether acute treatment with boldine could alter seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated to see if boldine's antioxidant properties play a role in its anti-convulsant activity. Boldine acute administration increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole model. Moreover, boldine increased seizure threshold induced by intravenous infusion of pentylenetetrazole. Additionally, acute doses of boldine reduced the duration of tonic hind-limb extension in the electroshock-induced seizure model. Non-effective dose of vitamin C (as an antioxidant agent) and boldine had anti-convulsant effect in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole and electroshock models. Boldine administration increased glutathione and superoxide dismutase levels in mice whole brain. The result showed boldine anti-seizure properties, which might be due to its antioxidant activity.

ANTICONVULSANT EFFECTS OF NIMODIPINE ALONE AND COMBINATION WITH PHENYTOIN ON MES INDUCED SEIZURES

Objective: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electro-convulsometer. In the first part of the study, animals were treated with Nimodipine (20 mg/kg i. p. and 40 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p. and 1.0 mg/100g i. p.), MES was induced and durations of various phases were noted. Duration of Tonic hindlimb extension (THLE) was taken as an index for antiepileptic activity. In the second part, the animals were treated with a combination of sub effective doses of Nimodipine (20 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in a dose-dependent manner. Phenytoin produced a significant antiepileptic effect in dose of 1.0 mg/100g, but failed to produce any such effect in a dose of 0.5 mg/100g, when administered alone. But when sub-effective doses. Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusion: Nimodipine posses significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

Anticonvulsive effects of nifedipine and flunarizine on maximal electroshock seizures induced seizures

Background: Epilepsy is a common neurological disorder but the mechanism of seizure generation has been only partially unraveled. Currently available antiepileptics have a low therapeutic index and furthermore, provide satisfactory seizures control in only 60–70% of patients. Therefore, the present study was done to review the basic mechanism of seizures with special attention on voltage gated calcium channels and search for new antiepileptic in order to improve the efficacy of current therapies. Aims and Objective: The current study aimed to evaluate the anticonvulsant activity of calcium channel blockers. Materials and Methods: The animals were treated with Nifedipine (100 μg/100 g ip and 200 μg/100 g ip) and Flunarizine (5mg ⁄ kg ip and 10 mg⁄kg ip) and maximal electroshock seizures (MES) was induced by technoelectro convulsometer, 2 hrs after the administration of drugs, and duration of various phases were noted. Duration of tonic hind limb extension (THLE) was taken as index for antiepileptic activity. Result: Nifedipine and Flunarizine when administered in dose of 100 μg/100 g ip and 5 mg/kg respectively did not produce any changes in any phases of the MES induced seizure. But in dose of 200 μg/100 g ip and 10 mg/kg ip respectively, it significantly reduced the duration of THLE. Conclusion: Nifedipine and Flunarizine have a significant action against MES induced seizures suggesting an important role of CCBs as future, promising antiepileptic drug.

A comparative experimental study of proconvulsive potential of ciprofloxacin and ofloxacin and assessment of proconvulsive potentiating action of caffeine coadministration with fluoroquinolones in rats

Background: Fluoroquinolones are one of the most common antimicrobials prescribed for a variety of infections. They have potential to lower seizure threshold. This can be harmful when prescribed to consumers of energy drinks as caffeine itself is a cortical stimulant. Aims and Objectives: The aim of this study is to compare proconvulsive potential of ciprofloxacin and ofloxacin in rats using pentylenetetrazole (PTZ) and maximal electroshock (MES) and to study potentiating effect of caffeine with fluoroquinolones. Materials and Methods: This study was performed in rats; 66 for MES and 66 for PTZ. In each model, 11 groups were made - normal saline, caffeine (2.5 and 5 mg/kg), ciprofloxacin (12.5, 25 and 50 mg/kg), ofloxacin (12.5, 25 and 50 mg/kg), ciprofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg, and ofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg. Each group had 6 rats. Duration of tonic hind limb extension (THLE) and clonic convulsions was noted for MES. The incidence of seizures, grade of convulsions, and onset of Grade 3 convulsions were noted for PTZ. Results: MES - prolongation of the duration of THLE and clonic convulsions was seen in caffeine 5 mg/kg, ciprofloxacin 50 mg/kg, and ofloxacin 25 and 50 mg/kg. Ciprofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg and ofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg significantly prolonged the duration of THLE and clonic convulsions in contrast to their individual administration (P < 0.05). PTZ - clonic convulsions with more than Grade 3 were seen in caffeine 5 mg/kg, ciprofloxacin 50 mg/kg, and ofloxacin 25 and 50 mg/kg. Ciprofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg and ofloxacin 12.5 mg/kg + caffeine 2.5 mg/kg caused clonic convulsions higher than Grade 3 which were not seen on their individual administration (P < 0.05). Conclusion: Ofloxacin is more proconvulsive than ciprofloxacin. Combinations of low doses of ciprofloxacin with caffeine and ofloxacin with caffeine yielded convulsions which were not seen with individual drugs.

