sincalide and Seizures

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

To evaluate the changes in serum CCK-8 and leptin levels in patients with refractory epilepsy treated with the ketogenic diet (KD).. In this prospective study, patients aged between one and 40 years with refractory epilepsy were included. CCK-8 and leptin were measured in serum at baseline and after three and 12 months of treatment with the KD using an enzyme-linked Immunoabsorbant Assay. Seizure frequency and responsiveness were calculated.. Fifty-four patients were included; 26 patients (48%) were still on the KD at 12 months. After three and 12 months, respectively, 39% and 26% were responders. CCK-8 values were statistically significantly increased at three months (p=0.005) and 12 months (p=0.012). In responders, at three months follow-up, this increase of CCK-8 was significant (p=0.020), whereas in the non-responders it was not (p=0.34). Leptin values were decreased at three and 12 months, the decrease at three months being statistically significant in post-pubertal men (p=0.028) and post-pubertal women (p=0.007).. In responders to the KD, serum CCK-8 increased statistically significantly during treatment at three months. Serum leptin decreased statistically significantly at three months in men and in post-pubertal women. It is plausible that the increase of CCK-8 and the decrease of leptin contribute to the anti-convulsive effect of the KD.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Cholecystokinin; Diet, Ketogenic; Drug Resistant Epilepsy; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Infant; Leptin; Male; Peptide Fragments; Prospective Studies; Seizures; Time Factors; Treatment Outcome; Young Adult

To evaluate the potential for lipofectin-mediated central nervous system gene transfer, the plasmid coding for cholecystokinin was administered intracerebroventricularly to rats, which have congenital audiogenic seizures and high responses to peripheral electric stimulation-induced analgesia. Previous studies had shown that low brain cholecystokinin levels may be the neurochemical variable of rat's audiogenic seizure and high responses to the analgesia because cholecystokinin is an anticonvulsant and anti-opioid neuropeptide. Gene transfer of cholecystokinin corrected the increased susceptibility to audiogenic seizures and the high responses to analgesia for about one week. Similar administration of plasmid expressing beta-galactosidase indicated that the vector mainly transfected ependymal cells lining the ventricle and pia mater cells. The increased cholecystokinin messenger RNA and immunoreactivity in the hippocampus following stereotactic intrahippocampal administration of cholecystokinin plasmid was also demonstrated with in situ hybridization and immunohistochemistry techniques. These results suggest that lipofectin-mediated gene transfer will be useful for studies of brain function, the modification of behavior and gene therapy for central nervous system disorders.

Topics: Acoustic Stimulation; Animals; Autoradiography; Behavior, Animal; DNA, Complementary; Epilepsy; Gene Transfer Techniques; Hippocampus; Immunohistochemistry; In Situ Hybridization; Liposomes; Male; Microinjections; Phosphatidylethanolamines; Plasmids; Rats; Rats, Mutant Strains; Rats, Wistar; RNA, Messenger; Seizures; Sincalide

Cholecystokinin-octapeptide (CCK-8S) is widely distributed in neurones of the central nervous system, where it is thought to act as a transmitter or modulator. CCK-8S has been shown to exert anti-convulsant activity in animal seizure models and changes in cortical and hippocampal CCK-immunoreactivity and preproCCK messenger RNA (mRNA) have been reported following electrically- and chemically-induced seizures. In the present study, the spatiotemporal effect of amygdaloid-kindled seizures on levels of preproCCK messenger RNA in rat brain were determined using quantitative in situ hybridization histochemistry. Stimulation-evoked seizures produced bilateral increases (45-70%) in preproCCK mRNA throughout layers II-III of the cerebral cortex. These increases were rapidly induced, occurring 30-60 min after the last stage 5 seizure, but transient, as no significant changes were detected after 2 h, or subsequently at 24 or 72 h, or 2-8 weeks, post-stimulation. Rapid changes in the relative levels of preproCCK mRNA, post-seizure, suggest a possible stabilization of preproCCK transcripts and increased production of CCK-8S peptide, which may be involved in anticonvulsant mechanisms in response to the acute seizures.

