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Anticonvulsant activity of α-terpineol isolated from myristica fragrans in gaers model of absence epilepsy

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Abstract

Epilepsy is a neurological disorder characterized by recurrent seizures resulting from excessive abnormal electrical discharges in the brain. Medicinal plants may play an invaluable role to discover the new antiepileptic drugs. The aim of the present study was to investigate the anticonvulsant activity of a-terpineol isolated from Myristica fragrans Hountt. The a-terpineol showed a significant inhibition of the seizure episodes and spikes in absence seizures model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) rats by using electroencephalography records. It showed dose-dependent anticonvulsant activity that was comparable to the known antiepileptic drug of diazepam. It showed a rapid onset and relatively short duration of anticonvulsant effects. The present findings suggest that a-terpineol might possess antiepileptic activities against the partial seizures of human because it prevented seizures in well-established genetic absence seizure animal model of GAERS rats.

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In Wistar rats with spontaneous non-convulsive absence epilepsy, absence seizures were dose dependently suppressed by intraperitoneal administration of the GABAB receptor antagonists CGP 36742, 50-400 mg/kg, and CGP 56999, 0.25-0.75 mg/kg, and by bilateral microinjections of the same compounds into the lateral nuclei of the thalamus. In rats susceptible to audiogenic seizures, intraperitoneal administration of both GABAB receptor antagonists, at doses which suppressed absence seizures, facilitated the elicitation of sound-induced tonic seizures. In non-epileptic control rats, intraperitoneal injections of higher doses of CGP 36742 (800-2400 mg/kg) and CGP 56999 (3-6 mg/kg) induced delayed clonic convulsions, which were suppressed by pretreatment with baclofen. c-Fos protein was expressed after GABAB receptor antagonist-induced seizures in the cortex, hippocampus, amygdala, perirhinal and piriform cortex. Intra-cortical and hippocampal microinfusion of both GABAB receptor antagonists produced focal seizures. In conclusion, GABAB receptor antagonists suppress non-convulsive absence seizures by blocking thalamic GABAB receptors, while they induce convulsions in cortical and limbic structures.
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The present study was undertaken to investigate the effect of an n-hexane extract of Myristica fragrans seeds on depression in mice by using the forced swim test (FST) and the tail suspension test (TST). M. fragrans extract (5, 10, and 20 mg/kg) was administered orally for 3 successive days to different groups of Swiss male young albino mice. M. fragrans extract significantly decreased immobility periods of mice in both the FST and the TST. The 10 mg/kg dose was found to be most potent, as indicated by the greatest decrease in the immobility period compared with the control. Furthermore, this dose of the extract was found to have comparable potency to imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.). The extract did not have a significant effect on locomotor activity of mice. Prazosin (62.5 microg/kg i.p.; an alpha (1)-adrenoceptor antagonist), sulpiride (50 mg/kg i.p.; a selective D(2) receptor antagonist), and p-chlorophenylalanine (100 mg/kg i.p.; an inhibitor of serotonin synthesis) significantly attenuated the M. fragrans extract-induced antidepressant-like effect in the TST. Thus, extract of M. fragrans elicited a significant antidepressant-like effect in mice, when assessed in both the TST and the FST. The antidepressant-like effect of the extract seems to be mediated by interaction with the adrenergic, dopaminergic, and serotonergic systems.
Article
Paroxysmal 7- to 12-Hz high-voltage rhythmic spike (HVRS) or spike-wave discharges often appear in several particular strains of rats. However, functional hypotheses of these 7-12 Hz high-voltage cortical oscillations (absence seizure vs. idling mu rhythm) are inconclusive. The mu rhythm can be provoked by flicker stimulation (FS) in most people, but FS is less effective at eliciting absence epileptic activity. Therefore FS and antiepileptic drugs were used to verify the role of HVRS activity in Long-Evans rats with spontaneous HVRS discharges and Wistar rats without spontaneous HVRS discharges. The occurrence of HVRS discharges was significantly reduced by antiabsence drugs (ethosuximide, valproic acid, and diazepam) in dose-dependent manners, but high-dose carbamazepine displayed little effect. On the other hand, oscillation frequencies and durations of spontaneous HVRS discharges were not altered by FS. Under asynchronous brain activity, many FSs (>60%) elicited small-amplitude mu-rhythm-like activity in the barrel cortex concomitant with FS-related rhythms in the occipital cortex and resulted in significant augmentation of 7-12 Hz power in the parietal region. Furthermore, a large portion of FSs (>60%) revealed increase of 7-12 Hz power of the parietal cortex after ethosuximide administration (100 mg/kg ip) in Long-Evans rats. Similar FS-elicited phenomena also appeared in Wistar rats. Characteristics of FS-elicited mu-rhythm-like activities were consistent with those observed in humans, and they remarkably differed from those of spontaneous HVRS discharges. These results support the hypothesis that HVRS activity in Long-Evans rats may be an absence-like seizure activity rather than the mu rhythm.
Article
Time-frequency dynamics of spike-wave discharges (SWDs) were investigated in patients with absence seizures and in WAG/Rij rats, a genetic model of absence epilepsy using a specially developed wavelet transform. Two types of SWDs were analyzed in both species: the most frequently occurring discharges (of minimal 3.6-4.0 s or more) and shorter ones recorded from various cortical regions. The more prolonged discharges had two phases: during the initial part (from tenth of seconds to 1 s) of the seizure the frequency decreased quickly from 5 to 3.5 Hz in patients and from about 15 to 10 Hz in rats. A slower frequency decrease with periodical fluctuations was observed in both species during the second part of the discharge: the frequency decreased towards the end of the discharge to 3 Hz in patients and to 6-7 Hz in rats. The frequency of the short discharges decreased fast during the whole discharge: from 5 to 2-2.5 Hz and from about 15 to 5 Hz in patients and rats, respectively. Comparison of data obtained in patients with typical absence epilepsy and WAG/Rij rats with genetic absence epilepsy revealed that the time-frequency dynamics of SWDs had similar properties but in a different frequency range. The study of time-frequency dynamics using this specially developed wavelet transform revealed two different types of SWDs, which most likely represent different dynamics in the cortico-thalamo-cortical loop during shorter and more prolonged discharges.
Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research
  • C P Panayiotopoulos
Panayiotopoulos CP. Typical absence seizures and related epileptic syndromes: assessment of current state and directions for future research. Epilepsia. 2008;49(12):2131-2139. doi: 10.1111/j.1528-1167. 2008.01777.
Pathophysiological mechanisms of genetic absence epilepsy in the rat
  • L Danober
  • C Deransart
  • A Depaulis
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  • C Marescaux
Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol. 1998;55(1):27-57. doi: 10.1016/S0301-0082(97)00091-9.
Detection of SWD in the cortical EEG of GAERS
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  • J P Marten
  • S Dedeurwaerdere
  • P Boon
  • Lamahieu
Van Hese P, Marten JP, Dedeurwaerdere S, Boon P, Lamahieu et al. Detection of SWD in the cortical EEG of GAERS. Phys Med Biol. 2003;48(12):1685-1700. doi:10.1088/0031-9155/48/12/302.
The spectrum of anticovulsant efficacy of retibine (ezogabine) in animal models: Implications for clinical use
  • C H Large
  • D M Sokal
  • A Nehlig
  • M J Gunthorpe
  • R Sankar
  • C S Crean
Large CH, Sokal DM, Nehlig A, Gunthorpe MJ, Sankar R, Crean CS, et al. The spectrum of anticovulsant efficacy of retibine (ezogabine) in animal models: Implications for clinical use. Epilepsia. 2012;53(3):425-436. doi: 10.1111/j.15281167.2011.03364.x.
EEG spike activity precedes epilepsy after kainite-induced status epilepticus
  • A White
  • P A Williams
  • J L Hellier
  • S Clark
  • F E Dudek
  • K J Staley
White A, Williams PA, Hellier JL, Clark S, Dudek FE, Staley KJ. EEG spike activity precedes epilepsy after kainite-induced status epilepticus. Epilepsia. 2010;51(3):371-383. doi: 10.1111/j.1528-1167.2009.02339.
Electrophysiological and pharmacological characteristics of two types of spike-wave discharges in WAG/Rij rats
  • I S Midzianovskaia
  • G D Kuznetsova
  • A M Coenen
  • A M Spiridonov
  • E L Van Luijtelaar
Midzianovskaia IS, Kuznetsova GD, Coenen AM, Spiridonov AM, van Luijtelaar EL. Electrophysiological and pharmacological characteristics of two types of spike-wave discharges in WAG/Rij rats. Brain Res. 2001;911(1):62-70. doi: 10.1016/S0006-8993 (01)02705-6.
Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats
  • E Sitnikova
  • G Van Luijtelaar
Sitnikova E, van Luijtelaar G. Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats. Epilepsia. 2007;48(12):2296-2311. doi: 10.1111/j.1528-1167. 2007.01250.
In: Epilepsy and related disorders
  • W G Lennox
  • M A Lennox
Lennox WG, Lennox MA. In: Epilepsy and related disorders. Volume 1&2. Boston (MA): Little Brown & Co;1960.
Pathophysiological mechanisms of experimental generalized absence seizures in rats
  • O C Snead
  • A Malafosse
  • P Genton
  • E Hirsch
  • C Marescaux
  • D Broglin
  • R Bernasconi
Snead OC. Pathophysiological mechanisms of experimental generalized absence seizures in rats. In: Malafosse A, Genton P, Hirsch E, Marescaux C, Broglin D, Bernasconi R, editors. Idiopathic Generalized Epilepsies: Clinic Exp Genetic Aspects. London (LN): John Libbey; 1994. p. 133-150.