Participation of metabotropic glutamate receptors in pentetrazol-induced kindled seizure.
OBJECTIVE
The present study was undertaken to clarify the effects of (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), a metabotropic glutamate receptor (mGluR) 1 antagonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a mGluR2/3 agonist, and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), a mGluR4/8 agonist, on pentetrazol-induced kindled seizures.


METHODS
Mice were anesthetized with pentobarbital; the electrodes and guide cannula were chronically implanted into the cortex and lateral ventricle. To induce kindling, pentetrazol at a dose of 40 mg/kg was injected once every 48 h. Behavioral and electroencephalographic seizures were monitored for 20 min following pentetrazol administration. Fully kindled mice were used for pharmacologic studies.


RESULTS
Intracerebroventricular injection of AIDA and L-AP4 showed significant inhibitory effects on pentetrazol-induced kindled seizures. In addition, simultaneous use of AIDA and (2R,4R)-APDC or L-AP4 caused more potent inhibition of seizure activities. The inhibitory effect of AIDA on pentetrazol-induced kindled seizures was antagonized by (RS)-3,5-dihydroxyphenylglycine ((RS)-3,5-DHPG), a group I mGluR agonist; (2S)-a-ethylglutamic acid (EGLU), a group II mGluR antagonist; and (RS)-α-methyl-4-phosphonophenylglycine (MPPG), a group III mGluR antagonist. On the other hand, the inhibitory effect of L-AP4 was antagonized only by MPPG.


CONCLUSIONS
It is proposed that mGluR1 antagonists and mGluR4/8 agonists show anticonvulsive effects on pentetrazol-induced kindled seizures. Furthermore, it is also proposed that the simultaneous use of an mGluR1 antagonist and an mGluR2/3 or mGluR4/8 agonist is a potential novel therapeutic strategy in epileptic disorders.
Department of Medicinal Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Tsushima-naka, Kita-ku, Okayama, Japan.
Yusuke
Y
Watanabe
Yuko
Y
Kaida
Satoko
S
Fukuhara
Kenshi
K
Takechi
Takashi
T
Uehara
Chiaki
C
Kamei
D000818:Animals; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010433:Pentylenetetrazole / Q000633:toxicity*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*
D018094:Receptors, Metabotropic Glutamate; D010433:Pentylenetetrazole