endothelin-1 and Seizures

We have demonstrated previously that activation of either the ET

Topics: Animals; Brain Ischemia; Endothelin-1; Hippocampus; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; 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

The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70nmol/μl) or ETB receptors (BQ788; 70nmol/1μl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1μl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures followin

Topics: Animals; Electroencephalography; Endothelin-1; Hippocampus; Injections, Intraventricular; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Seizures

Endothelin-1 (ET-1) is a neuroactive protein produced in most brain cell types and participates in regulation of cerebral blood flow and blood pressure. In addition to its vascular effects, ET-1 affects synaptic and nonsynaptic neuronal and glial functions. Direct application of ET-1 to the hippocampus of immature rats results in cerebral ischemia, acute seizures, and epileptogenesis. Here, we investigated whether ET-1 itself modifies the excitability of hippocampal and cortical circuitry and whether acute seizures observed in vivo are due to nonvascular actions of ET-1. We used acute hippocampal and cortical slices that were preincubated with ET-1 (20 μM) for electrophysiological recordings. None of the slices preincubated with ET-1 exhibited spontaneous epileptic activity. The slope of the stimulus intensity-evoked response (input-output) curve and shape of the evoked response did not differ between ET-1-pretreated and control groups, suggesting no changes in excitability after ET-1 treatment. The threshold for eliciting an evoked response was not significantly increased in either hippocampal or cortical regions when pretreated with ET-1. Our data suggest that acute seizures after intrahippocampal application of ET-1 in rats are likely caused by ischemia rather than by a direct action of ET-1 on brain tissue.

Topics: Animals; Endothelin-1; Excitatory Postsynaptic Potentials; Hippocampus; Male; Rats; Rats, Wistar; Seizures; Synaptic Transmission

Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit.. 3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit).. Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801.. The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Endothelin-1; Gait Disorders, Neurologic; Glutamic Acid; Male; Pentylenetetrazole; Phenylalanine; Rats; Rats, Sprague-Dawley; Reflex, Startle; Seizures; Stroke

The aim was to test the hypothesis that occlusion of the middle cerebral artery (MCA) results in the development of epilepsy in rats. Further, we investigated whether lesion volume, hippocampal pathology, early seizures, or severity of behavioral impairment is associated with the development and severity of epilepsy or interictal spiking. MCA occlusion was induced by intracerebral injection of endothelin-1 (ET; 120 pmol). One group of ET-injected rats were followed-up for 6 months (n = 15) and another for 12 months (n = 20). Sham-operated animals were injected with saline (n = 12). Occurrence of early and late seizures was monitored by intermittent video-electroencephalography. Sensorimotor function was tested with the running wheel and tapered beam-walking tests. Emotional learning and memory were assessed with the fear conditioning test and spatial learning and memory with the Morris water maze. Finally, brains were processed for histology. Only one rat developed late spontaneous seizures (i.e., epilepsy). Epileptiform interictal spiking was detected in 9 of 26 animals. Early seizures did not predict the development of epilepsy, spiking activity, or severity of behavioral impairment. Production of MCA stroke by intracerebral injection of ET was not a strong trigger of epileptogenesis in adult rats. Further studies are needed to investigate the effect of age, genetic background, and location of ET-injection on the development of hyperexcitability and the risk of post-stroke epileptogenesis.

Topics: Animals; Behavior, Animal; Cerebrovascular Disorders; Conditioning, Psychological; Electrodes, Implanted; Electroencephalography; Endothelin-1; Epilepsy; Follow-Up Studies; Hippocampus; Male; Maze Learning; Middle Cerebral Artery; Rats; Rats, Sprague-Dawley; Seizures; Stroke; Video Recording

The role of endothelin receptor subtypes, i.e., ET(A) and ET(B) receptors, in the behavioral effects of the intracerebroventricular (ICV) administration of endothelin-1 were examined in conscious rats. ICV administration of endothelin-1 (1-9 pmol/rat) dose dependently produced barrel rolling and other convulsive behaviors including bodily twitching, rigidity, back crawling, fore/hindlimb dystonia, fore/hindlimb clonus, tail extension, and facial clonus. Moreover, a marked increase in spontaneous locomotor activity was observed in animals that were treated with a low dose of endothelin-1 (1 pmol/rat, ICV). Endothelin-1 (9 pmol/rat, ICV)-induced barrel rolling and other convulsive behaviors were completely suppressed by the coadministration of BQ-123 (15 nmol, ICV), a specific endothelin ET(A) receptor antagonist, but not of BQ-788 (15 nmol/rat, ICV), a specific endothelin ET(B) receptor antagonist. In contrast, increased locomotor activity produced by treatment with a low dose of endothelin-1 (1 pmol/rat, ICV) was antagonized by coadministration of BQ-788, but not of BQ123. These results indicate that endothelin-1, which has affinity for both endothelin ET(A) and ET(B) receptors, most likely acts on central ET(A) receptors to evoke barrel rolling and other convulsive behaviors. In addition, activation of central ET(B) receptors may be involved in the increase in spontaneous locomotor activity. These results suggest that brain endothelin receptor subtypes may be involved in the regulation of various physiological functions.

Topics: Animals; Behavior, Animal; Endothelin Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Male; Motor Activity; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Seizures

Topics: Acoustic Stimulation; Adenosine Triphosphate; Animals; Basilar Artery; Brain; Cerebrovascular Circulation; Endothelin-1; Epilepsy; Muscle Contraction; Muscle Relaxation; Rats; Rats, Inbred Strains; Rats, Wistar; Seizures; Species Specificity; Subarachnoid Hemorrhage

Endothelin (ET) is a potent vasoconstrictor which has also been proposed to act as a neuromodulator. We have investigated the action of ET-1 on neurones in vivo, using c-fos as a marker of neuronal activation. Intrastriatal injection of ET-1 caused seizures and barrel rolling which were prevented by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and attenuated by the nitric-oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA). In association with these behaviours, a dramatic increase in c-fos mRNA expression was seen in the cerebral cortex. This increase was blocked by both MK-801 and L-NNA. We suggest that ET-1 modulates the activity of cortical afferents to the striatum, and causes seizures via an NMDA receptor-dependent mechanism.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Endothelin-1; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hippocampus; In Situ Hybridization; Injections; Male; Neostriatum; Nitric Oxide Synthase; Nitroarginine; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures