Effects of Dextromethorphan, a Nonopioid Antitussive, on Development and Expression of Amygdaloid Kindled Seizures

The effects of dextromethorphan (DM), a nonopioid antitussive and a functional N-methyl-D-aspartate (NMDA) antagonist, on expression and development of amygdaloid kindled seizures were examined. The maximum anticonvulsant effect of DM (30 mg/kg) on fully kindled seizures appeared within 30 min of administration and lasted for at least 2 h. DM decreased, in a dose-dependent manner [10-70 mg/kg, intraperitoneally (i.p.)], the severity of kindled seizures 30 min after injection, but the estimated ED50 was 3 times higher than the previously reported value for maximal electroshock convulsions. Furthermore, the high dose (70 mg/kg), while suppressing kindled seizures, produced myoclonus which coincided with EEG spike activity in the amygdala and the cortex. When tested on the development of kindling, 30 mg/kg DM retarded the growth of afterdischarge in the amygdala and the cortex, but had no effect on the development of behavioral seizures. DM 60 mg/kg accelerated development of kindling and produced spontaneous seizures. These results indicate that DM, unlike other NMDA antagonists, has a narrow therapeutic window as an anticonvulsant on kindled seizures and that higher doses may potentiate the kindling process.     

Immunosupressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat

Calcineurin (CaN) immunoreactivity and content increased markedly in kindled rat brain, and this increment was due to CaN in the membrane fraction. Investigation of the effects of cyclosporin A and FK506 (immunosuppressants which inhibit CaN activity in T lymphcytes) in the kindling phenomena showed that the kindling stage progression was reversibly blocked by these drugs. These findings suggest that calcineurin may play an essential role in acquiring epileptogenesis in kindling.     

Amygdaloid Kindling Elicits Persistent Changes in Pertussis Toxin-Catalyzed ADP-Ribosylation

Summary: We examined the changes in pertussis toxin (PTX)-catalyzed ADP-ribosylation in amygdaloid-kindled rats to clarify the role of G proteins in the basic mechanisms of epilepsies. Autoradiographic analysis showed a remarkable increase in PTX-catalyzed ADP-ribosylation in 39–4 1-kDa proteins in hippocampus and cerebral cortex of kindled animals. The 39-to 41-kDa proteins were shown to be a -subunits of Gi and Go by immunoblotting with specific anti-Cia and anti-Goa. The increase in ADP-ribosylation of these proteins was observed on stimulated and unstimulated sides of brains 24 h after the last genralized seizure and persisted for at least 3–4 weeks. These results suggest that persistent alterations in signal transduction through Gi and Go might be related to acquisition of long-lasting epileptogenesis.     

Facilitation of kindling by prior induction of long-term potentiation in the perforant path

Previous studies have revealed that a form of synaptic potentiation resembling long-term potentiation (LTP) occurs at various sites as a result of stimulation that leads to kindling. The present study evaluates what role this synaptic potentiation plays in the development of kindling following periodic stimulation of the entorhinal cortex of the rat. LTP was repetitively induced in the pathway from the entorhinal cortex (EC) to the dentate gyrus (DG) by daily stimulation with high frequency trains that led to LTP, but did not evoke afterdischarge (AD). Subsequently, animals received stimulation designed to induce kindling (that led to AD), and this stimulation was delivered once per day until kindled seizures were induced. While repetitive induction of LTP was not sufficient to produce kindling, prior induction of LTP significantly increased the rate of subsequent kindling as evidenced by a decrease in the number of kindling stimulations required to induce the kindled state. As a group, animals that had received stimulation designed to induce LTP developed kindled seizures after an average of 10 AD's, whereas a control group that had received non-potentiating stimulation required 25 AD's. These results indicate that LTP at EC-DG synapses cannot represent the mechanism of kindling following EC stimulation. However, synaptic potentiation at this site can facilitate the development of epileptogenesis in response to subsequent activation of the perforant path.     