ANTI CONVULSANT EFFECT OF NIFEDIPINE, DIAZEPAM AND IN COMBINATION ON MES INDUCED EPILEPSY IN RATS

Background: The role of calcium in the process of epileptogenesis and neurotoxicity and excitotoxicity during status epilepticus is involved. In fact, epileptiform bursts are often associated with influx of calcium ion into the nerve cells and a decrease in the extracellular concentration of calcium precedes the onset of seizures. Aim: To investigate the activity of nifedipine, the dihydropyridine calcium channel blocker, diazepam, the benzodiazepine anti- convulsant of established efficacy and their combinations against rat models of MES induced tonic seizure. Method: Wister albino rats of either sex, weighing between 150-220 gm were used for maximal electroshock method. Rats were divided into 10 groups, in each group n=6 total N=60.Group 1: Control, Group 2-4:Nifedipine 2, 4 and 8 mg/kg accordingly, Group 5-7: Diazepam 1,2 and 4 mg/kg accordingly, Group 8:Nifedipine (3.3mg) + Diazepam (3mg), Group 9:Nifedipine (6.6mg) + Diazepam (3mg), Group 10: Phenytoin (25mg/kg). The Controls in the central panel was set at 120 mA current. The Start-Reset knob was switched in the reset position with time of 0.2 seconds was set. The following parameters were observed. Latent period of convulsions, duration of flexion, tonic hind limb extension, posttictal sleep. Results: Nifedipine in doses of 4 and 8 mg / Kg., diazepam in all doses (1, 2 and 4 mg / Kg.) and their combinations were significantly reducing the duration of tonic hind limb extension (THLE). Only Nifedipine in doses of 2 mg / Kg. had no significant change in duration of THLE in comparison to Normal saline. The effect of Nifedipine 8 mg / Kg. on reducing the duration of THLE, indicative its anti-seizure activity on MES seizure was comparable to Diazepam in the dose of 1 mg / Kg. The MES-induced anti-seizure activity of Diazepam in doses of 1 mg / Kg. It was significantly less than Diazepam in doses of 2 and 4 mg / Kg or from the combination doses. Diazepam in 4 mg / Kg. dose was equally effective as the combination. But its effect was also equi-effective with Phenytoin. Conclusion: Nifedipine alone is inferior to diazepam in generalized tonic-clonic seizure and their combination is not having superadditive effect. Key words: Calcium channel blockers; Diazepam; Epilepsy; Maximum electrical shock.

Insignificant anticonvulsant activity of Padina tetrastromatica (Brown macroalgae) in mice

Introduction: Marine macroalgae or seaweeds are found in the coastal region have created a promising significance in the biomedical area, mainly because of their contents of bioactive substances. The objective of the present study was to investigate the anticonvulsant activity of chloroform and ethanol extracts of Padina tetrastromatica (PT), a marine macroalgae (brown algae) in mice. Materials and Methods: The anticonvulsant activity of chloroform and ethanol extracts of PT was studied at 400 and 600 mg/kg, against maximal electroshock (MES) and pentylenetetrazole (PTZ) induced convulsion in mice. The duration of tonic hind limb extension (THLE), latency to onset of clonic convulsions and percent protection was noted in MES and PTZ tests, respectively. Phenytoin (25 mg/kg) and phenobarbitone (20 mg/kg) served as reference standards. Results: The chloroform extract of PT at 600 mg/kg significantly decreased the duration of THLE, while ethanol extract did not alter the duration of THLE in MES model. Further, chloroform and ethanol extracts of PT was found to be ineffective as an anticonvulsant when assessed by PTZ-induced convulsive model, as compared to their respective vehicle-treated groups. Conclusion: From the results of the present study it can be concluded that the chloroform extract of PT at 600 mg/kg showed significant anticonvulsant activity, while other extracts lack anticonvulsant activity in MES and PTZ model. However, further studies are required using different animal models to support these findings.

Evaluation and comparison of anticonvulsant activity of telmisartan and olmesartan in experimentally induced animal models of epilepsy.

Epilepsy is one common neurological disorder requiring newer targets and newer drugs for its efficient management. In the recent days brain renin angiotensin system has gained immense importance because of its involvement in seizure regulation. To evaluate and compare antiepileptic activity of different doses olmesartan and telmisartan on MES and PTZ induced seizure models. Swiss albino mice weighing around 25-30g of either sex were divided into 6 groups: Control ( Distilled Water- 10ml/kg), Standard - Sodium valproate (40mg/kg), O1 - Olmesartan (2.5mg/kg), O2 - Olmesartan (5mg/kg), T1 - Telmisartan (5mg/kg), T2 - Telmisartan (10mg/kg). After 1hour of administration of control , test and standard drugs (orally), convulsions were induced by administering PTZ (70mg/kg - i.p.) in PTZ model. Seizure latency was the parameter recorded. In MES model, suppression of tonic hind limb extension was taken as measure of efficacy. The results were analysed by one-way-ANOVA followed by Bonferroni's multiple comparison test. In MES test, dose dependently olmesartan and telmisartan significantly reduced the duration of tonic hindlimb extension in comparison to control (p<0.05). T2 - 9 + 0.89secs significantly reduced the tonic hind limb extension compared to other test groups (p<0.05). The percentage inhibition of seizure was T2-44.3%, O2-28.2%, T1-17.5%, O1- 12.3% respectively. In PTZ test, dose dependently olmesartan and telmisartan produced significant increase in seizure latency (p<0.05). T2 - 206.6+9.83secs significantly increased seizure latency compared to other test groups (p<0.05). Percentage protection from seizure is T2-52.6%, O2- 45.13%, T1- 37.5%, O1- 38.4% respectively. AT1 receptor antagonist, telmisartan and olmesartan in a dose dependent manner showed increase in antiepileptic activity. Temisartan at higher dose produced significant antiepileptic activity in comparison to olmesartan.

Role of saponins for the anticonvulsant effect of adventitious roots of Ficus religiosa

Context: The adventitious roots of Ficus religiosa L. (Moraceae) have been extensively used in traditional medicine for treatment of several disorders, including epilepsy.Objective: To investigate the possible anticonvulsant effect of the adventitious roots of Ficus religiosa, and to find the biologically active fraction, to substantiate its traditional use in epilepsy.Methods: The hydroethanolic extract of adventitious roots (5, 10, and 20 mg/kg; i.p.) of Ficus religiosa and its different fractions (hexane, chloroform, ethyl acetate, butanol, aqueous, saponins-rich, and saponins-lacking) at a dose equivalent to 20 mg/kg of the extract were administered 30 min prior to the induction of maximal electroshock (MES) and pentylenetetrazol (PTZ) convulsions. Duration of tonic hind-limb extension (THLE) and latency to clonic convulsions were noted in MES and PTZ tests, respectively. Neurotoxicity was assessed using rotarod test.Results: Treatment with the root extract (5, 10, and 20 mg/kg; i.p.), butanolic (6 mg/kg; i.p.) and saponins-rich fractions (3.4 mg/kg; i.p.) significantly (p < 0.05) decreased the duration of THLE in MES test, as compared to control. The same treatment also significantly (p < 0.05) increased the latency to PTZ-induced clonic convulsions in comparison to control. The other fractions were found to be ineffective. The root extract and its active fractions at their effective doses showed no neurotoxic effects.Conclusion: The present study concluded that the hydroethanolic extract of adventitious roots of Ficus religiosa has anticonvulsant activity. Retention of anticonvulsant effect in the saponins-rich fraction-treated animals indicated the role of saponins for the activity.

Experimental manipulations of the subthalamic nucleus fail to suppress tonic seizures in the electroshock model of epilepsy

Recently, it has been shown that the subthalamic nucleus (STN) has anticonvulsant effects on epileptic seizures originating from the forebrain. The aim of the present study was to determine whether the anticonvulsant properties of the STN extend to the suppression of tonic seizures originating from the brainstem elicited by electroshock in rats. Three different procedures were used to manipulate activity in the STN and in each case the duration of tonic hindlimb extension elicited by electroshock was used as a measure of seizure-severity. Under general anesthesia, two groups of rats received chronic implants of either bilateral stainless steel guide cannulae or bilateral bipolar stimulating electrodes stereotaxically implanted and aimed at the STN. After 3 days of recovery, each rat in the first group was tested with electroshock on three consecutive days after having received 220 nl bilateral microinjections into the STN of either 200 or 400 pmol of muscimol (a GABA agonist) dissolved in saline or the same volume of normal saline. In the second group the electroshock test was conducted, again on three consecutive days, immediately following high frequency electrical stimulation (HFS) of the STN at 130 or 260 Hz or a no current control condition. In the third group, rats were tested with electroshock before and after bilateral excitotoxic lesions of the STN with either kainic or ibotenic acids. None of these manipulations produced significant suppression of the tonic hind limb extension elicited by electroshock compared with the relevant control conditions. This suggests that, within the limitations of the current procedures, the anticonvulsant properties of the STN appear to be ineffective against tonic seizures originating in the brainstem.

