1995 Fiscal Year Final Research Report Summary
Production under control of microorganism and pharmacological use of spontaneously epileptic rats.
| Project/Area Number |
06557141
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
SASA Masashi Hiroshima Univ.Sch.of Med.Professor, 医学部, 教授 (20025654)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Toshiyuki Toyo Sangyo Co.Dev.of System Engineering, 研究員
UJIHARA Hisamitsu Kochi Medical College Dept.Psychiatry, Assistant Professor, 講師 (00213421)
SERIKAWA Tadao Kyoto Unvi.Facutly of Med.Professor, 医学部, 教授 (30025655)
KOHNO Shizuko Hiroshima Univ.Sch.of Med.Research Associate, 医学部, 助手 (30034028)
ISHIHARA Kumatoshi Hiroshima Univ.Sch.of Med.Assistant Professor, 医学部, 講師 (20212912)
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| Project Period (FY) |
1994 – 1995
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| Keywords | Spontaneously epileptic rats / Tonic convulsion / Absence-like seizure / TRH analogue / CNK-602A / Ca^<2+> channel / Ca^<2+> antagonist |
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| Research Abstract |
The spontaneously epileptic rat (SER : zi/zi, tm/tm) is obtained by mating heterozygous tremor rat (tm/+) with monozygous zitter rat (zi/zi). SER shows both tonic convulsion and absence-like seizures spontaneously. The seizures are easily induced by light stimuli such as tactile stimulation. SER is now reproduced by mating the zitter-homozygous and tremor-heterozygous animals (zi/zi, tm/+) each other. When male and female animals were housed in clean racks with a ratio of 1 : 1 or 1 : 2 at 22-26ﾟC and 50-65 % relative humidity in stress-free conditions, the SER was most efficiently reproduced. Previous attempts with a single i.v.injection of thyrotropine releasing hormone analogue, CNK-602A.inhibited both tonic and absence-like seizures. Under such conditions, effects of chronic intake of CNK-602A on epileptic seizures and survival time of SER were examined. CNK-602A significantly inhibited tonic convulsion and extended survival time from 19.0 <plus-minus> 0.6 to 21.7 <plus-minus>0.7 w
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eeks without affecting weight gain and serum T3 and T4 levels. These findings suggestthat this drug may be effective against convulsive seizures in patients with epilepsy. In slice preparations of SER hippocampus, long-lasting depolarization shifts accompanied repetitive firings in the CA1 cells were evoked with a single electronic stimulation of mossy fiber. This phenomenon were blocked by calcium channel blockers such as nicardipine. In addition, the calcium voltage induced by intracellular depolarizing pulse was inhibited by nicardipine at a dose lower than that required to inhibit the voltage of normal rats. In isolated CA3 neurons studied with patch clamp method revealed that the I-V curve of calcium currents in young SER before induction of epileptic seizures resembled that of normal Kyoto Wistar rat. However, the threshold for openning the calcium channel was lower in matured SER than that observed in normal rat. In addition, this current was inhibited by calcium antagonists at a dose much lower than that required to block the current in normal rats. Furthermore, a newly synthesized calcium channel blocker, S-312-d, inhibited the epileptic seizures in SER subjected to both single and repeated (once daily for 4 consecutive days) oral administrations. These findings suggest that calcium channel blockers are useful in human epilepsy. In summary, SER may be serve as a useful animal model for acute and chronic evaluations of novel antiepileptic drugs against non-remeidal epilepsy. Moreover, SER may also be used to study the mechanism underlying epileptic seizu Less
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