Lack of development of tolerance to anticonvulsant effects of two excitatory amino acid antagonists, CGP [corrected] 37849 and CGP 39551 in genetically epilepsy-prone rats.

Two selective excitatory amino acid antagonists, DL-(E)-2-amino-4-methyl- 5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551), were studied against audiogenic seizures in genetically epilepsy-prone rats following oral administration. Acute administration of CGP 37849 attenuated the clonic and tonic phases of the audiogenic seizures (109 dB, 12-16 kHz) 120 min after pretreatment (ED50 19.7 and 11.2 mumol kg-1, respectively). Similarly, CGP 39551 attenuated the clonic and tonic phases of audiogenic seizures 120 min after acute treatment with ED50 values of 17.2 and 8.8 mumol kg-1, respectively. For chronic studies animals were treated orally once daily (at 10 h) for 4 weeks with CGP 37849 (20 or 40 mumol kg-1) or CGP 39551 (15 or 30 mumol kg-1). In order to assess anticonvulsant activity, rats were subjected to auditory stimulation 120 min after drug administration on days 1, 3 and 5 and then every 3 or 4 days. Following 2 and 4 weeks of repeated drug administration with CGP 37849 (20 and 40 mumol kg-1) the ED50 values against clonic and tonic seizures were not significantly different from those observed following an acute administration. Similarly, 2 and 4 weeks after repeated treatment CGP 39551 (15 and 30 mumol kg-1) the ED50 values against clonic and tonic seizures were not significantly different from those observed following an acute administration. There was no significant difference between the ED50 values following either acute or repeated treatment of the two excitatory amino acid antagonists suggesting a lack of development tolerance. The duration of anticonvulsant activity observed between 0.5 and 24 h following administration of CGP 37849- and CGP 39551 was similar in acute and chronic treatment. The effects of CGP 37849 and CGP 39551 on motor behaviour was also evaluated following acute and repeated treatment by a rotarod apparatus 110 min following drug administration. The TD50 values for CGP 37849 and CGP 39551-induced impairment of locomotor performance recorded 2 or 4 weeks of repeated administration were not significantly different from those observed following an acute administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance were 87.6 and 70.8 mumol kg-1 i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mumol kg-1 i.p. respectively following 4 weeks treatment. The doses of CGP 37849 and CGP 39551 required to elicit motor impairment were at least an order of magnitude above required for anticonvulsant activity. Since these compounds showed anticonvulsant properties after oral administration and lack of development of tolerance after repeated treatment, a potential use for antiepileptic therapy in man is suggested.

Effects of some excitatory amino acid antagonists on imipenem-induced seizures in DBA/2 mice.

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.

Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats.

The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the beta-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).

Effects of some quinolones on imipenem-induced seizures in DBA/2 mice.

1. The behavioural and convulsant effects of imipenem, a carbapenem derivative, were studied after i.p. administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures and in Swiss mice. 2. It was found that DBA/2 mice were more susceptible to seizures induced by imipenem than Swiss mice. 3. The proconvulsant effects of some quinolones were also evaluated in DBA/2 mice on seizures evoked by means of i.p. administration of imipenem. The present study demonstrated that the order of proconvulsant activity in our epileptic model was pefloxacin > enoxacin > ofloxacin > nalidixic acid > rufloxacin > norfloxacin > ciprofloxacin > cinoxacin > temafloxacin. 4. The relationship between the chemical structure and the proconvulsant activity of quinolone derivatives was studied. The relationship between the lipophilicity and the proconvulsant activity was also investigated. 5. Although the main mechanism for seizure potentiation cannot be easily determined potential drug interactions exist. It has been reported that imipenem and quinolones are all believed to increase excitation of the central nervous system by inhibition of GABA binding to receptors. 6. A slow clearance from the central nervous system and from the kidney may also occur following the concomitant administration of some quinolones and imipenem.

Only some anticonvulsants protect against seizures induced by aminophylline in quinolone-treated genetically epilepsy prone rats.

1. The effects of some anticonvulsant drugs against seizures induced by a combined treatment with aminophylline and quinolone in genetically epilepsy-prone rat have been investigated. 2. Animals were intraperitoneally pretreated with carbamazepine, diazepam, phenobarbital, CPPene and dizocilpine or saline and 15 min later administered orally with 51.86 mumol/kg b. wt of either cinoxacin or ciprofloxacin. 60 min after quinolones, rats received intraperitoneally aminophylline (100, 120, 140, 160 or 180 mg/kg b. wt). 3. Ciprofloxacin showed to be more effective than cinoxacin in potentiating the aminophylline convulsant effects. 4. Neither carbamazepine nor diazepam and phenobarbital, at the lowest dose used, elicited any effect in reducing the aminophylline-induced seizures in both cinoxacin- and ciprofloxacin-treated animals. Whereas, diazepam and phenobarbital when administered i.p. at 2.5 and 60 mg/kg b. wt respectively demonstrated protective properties. 5. CPPene and dizocilpine, two excitatory amino acid antagonists, were both very effective in antagonizing the seizures produced by concomitant treatment with cinoxacin or ciprofloxacin plus aminophylline. 6. The present results suggest an involvement of the excitatory amino acid receptors in mediating the seizures induced by the combined treatment with quinolones and aminophylline.