Regional distribution of the anticonvulsant and behavioural effects of bicuculline injected into the pontine reticular formation of rats.

Previous experimental work has established that activation of sites in the dorsal midbrain can suppress tonic hindlimb extension in the electroshock model of epilepsy. The most sensitive region for this effect is centred on the intercollicular area and is referred to as the dorsal midbrain anticonvulsant zone (DMAZ). Subsequent experiments have shown that the ipsilateral descending projection from this region to the ventrolateral pons is critically involved in mediating its tonic seizure-suppressing properties. The purpose of the present investigation was to test whether direct anticonvulsant effects in the electroshock model could be obtained from selective manipulation of DMAZ target regions in the ventrolateral pons. Animals were prepared with chronically implanted guide cannulae through which microinjections could be made directly into the lateral pontine reticular formation. Animals received injections of saline or bicuculline (25-100 pmol) administered either bilaterally or unilaterally. The effects of these injections on the animals' behaviour were determined in an open arena, after which maximal electroshock (1 s, 40 mA, 50 Hz AC) was administered via ear-clip electrodes and the duration of tonic hindlimb extension was recorded. Bilateral injections of bicuculline (100 pmol) suppressed tonic seizures at a significantly higher proportion of sites centred on DMAZ target regions of the ventrolateral pons than surrounding areas. For injections centred on this region the suppressive effects of bicuculline were dose-related in the range 25-100 pmol. Unilateral injections of bicuculline into the ventrolateral pons also effectively suppressed tonic seizures in the electroshock model. Within the ventral pons there was a significant association between the behavioural and anticonvulsant effects of bicuculline; injections suppressing tonic seizures were associated with the induction of fast continuous locomotor activity. These data confirm that the DMAZ recipient region of the ventrolateral pontine reticular formation is part of a circuit which can suppress the manifestation of tonic hindlimb extension in the electroshock model. Whether this property is related to the participation of this region in normal locomotion and posture remains to be determined.

Effects of intranigral application of clinically-effective anticonvulsants on electroshock-induced seizures

The authors sought to determine whether focal application of clinically-effective anti-convulsants to the substantia nigra produced anticonvulsant effects. To this end, the effects of phenobarbital, carbamazepine and phenytoin were examined on the electroshock seizure model in rats. Anticonvulsant efficacy was assessed by measuring the duration of tonic hindlimb extension before and after injection. It was found that application of phenobarbital into the nigra produced behavioral stereotypy and suppressed tonic hindlimb extension in a dose-dependent manner. These effects were spatially specific to the substantia nigra. By contrast, application of phenytoin or carbamazepine to the nigra produced neither anticonvulsant effects nor behavioral changes. Direct measurement of phenobarbital and carbamazepine in the substantia nigra showed that differences in concentration in the substantia nigra did not account for the lack of efficacy of carbamazepine. Moreover, concentrations of phenobarbital in the nigra after effective injection into the nigra exceeded concentrations in the nigra after effective systemic injections, by tenfold. Taken together, these data provide no compelling evidence that an action of the substantia nigra alone is sufficient to explain the therapeutic action of clinically-useful anticonvulsants.

Anticonvulsant action of GABA receptor blockade in the nigrotectal target region

Anticonvulsant activity in a wide variety of experimental seizure models can be obtained by enhancing γ-aminobutyric acid (GABA) transmission within the pars reticulata of substantia nigra. Recent evidence indicates that the nigrotectal projection may mediate some of the nigra-evoked anticonvulsant effects. The action of GABA within substantia nigra would, by inhibiting the GABAergic nigrotectal projections, cause disinhibition of target neurons in the supers or colliculus. This hypothesis predicts that administration of GABA antagonists into the region of the superior colliculus that receives nigrotectal terminals should also have anticonvulsant actions. We therefore examined the effects of injections of bicuculline methiodide aimed at rostrolateral superior colliculus upon maximal electroshock convulsions. The incidence and duration of tonic hindlimb extension was substantially reduced by these injections, a result consistent with the hypothesis that the nigrotectal GABAergic pathway may mediate the anticonvulsant actions of GABA transmission in the substantia nigra.

Lesions of substantia nigra protect against experimentally induced seizures

Bilateral lesions of substantia nigra (SN) were evaluated for anticonvulsant effects in rats. Electrolytic and kainic acid lesions of SN reduced bicuculline-elicited seizure activity; lesions in the ventral midbrain tegmentum adjacent to SN were without an anticonvulsant effect. Lesions of SN also reduced the incidence and duration of tonic hindlimb extension in the maximal electroshock seizure test. Bilateral SN lesions appeared to decrease seizure susceptibility to a given stimulus intensity rather than altering the motor pattern of the seizures. Our results support the view that SN efferents constitute a critical gating mechanism in the propagation of seizure activity.