endothelin-1 and Epilepsy

Migraine is a common disabling headache disorder that is conventionally classified according to the presence or absence of aura. The pathogenesis of this disorder entails a complex interplay of neurovascular factors, that trigger reduction of cerebral blood flow followed by reactive vasodilatation. Despite major emphasis has been placed on the investigation of putative biomarkers that could predict response to specific treatments and prophylaxis, less focus has been directed at the association between migraine and erythrocytosis. Erythrocytosis is typically accompanied by hyperviscosity, that is now considered a crucial determinant in the pathogenesis of migraine. The results of some epidemiological investigations are in substantial agreement to confirm the existence of a significant relationship between increased haemoglobin levels and migraine, whereas some case reports have also reported an effective improvement of symptoms after reduction of erythrocyte count by therapeutic venesection. Interesting evidence has recently emerged from the assessment of red blood cell distribution width (RDW), a simple and inexpensive measure of anysocytosis that has been also associated with a variety of ischaemic and thrombotic disorders other than migraine. The aim of this review was to provide an overview of the current clinical and epidemiological evidence linking migraine and erythrocyte biology.

Topics: Brain; Endothelin-1; Epilepsy; Erythrocyte Count; Erythrocyte Indices; Erythrocytes; Hemoglobins; Hemorheology; Humans; Migraine Disorders; Nitric Oxide; Phlebotomy; Polycythemia; Vasoconstriction

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.

Topics: Amino Alcohols; Animals; Anticonvulsants; Chemistry, Physical; Dose-Response Relationship, Drug; Drug Design; Epilepsy; Male; Mice; Microsomes, Liver; Molecular Structure; Pilocarpine

The diagnosis of vasovagal syncope continues to be difficult despite the use of accurate histories, tilt testing and implantable loop recorders. A circulating biomarker might be useful to facilitate diagnoses. Both endothelin-1 and vasopressin are increased during positive tilt tests resulting in syncope. Copeptin is a stable cleavage product of vasopressin formation. We conducted a pilot study to assess the utility of endothelin-1 and copeptin as circulating biomarkers of vasovagal syncope.. Three populations were studied: syncope patients, epilepsy patients and controls. Vasovagal syncope diagnosis was ascertained with the Calgary Syncope Score and epilepsy diagnosis was confirmed with EEG. Plasma levels of endothelin-1 were measured using by ELISA and copeptin levels were determined using an EIA kit.. Asymptomatic control subjects had mean age 35 ± 11 years (7/22 male); epileptic subjects had mean age 32 ± 7 years (4/15 male); and syncope subjects had mean age 33 ± 16 years (4 of 21 male). Circulating plasma levels of endothelin-1 and copeptin were no different among the three groups. Mean concentrations of endothelin-1 were as follows: syncope, 23 ± 32 pg/mL; controls, 21 ± 17 pg/mL; and epileptics, 18 ± 12 pg/mL. Mean concentrations of copeptin were as follows: syncope, 1·29 ± 0·79 ng/mL; controls, 1·25 ± 0·79 ng/mL; and seizures, 1·23 ± 0·45 ng/mL. There were no significant correlations between syncope frequency and copeptin or endothelin-1 levels.. Circulating plasma endothelin-1 and copeptin levels are not significantly different among populations of controls, syncope patients and seizure patients.

Topics: Adult; Biomarkers; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Glycopeptides; Humans; Immunoenzyme Techniques; Male; Middle Aged; Syncope, Vasovagal; Young Adult

The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.

Topics: Animals; Blood Pressure; Brain; Caspase 3; Disease Models, Animal; Endothelin-1; Epilepsy; Heart Rate; Hydrocarbons, Brominated; Infarction, Middle Cerebral Artery; Male; Motor Activity; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Stroke; Tyrosine

The goal of this study was to develop a new model of ischemia-induced seizures in immature rats using injection of vasoconstrictor Endothelin-1 (ET-1) into the brain. ET-1 (10, 20, or 40 pmol) was infused into the left dorsal hippocampus of freely moving Wistar rats 12 (P12) and 25 (P25) days old. Animals were then video/EEG-monitored for 100 min and monitoring was repeated 22 h later. Parameters of electrographic seizures (frequency and mean duration) as well as pattern of their behavioral correlates were evaluated. The pattern of behavioral seizures was used to develop model-specific scoring system. Cresyl violet and Fluoro Jade-B-staining were used to evaluate brain damage. Extension of the lesion was correlated with seizure severity. After ET-1-injection, seizures occurred in 83-100% animals of all age-and-dose groups and persisted for 24 h except P12 rats with 10 pmol. There were no differences in average seizure duration (18-40 s) or seizure frequency (3-7 seizures/100 min) among individual dose-groups. Between the 1st and 2nd observation period, total seizure duration decreased in 71% of P12 and 47% of P25 rats. Electrographic seizure activity was most frequently accompanied by clonus, incidence of more severe convulsions (barrel rolling or generalized clonic seizures) increased with dose of ET-1. Morphologic examination did not reveal any dose-related difference in damage severity, hippocampal damage was however more extensive in P12 compared to P25 animals. Seizure severity correlated positively with severity of the damage in both age groups. Our study presents focal injection of ET-1 into the brain as a new and practical model of ischemia-induced seizures in immature rats.

Topics: Animals; Animals, Newborn; Brain Ischemia; Disease Models, Animal; Electroencephalography; Endothelin-1; Epilepsy; Hippocampus; Injections; Male; Rats; Rats, Wistar; Videotape Recording

The direct injection of endothelin-1 (ET-1) into brain parenchyma was recently suggested as a suitable model of stroke. The present study was designed to assess whether intrahippocampal injection of ET-1 in immature rats causes neurodegeneration and immediate seizures, and results in impairment of motor development, cognitive decline, epilepsy and chronic hippocampal lesion. ET-1 was injected unilaterally into the dorsal hippocampus in doses of 20 or 40 pmol at the age of 12 (P12) or 25 (P25) days. Video-electroencephalographic monitoring performed during 100 min after the injection of ET-1 demonstrated the development of convulsive epileptic seizures in 75-100% of animals of individual age-and-dose groups. Long-term behavioral follow-up did not reveal impairment of motor development in any dose-and-age group. At 2 months after ET-1 injection, impairment of spatial memory occurred only in rats with 40 pmol of ET-1 at P12. At 3 months after ET-1 injection spontaneous electrographic seizures occurred in 62.5-100% animals of both ages with no relation to the dose used. Seizures were always non-convulsive. The total seizure duration per 24 h was higher in the P12 than the P25 group, suggesting more severe epilepsy. The extent of the hippocampal lesion increased with the dose of ET-1 and was significantly higher in the P12 than the P25 group. The severity of the ET-1-induced lesion correlated positively with total seizure duration per 24 h at both ages. Our results document that early intrahippocampal injection of ET-1 results in lesion development and both immediate seizures and chronic epilepsy in either age group. Cognitive impairment occurred only in rats with ET-1 injection at P12.

Topics: Age Factors; Animals; Animals, Newborn; Cerebral Arteries; Cerebrovascular Circulation; Developmental Disabilities; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Endothelin-1; Epilepsy; Hippocampus; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Memory Disorders; Nerve Degeneration; Rats; Rats, Wistar; Stroke; Vasoconstrictor Agents

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

An increased level of endothelin (ET)-1 seems to be involved in the development of augmented cerebrovascular resistance in different pathological conditions, most notably vasospasm after subarachnoid hemorrhage. Therefore, interfering with the ET synthesis or ET receptor blockade may be a promising approach in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Although the receptors mediating the effects of ET-1 human cerebrovasculature are well characterized, data concerning the functionally relevant ET-converting enzyme (ECE) activity are scarce.. ECE activity was determined in organ bath studies by the use of intraoperatively harvested human pial arteries. The level of ECE activity was analyzed by comparing the shift in the concentration effect curves obtained for ET-1 and its precursor, big ET-1. In addition, the presence of ECE-1alpha immunoreactivity was studied in human cerebral tissue.. ECE-1alpha immunoreactivity was found, although not consistently, in human cerebral arteries and was restricted to the endothelium. In isolated pial arterial segments, ET-1 and big ET-1 induced concentration-related contractions with mean pD(2) values of 9.25 +/- 0.34 and 7.13 +/- 0.17, respectively, yielding a 123-fold shift of big ET-1 versus mature ET-1. Preincubation with phosphoramidon (10(-4) mol/L) resulted in a small yet significant inhibition of the contraction induced by big ET-1.. The results of our study indicate the presence of functional ECE activity and ECE-1alpha immunoreactivity in human cerebral arteries. Furthermore, the data suggest the presence of ECE-like activity that differs from that of ECE-1alpha.

Topics: Adult; Arteries; Aspartic Acid Endopeptidases; Brain Neoplasms; Cerebrovascular Circulation; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Epilepsy; Female; Glycopeptides; Humans; Immunohistochemistry; In Vitro Techniques; Intraoperative Period; Isoenzymes; Male; Metalloendopeptidases; Middle Aged; Osmolar Concentration; Pia Mater; Protein Precursors; Tissue Distribution; Vasoconstriction

Endothelin-1 (ET) has been shown to be involved in human pathological conditions, but its physiological function remains to be elucidated. The aim of this work was to assess whether endothelium-derived ET was involved in the overall responsiveness of freshly isolated human pial arteries.. Samples of cerebral cortex, otherwise discarded, were obtained during tumor or epileptic lesion resections (n = 10 donors). Arterial segments were isolated and mounted on a microvessel myograph.. Inhibition of nitric oxide (NO) formation with N omega-nitro-L-arginine (L-NA, 100 micromol/L) increased basal tone by 7+/-1% Emax (n=5). This increase in tone was fully abolished in the presence of BQ123 (1 micromol/L; ET(A) receptor antagonist, P<.05) but potentiated by a subthreshold concentration of exogenous ET (1 nmol/L; 33+/-8% Emax; P<.05). In the presence of L-NA, serotonin (10 micromol/L)-induced tone was doubled compared with the control response (P<.05) but reduced by 90% in the presence of BQ123 (P<.05). In the absence of L-NA, BQ123 prevented serotonin-induced tone (n=3). Oxymetazoline, a selective alpha2-adrenergic receptor agonist, induced an endothelium-dependent relaxation of preconstricted human pial arteries. The relaxation was partially sensitive to NO synthase inhibition and fully prevented by the addition of ET, whereas substance P-induced relaxation was preserved. Glibenclamide (1 micromol/L), an inhibitor of ATP-sensitive K+ channels and tetraethylammonium (1 mmol/L), an inhibitor of Ca2+-activated K+ channels had no effect on oxymetazoline-induced relaxation.. The results of this study suggest first that ET is involved in the tonic response induced by NO synthase inhibition; second, part of the contractile response induced by serotonin is endothelium-dependent and sensitive to BQ123; and third, the data suggest that activation of alpha2-adrenergic receptors generated an endothelium-dependent relaxation that was selectively inhibited by exogenous ET.

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Arteries; Brain Neoplasms; Cerebral Cortex; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Epilepsy; Female; Glyburide; Humans; Hypoglycemic Agents; Male; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxymetazoline; Peptides, Cyclic; Pia Mater; Potassium Channel Blockers; Serotonin; Substance P; Tetraethylammonium; Vasoconstrictor Agents; Vasodilator Agents

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