Repeated treatment with quinolones potentiates the seizures induced by aminophylline in genetically epilepsy-prone rats.

1. The effects of a chronic treatment with several quinolone derivatives on on the aminophylline-induced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg.kg-1, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg-1 of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.

Ultrastructural changes of crop-sac and lactotrophs after systemic or intraventricular administration of drugs enhancing cholinergic transmission in pigeons.

The ultrastructural effects of drugs enhancing, by different mechanisms, cholinergic transmission in the crop-sac (the target for prolactin secretion in birds) and the anterior pituitary lactotrophs, were studied in pigeons (Columba livia). The systemic or intraventricular administration of physostigmine, carbachol and muscarine produced maximal crop-sac stimulation with milk-like secretion, as demonstrated by the observation of ultrastructural changes in the lactiferous areas through scanning and transmission electron microscopy of the crop-sac mucosa. A marked activation was also observed in anterior pituitary lactotrophs. Crop-sac and anterior pituitary lactotrophs stimulatory effects were prevented by an atropine pretreatment, but not by mecamylamine and pempidine pretreatments. The present results suggest that muscarinic receptors at the hypothalamic and/or anterior pituitary level are involved in avian species in the control of prolactin secretion.

Ribavirin-induced behavioral, body temperature and electrocortical spectra effects in the rat.

Behavioral, electrocortical spectra and body temperature effects, following a single intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of ribavirin, were studied in male adult rats. Ribavirin, when administered i.p., induced squatting posture, sedation, electrocortical synchronization, piloerection and a slight decrease of tactile and/or auditory stimuli/responses lasting from 45 min to 16 hr, as well as a longer lasting hypothermic effect. Following i.c.v. administration, ribavirin (50, 100 and 200 micrograms) elicited a soporific effect and produced changes in the electrocortical spectra. Pretreatment, 15 min before, with either prazosin (10 mg/kg, i.p.), an alpha 1-adrenoceptor blocker, or piperoxan (20 mg/kg, i.p.) and yohimbine (1 mg/kg, i.p.), two alpha 2-adrenoceptor blockers, or naloxone (1 mg/kg, i.p.), an opioid antagonist, did not prevent the hypothermic and behavioral effects induced by i.p. or i.c.v. administration of ribavirin. The present findings exclude an involvement of alpha-adrenergic and opioid neurotransmission in mediating the hypothermic, electrocortical and behavioral effects induced by ribavirin.

Anticonvulsant effects of avermectin in DBA/2 mice and rat.

The anticonvulsant activity of avermectin B (AVM) was studied after systemic administration in DBA/2 mice (seizures induced by sound) and rats (seizures induced by pentylenetetrazol, cephazolin and maximal electroshock test). Protection against sound-induced seizures was given after intraperitoneal administration of AVM (30 and 50 mg/kg). Cephazolin-induced seizures in rats were attenuated by intraperitoneal administration of AVM (10 and 20 mg/kg). AVM increased the antipentylenetetrazol activity of diazepam. No significant protection against the tonic component in the electroshock test was observed. Behavioural effects of AVM included signs of sedation in both mice and rats. In all, these results indicate that, besides its specific anthelmintic effects, AVM possesses anticonvulsant properties, the mechanism(s) of which still remain to be elucidated.

Lack of effects of thallium on GABAergic mechanisms in discrete areas of the rat brain.

The effects of intramuscular treatment for 3 and 5 consecutive days with thallium sulphate (2.5, 5 and 10 mg/Kg) on GABA content, glutamate - decarboxylase (GAD) and GABA-transaminase (GABA-T) activity in different areas of the rat brain were studied. Thallium at the dose levels used did not produce significant changes in GABA content, GAD and GABA-T activity in the brain hemispheres, brainstem, hypothalamus, diencephalon and caudate nucleus.

Long-lasting hypothermic effects of vincristine in rats.

The effects of vincristine given intravenously on deep and superficial body temperature were assessed in rats kept at ambient temperature within the thermoneutral range. Vincristine (0.5 and 1 mg/kg i.v.) produced a gradual but marked hypothermic response which was dose-dependent, reached its maximum after approximately 3 h and lasting approximately 48 h. Vincristine induced a decrease in deep body temperature which was accompanied by piloerection and a decrease in skin temperature. Pretreatment with phentolamine, an alpha-adrenoceptor blocking agent (0.5 mg/kg i.v. 15 min before) prevented the hypothermic effects induced by subsequent administration of vincristine (0.5 mg/kg i.v.). These experiments showed that vincristine produced a marked hypothermic response in rats. However, the precise site of action remains to be established.