cgp-37849 and Epilepsy

Epileptic afterdischarges elicited by stimulation of sensorimotor cortex were chosen to test anticonvulsant effects of NMDA receptor antagonists in developing rats (12, 18 and 25 days old) with implanted electrodes. Afterdischarges were elicited four times with 10-min intervals in the experiments with dizocilpine and 20 min with the other two drugs. Dizocilpine (0.5 or 1 mg/kg), CGP 40116 (0.1, 0.5 or 1 mg/kg) or 2-amino-7-phosphonoheptanoic acid (AP7, 30 or 60 mg/kg) was injected intraperitoneally between the first and second stimulation. Intensity of movements accompanying stimulation was diminished regularly only by CGP 40116. Duration of afterdischarges was reduced and intensity of clonic seizures was decreased by CGP 40116 in all age groups; dizocilpine exhibited similar action in 25- and 18-day-old rats, AP7 only in 25-day-old animals. Anticonvulsant action of the three NMDA antagonists exhibited different developmental profiles in our model; this difference might be due to developmental changes of NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Dizocilpine Maleate; Electric Stimulation; Epilepsy; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Motor Cortex; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors

Pentraxin 3, a prototypic long pentraxin, is induced by proinflammatory signals in the brain. Inflammatory cytokines are rapidly induced in glia by epileptic activity. We show that pentraxin 3 immunoreactivity and mRNA are enhanced in the rat forebrain above undetectable control levels by limbic seizures with a dual pattern of induction. Within 6 h from seizure onset, pentraxin 3 immunoreactivity was increased in astrocytes. Eighteen to 48 h later, specific neuronal populations and leucocytes were strongly immunoreactive only in areas of neurodegeneration. This staining was abolished when neuronal cell loss, but not seizures, was prevented by blocking N-methyl-D-aspartate receptors. Pentraxin 3 -/- mice had a more widespread seizure-related neuronal damage in the forebrain than their wild-type littermates although both groups had similar epileptic activity. Our results provide evidence that pentraxin 3 is synthesized in brain after seizures and may exert a protective role in seizure-induced neurodegeneration.

Topics: 2-Amino-5-phosphonovalerate; Animals; C-Reactive Protein; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fluorescent Dyes; Genetic Predisposition to Disease; Immunohistochemistry; Kainic Acid; Limbic System; Male; Mice; Mice, Knockout; Nerve Degeneration; Neurons; Neuroprotective Agents; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Serum Amyloid P-Component

In this study, the anticonvulsant and adverse effects of compounds that belong to four different categories of systemically available N-methyl-D-aspartate (NMDA) receptor ligands were compared, namely the competitive antagonist CGP 40116, the noncompetitive antagonist MK-801 (dizocilpine), the glycineB receptor antagonist L-701,324, and the glycineB receptor high-efficacy partial agonist D-cycloserine. The maximal electroshock seizures (MES), which are widely used to detect drug efficacy against generalized tonic-clonic seizures in humans, were produced by transcorneal electrical stimulation. Abolition of tonic hind-limb extension was taken as the end-point. The drug-induced motor and long-term memory deficits were quantified by using the inverted screen test and the step-through passive-avoidance test, respectively. All tested compounds exhibited significant anticonvulsant effect. The rank order of potency for the respective compounds was: MK-801 = CGP 40116 > L-701,324 >> D-cycloserine. All of these compounds induced motor impairment at doses close to those found to be anticonvulsant, however, hyperlocomotion and stereotyped behavior occurred only with MK-801. The highest protective indices [PI = TD50 (inverted screen)/ED50 (MES)] were calculated for CGP 40116 and D-cycloserine (2.4 and 2.2, respectively). When tested for memory impairment at one-half the MES ED50, again only MK-801 induced significant memory disruption in the passive avoidance test. In conclusion, these results suggest that glycineB receptor high-efficacy partial agonists and competitive NMDA receptor antagonists may be advantageous to noncompetitive NMDA antagonists and glycineB receptor antagonists as potential antiepileptic drugs.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Antimetabolites; Avoidance Learning; Binding, Competitive; Brain Chemistry; Cycloserine; Dizocilpine Maleate; Electroshock; Epilepsy; Excitatory Amino Acid Antagonists; Ligands; Male; Mice; Neurotoxins; Quinolones; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

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 o

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Drug Administration Schedule; Drug Tolerance; Epilepsy; Excitatory Amino Acid Antagonists; Genetic Predisposition to Disease; Male; Motor Activity; Rats; Rats, Sprague-Dawley

Sound-induced seizures in genetically epilepsy-prone rats were used to compare the anticonvulsant effect of phenytoin and diazepam with compounds which decrease glutamatergic neurotransmission including excitatory amino acid antagonists acting at N-methyl-D-aspartate (NMDA) receptors: D(-)CPPene, CGP 37849 and MK 801 or at the glycine/NMDA site: ACPC (1-aminocyclopropane-dicarboxylic acid) (partial agonist) or non-NMDA receptors: NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline.Li) and GYKI 52466 (1-(aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepin e.HCl) or acting at sodium channels to decrease glutamate release: lamotrigine and BW 1003C87 (5(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate). ED50 values against clonic seizures (in mumol/kg at the time of peak anticonvulsant effect) were: phenytoin 30.5 (2 h), diazepam 0.5 (0.5 h), MK 801 0.01 (4 h), D(-)CPPene 1.9 (4 h), CGP 37849 2 (1 h), GYKI 52466 24 (0.25 h), NBQX 40 (0.5 h), ACPC 1053 (0.5 h), BW 1003C87 2.2 (1 h), lamotrigine 4.8 (4 h). BW 1003C87, lamotrigine, MK 801, phenytoin, diazepam and CGP 37849 had the most favourable therapeutic indices (rotarod locomotor deficit ED50/anticonvulsant ED50).

Topics: 2-Amino-5-phosphonovalerate; Acoustic Stimulation; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Female; Lamotrigine; Male; Motor Activity; Phenytoin; Pyrimidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors; Triazines