Topics: Amygdala; Animals; Brain; Cerebral Cortex; Cholecystokinin; Kindling, Neurologic; Kinetics; Male; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Sincalide; Time Factors; Transcription, Genetic

Immunocytochemistry and in situ hybridization techniques were used for investigating changes in cholecystokinin immunoreactivity and mRNA in the cerebral cortex and hippocampus after kainic acid-induced limbic seizures in the rat. Marked increases in cholecystokinin mRNA concentrations were observed in layers II/III and V/VI of the cerebral cortex, in CA1 pyramidal neurons of the hippocampus, and in presumptive basket cells of the dentate gyrus 1 and 2 days after the acute seizures. Whereas cholecystokinin mRNA contents returned to normal in the cerebral cortex and the CA1 sector at later intervals, high concentrations were observed in basket cells even 2 months after the initial seizures. Accordingly, cholecystokinin-like immunoreactivity was intensified in the cerebral cortex, CA1 sector and in presumed basket cells of the hippocampus 30 days after kainic acid. Besides its high content in basket cells, cholecystokinin-like immunoreactivity was primarily present in neuronal fibers or diffusely distributed in the respective brain area. In the hippocampus, strongly enhanced staining for cholecystokinin was also observed in the alveus, the stratum lacunosum moleculare, and in the inner molecular layer, suggesting increased concentrations of the peptide in afferent and efferent fibers of the hippocampus. The present experiments suggest a strong activation of cholecystokinin systems in the brain after kainic acid-induced limbic seizures in the rat. This is indicated by pronounced increases in cholecystokinin mRNA in the cortex and individual cell types of the hippocampus (basket cells, granule cells, and CA1 pyramidal neurons). The subsequent increases in cholecystokin immunoreactivity even surpass those in mRNA. The observed changes may be part of the self-defense mechanisms that protect the animals during subsequent epileptic episodes.

Topics: Amygdala; Animals; Cerebral Cortex; Gene Expression; Hippocampus; Immunoenzyme Techniques; Immunohistochemistry; In Situ Hybridization; Kainic Acid; Male; Neurons; Parietal Lobe; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Sincalide

Utilizing audiogenic seizure-prone P77PMC rats, the effects of cholecystokinin octapeptide (CCK-8) on genetic seizure susceptibility were studied in vivo, in cerebral cortical synaptosomes, and in cortical neuronal cell cultures. The results showed that CCK-8 could decrease seizure susceptibility, and that the K(+)-stimulated release of GABA in cerebral cortex synaptosomes from seizure-prone animals was depressed. The presence of exogenous CCK-8 (10(-7) M) together with elevated K+ (25 mM) causes a higher increased magnitude in GABA release from synaptosomes (enhanced by 100%) and cell cultures (17 days in vitro, increased by 177%) derived from seizure-prone rats than the controls (increased by 42%, in synaptosomes; and 107% in cell cultures). These preliminary results raise the possibility that the developmental abnormalities in modulation effect of CCK-8 on GABA release in central nervous system may play a role causing greater seizure susceptibility in genetic seizure-prone rats. The analysis of the brain tissue level and gene-expression of CCK-8 will be the important step of further investigation.

Topics: Animals; Cells, Cultured; Cerebral Cortex; Disease Susceptibility; gamma-Aminobutyric Acid; Injections, Intraventricular; Male; Rats; Rats, Inbred Strains; Seizures; Sincalide; Synaptosomes

Pronounced changes in the content of cholecystokinin octapeptide (CCK-8) have been found after limbic seizures induced by i.p. injection of kainic acid. Three hours after injection of the toxin a significant decrease in CCK-8 was observed in the frontal cortex and amygdala/pyriform cortex reflecting an increased release during acute seizures. A persistent decrease in the content of the peptide in the amygdala/pyriform cortex suggests destruction of the respective neurons. In the substantia nigra and in the striatum and, more moderately, in the hippocampus and frontal cortex increases in CCK-8 were observed 10 days after injection of kainic acid suggesting an increased synthesis or decreased release of the peptide in these brain areas subsequently to the acute seizures.

Topics: Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Injections, Intraperitoneal; Kainic Acid; Male; Rats; Rats, Inbred Strains; Seizures; Sincalide

The anticonvulsive activity of cholecystokinin octapeptide sulphate ester (CCK-8-SE), non-sulphated cholecystokinin octapeptide (CCK-8-NS) and three different N- and C-terminal fragments were investigated against seizures induced by picrotoxin and electroshock in rats after intracerebroventricular administration. Doses of 0.8 and 80 pmol of CCK-8-SE and CCK-8-NS significantly enhanced the latency of seizures induced by picrotoxin and shortened the duration of the clonic phase of the seizures induced by electroshock. Only CCK-8-SE shortened the recovery time and only 0.8 pmol of CCK-8-SE could shorten the duration of the tonic phase of convulsions induced by electroshock. Doses of the octapeptides of 8000 pmol were ineffective, with the exception of CCK-8-NS in the picrotoxin test. Of the fragments tested, the C-terminal tetrapeptide, CCK-5-8, enhanced the latency of seizures induced by picrotoxin in a dose of 0.8 pmol, and had a dose-dependent biphasic effect on the duration of the clonic phase of seizures induced by electroshock. Intracerebroventricular administration of diazepam enhanced only the latency of tremor and clonic seizures induced with picrotoxin in a dose of 40 nmol. Twelve nmole of diazepam shortened the clonic phase of convulsions induced by electroshock. The peptides tested were much more active than diazepam, and their effective doses were comparable to the amounts of cholecystokinin octapeptide found in brain structures.