Further evidence for abnormal GABAergic circuits in amygdala-kindled rats

In amygdala-kindled rats, synaptosomal levels of γ-aminobutyric acid (GABA) and its synthesizing enzyme glutamate decar☐ylase as well as [³H]GABA binding to synaptic membranes were determined in several brain regions which, except for the amygdala, were pooled from both hemispheres to obtain enough tissue for the subcellular fractionations. Compared to controls, GABA synthesis was reduced in the ipsilateral (stimulated) amygdala and in corpus striatum and substantia nigra. GABA receptor binding was decreased in amygdala and substantia nigra but significantly increased in the striatum. The data suggest that abnormal GABAergic transmission in discrete brain areas may be involved in the generation and propagation of amygdala-kindled seizures.     

The effects of chronic desmethylimipramine on entorhinal cortical kindling in rats

Chronic pretreatment of rats with desmethylimipramine (DMI) significantly slowed the rate of seizure generalization elicited by repeated electrical stimulation of the entorhinal cortex (kindling). An identical drug regimen administered to either fully kindled rats or rats partially kindled to early motor seizure stages failed to significantly alter kindling profiles in these animals. Under these latter conditions, in fact, there was a tendency for chronic DMI to exacerbate seizure activity. The effect of chronic DMI pretreatment to slow the development of kindled seizure generalization did not occur if a two-week delay was interposed between the end of drug treatment and the beginning of kindling trials. Results suggest that the retardation of entorhinal cortical kindling rate is dependent on DMI-induced CNS adaptations which recover within two weeks following treatment, and this effect is dependent on the presence of DMI-induced adaptations in a naive (unkindled) nervous system. Alterations of either the kindled state or the adaptational state produced by chronic drug eliminate the slowing of seizure generalization observed when both conditions are present.     

乙醇对大鼠杏仁核点燃的抑制作用

目的：研究并测定乙醇对大鼠杏仁核点燃的抑制作用.方法：建立大鼠杏仁核点燃模型,观察乙醇对点燃发展及发作的影响,并通过联合用药探讨乙醇对点燃的作用及其可能机制.结果：乙醇0.5～1.5 g•kg 1皮下注射均能升高杏仁核点燃后放电阈值,降低Racine发作强度和全身发作的百分率,抑制点燃发展进程(P＜0.01)和点燃发作(P＜0.05).在对点燃均无明显影响的低剂量下,乙醇与地西泮或苯巴比妥合用对后放电时程和Racine分级无明显影响.结论：乙醇对大鼠杏仁核点燃发作及其发展有抑制作用,但低剂量乙醇与苯巴比妥或地西泮并无协同作用.     

Developmental Aspects of Epileptogenesis

Summary: Several factors may contribute to the propensity for the developing brain to have seizures and develop epilepsy. Hypersynchrony of neuronal circuits contributes to the seizure potential and several neurobiological features of the immature brain may support synchronized neuronal firing. The immature cerebral cortex and hippocampus have an increased density of synapses compared to adults and also a higher density of gap junctions and of excitatory amino acid receptors. Enhanced regenerative responses to injury in the developing brain may also contribute to the formation of abnormal hippocampal connections that support epilepsy. Molecular mechanisms that contribute to enhanced synaptic plasticity in the child's brain can also contribute to epileptogenesis in certain circumstances. The phenomenon of kindling, where repeated electrical stimulation of neuronal circuits leads to the development of epileptic seizures, is easily elicited in young animals. Longterm potentiation (LTP), where repeated synpatic stimulation leads to a reduced threshold for activation of that pathway and enhanced postsynaptic potentials, is much more robust in the immature cerebral cortex and may contribute to kindling and epileptogenesis. Age related enhancement of N-methyl d-asparatetype glutatmate receptors, which are important for the activity dependent plasticity in the developing brain, appears to participate in LTP. This information suggests that normal developmental features of synaptic development make the immature brain more excitable than the adult brain and may contribute to epileptogenesis.