mast-cell-degranulating-peptide and Seizures

Both the Mast Cell Degranulating (MCD) peptide and Dendrotoxin I (DTX(I)), two blockers of fast activation and slowly inactivating K+ channels, induced epileptiform seizures and brain damage after intracerebroventricular injection (200 pmol) in Sprague-Dawley rats. A considerable variation in the response of the rats was observed for each toxin. The neurodegeneration included the hippocampal formation, subiculum, septum, amygdala, and the cerebellum for both toxins, and the neocortex and anterior thalamic nuclei exclusively for DTX(I) treatment.

Topics: Animals; Bee Venoms; Behavior, Animal; Cerebellum; Elapid Venoms; Hippocampus; Injections, Intraventricular; Ion Channel Gating; Male; Nerve Degeneration; Neurotoxins; Peptides; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Seizures

Using electroencephalographic (EEG) recordings in freely moving rats and extracellular neuronal firing-rate recordings in hippocampal slices, we examined the effects of riluzole (RP 54274), a compound with anti-glutamate properties, against the convulsive seizures and the cellular hyperexcitability produced by the mast-cell degranulating peptide (MCD), dendrotoxin I (DTXi) and 4-aminopyridine (4-AP). I.c.v. administration of riluzole (10 nmol) prevented the seizures induced by MCD, and to a lesser extent those due to DIXi, whilst leaving 4-AP seizures unaffected. This effect was also present after oral administration of the compound (4 mg kg-1) and lasted for approximately 6 h. Electrophysiological recordings in vitro confirmed that riluzole dose dependently and reversibly abolished the sustained increase in firing rate induced by both MCD and DTXi in the hippocampus. These results indicate that the anti-epileptic spectrum of riluzole in this model has similarities with, but is not identical to, that of classical potassium channel openers, and differs from that of calcium channel blockers or other glutamate antagonists such as D(-)-2-amino-5-phosphono-valeric acid. However, since MCD releases glutamate, the preventive effect of riluzole in this model may involve direct or indirect interaction with glutamatergic processes.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Elapid Venoms; Electroencephalography; Hippocampus; Injections, Intraventricular; Male; Peptides; Rats; Rats, Inbred Strains; Riluzole; Seizures; Thiazoles

Intracerebroventricular injection of mast-cell degranulating peptide (MCD), dendrotoxin I (DTXI) and 4-aminopyridine (4-AP), 3 blockers of a subclass of K+ channel, produces seizures and convulsions. Three different K+ channel openers are potent blockers of MCD-induced hyperexicitatory effects when they are administered preventively but they are unable to inhibit the epileptogenic effects induced by DTXI and 4-AP which were thought to block the same K+ channel which is blocked by MCD.

Topics: 4-Aminopyridine; Aminopyridines; Animals; Elapid Venoms; Injections, Intraventricular; Male; Neurotoxins; Peptides; Potassium Channels; Rats; Rats, Inbred Strains; Seizures

Both the bee venom toxin, mast cell degranulating (MCD) peptide, and the snake toxin, dendrotoxin 1 (DTX1) induce epileptiform activity and paroxystic seizures after intracerebroventricular (i.c.v.) injection to rats. Although many of the properties of the two toxins, which are blockers of the same K+ channel, appear to be very similar, a number of differences have been found. (1) Induced seizures have an hippocampal origin for MCD and two different origins, situated in the cortex and in the limbic system, for DTX1. (2) A first i.c.v. administration of DTXI desensitizes against a second ipsilateral injection of the same peptide as we had previously observed for MCD. However no cross-desensitization was observed between the two different toxins. (3) The number of high affinity (Kd = 41 pM) binding sites for 125I-DTXI in synaptic membranes is about 5 times higher than the number of high affinity (Kd = 158 pM) binding sites for 125I-MCD. (4) Autoradiographic analysis of the distribution of high affinity 125I-DTX1 binding sites has been compared to our previous analysis of high affinity 125I-MCD binding sites. High levels of high affinity binding sites for both toxins seem to be localized in synapse-rich areas. However high affinity binding sites for the two toxins are not always co-localized. Analysis of the mutual interactions between DTXI and MCD binding sites has revealed the presence of classes of low affinity binding sites for MCD. In most areas of the brain, a large proportion of high affinity binding sites for DTXI is allosterically related to low affinity binding for MCD.

Topics: Animals; Autoradiography; Binding Sites; Brain; Convulsants; Elapid Venoms; Injections, Intraventricular; Male; Neurotoxins; Peptides; Potassium Channels; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Seizures

High densities of MCD receptors were found in the stratum radiatum of Ammon's horn, the neocortex, the molecular layer of the cerebellum, colliculi and pons. Conversely areas such as the stratum lacunosum moleculare of Ammon's horn contained only low levels of MCD binding sites. The density of MCD receptors is low during the perinatal period and increases rapidly by postnatal day 10 with a decrease of the receptor affinity for MCD. The adult distribution of MCD receptors was reached at postnatal day 30. Increases in density of MCD receptors are discussed in relation with increased neurotoxicity of MCD during brain development. Effects of MCD during the perinatal period are very weak. However, the threshold MCD dose to induce seizures drastically decreased after the first postnatal week. The efficient dose corresponding to adult stage is reached after postnatal day 40.

Topics: Aging; Animals; Autoradiography; Bee Venoms; Brain; Cell Membrane; Iodine Radioisotopes; Kinetics; Neurotoxins; Peptides; Rats; Receptors, Cholinergic; Receptors, Peptide; Seizures; Synaptosomes

The mast cell-degranulating peptide (MCD) isolated from bee venom has been found previously to have receptor sites in rat brain. Behavioral and electrocorticographic responses following intracerebroventricular injections of various doses of MCD have been analyzed. MCD produced a quasi-permanent hippocampal theta rhythm in the motionless animal alternating with epileptiform spike waves and paroxystic seizures. At a dose of 70 pmol seizures occurred for half of the treated rats. At a dose of 100 pmol generalized paroxystic crises were observed for all the rats. These effects were not antagonized by naloxone, morphine, diazepam and progabide. Rats recovered 24 h after a 100 pmol injection of MCD. A second ipsilateral injection to these rats showed the occurrence of a desensitization phenomenon. Desensitization was not observed when the second injection was contralateral. These physiological responses were studied in relation with a biochemical approach on membrane sites of action of MCD using [125I]MCD and their behavior in the desensitization process. The target of [125I]MCD is the ipsilateral hippocampus. Recovery from MCD effects was not due to MCD degradation. Desensitization was not due to down-regulation of the MCD receptor level.

Topics: Animals; Bee Venoms; Behavior, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Peptides; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Seizures; Subcellular Fractions; Theta Rhythm