Topics: Animals; Anticonvulsants; Diazepam; Electroshock; Injections, Intraventricular; Male; Peptide Fragments; Picrotoxin; Rats; Seizures; Sincalide

Intraperitoneal administration of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and nonsulphated cholecystokinin octapeptide (CCK-8-NS) enhanced the latency of seizures induced by picrotoxin in mice. Experiments with N- and C-terminal fragments revealed that the C-terminal tetrapeptide (CCK-5-8) was the active centre of the CCK octapeptide molecule. The analogues CCK-8-SE and CCK-8-NS (dose range 0.2-6.4 mumol/kg) and caerulein dose range 0.1-0.8 mumol/kg) showed bell-shaped dose-effect curves, with the greatest maximum inhibition for CCK-8-NS. The peptide CCK-5-8 had weak anticonvulsant activity in comparison to the octapeptides, 3.2 mumol/kg and larger doses of the reference drug, diazepam, totally prevented picrotoxin-induced seizures and mortality. The maximum effect of the peptides tested was less than that of diazepam. Experiments with analogues and derivatives of CCK-5-8 demonstrated that the effectiveness of the beta-alanyl derivatives of CCK-5-8 were enhanced and that they were equipotent with CCK-8-SE. Of the CCK-2-8 analogues, Ser(SO3H)7-Ac-CCK-2-8-SE and Thr(SO3H)7-Ac-CCK-2-8-SE and Hyp(SO3H)-Ac-CCK-2-8-SE were slightly more active than CCK-8-SE.

Topics: Animals; Cholecystokinin; Dose-Response Relationship, Drug; Male; Mice; Peptide Fragments; Picrotoxin; Seizures; Sincalide; Structure-Activity Relationship

Cholecystokinin octapeptide (CCK-8), caerulein and diazepam inhibited exploratory rearing activity and harman-induced convulsions in mice. Pretreatment with the selective benzodiazepine receptor antagonist Ro 15-1788, reduced or abolished the sedative and anticonvulsive effects of diazepam, but left the same effects of both peptides unaffected. The peptide-induced ptosis was even increased by Ro 15-1788. The results suggest that the CCK-like peptides do not directly interact with the benzodiazepine receptor.

Topics: Animals; Anticonvulsants; Benzodiazepinones; Blepharoptosis; Body Temperature; Ceruletide; Cholecystokinin; Diazepam; Flumazenil; Harmine; Hypnotics and Sedatives; Male; Mice; Peptide Fragments; Seizures; Sincalide

Caerulein, cholecystokinin octapeptide (CCK-8) and diazepam delayed the onset of seizures produced by harman and thiosemicarbazide (TSC). Caerulein had the potency of diazepam, whereas CCK-8 was less active by a factor of four. The convulsions induced by isoniazid (INH) were very resistant to both caerulein and diazepam; CCK-8 was not tested against isoniazid. Haloperidol did not influence the effect of TSC; it enhanced isoniazid-induced seizures, and antagonized the convulsant effect of harman.

Topics: Animals; Anticonvulsants; Ceruletide; Cholecystokinin; Diazepam; Haloperidol; Harmine; Isoniazid; Male; Mice; Mice, Inbred Strains; Seizures; Semicarbazides; Sincalide

Caerulein and the C-terminal octapeptide of cholecystokinin (CCK-8), after subcutaneous administration to mice, both delayed the onset and retarded the development of toxic effects of convulsants such as strychnine, pentetrazol, bicuculline, and picrotoxin. They also increased the seizure threshold doses of intravenously infused pentetrazol and picrotoxin. In this regard, both peptides were at least equipotent with diazepam.

Topics: Animals; Anticonvulsants; Bicuculline; Ceruletide; Cholecystokinin; Diazepam; Kinetics; Male; Mice; Pentylenetetrazole; Seizures; Sincalide; Strychnine; Time Factors