Cyclothiazide prolongs low [Mg2+]-induced seizure-like events.
Here we address the effects of cyclothiazide (CTZ), an allosteric inhibitor of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor desensitization, on low [Mg(2+)]-induced seizure-like events (SLEs) recorded from the CA3 pyramidal layer of juvenile rat hippocampal slices. CTZ (100 microM) made the period of tonic-like discharges (161 +/- 18% of control) and the whole SLE (151 +/- 15% of control) longer (in 7 of 9 slices) or induced endless SLE by stabilizing clonic-like bursting (in 2 of 9 slices). CTZ (30 microM) had no significant effects on SLE dynamics (n = 4), whereas 300 microM CTZ induced endless SLEs in four of eight slices. Co-application of CTZ (100 microM) with 100 microM GYKI-52466, the allosteric inhibitor of AMPA receptor function, restrained the effects of CTZ and shortened SLEs and their tonic phases to 37 +/- 4.2 and 47 +/- 4.2% of the control, respectively. Effects of GYKI-52466 and GYKI-52466 with CTZ on SLE dynamics were indistinguishable. 4-aminopyridine (4-AP; 50 microM) alone (n = 5) or in combination with CTZ (n = 6) transformed recurrent SLE pattern into incessant epileptiform activity with patterns distinguishable from those under 100 microM CTZ application. The effect of 4-AP may suggest a role for facilitated presynaptic glutamate release in disrupting recurrent dynamics. In contrast, the self-similar slow-down of low [Mg(2+)]-induced SLE dynamics by CTZ indicate AMPA receptor desensitization as a parameter shaping SLEs.
Lasztóczi
Bálint
B
Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, Budapest H-1025, Hungary. laszto@chemres.hu
Kardos
Julianna
J
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008275:Magnesium Deficiency / Q000503:physiopathology*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology
D001581:Benzothiadiazines; D004232:Diuretics; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D018091:Receptors, AMPA; D017661:Receptors, Presynaptic; C061950:GYKI 52466; D001569:Benzodiazepines; D018698:Glutamic Acid; D015761:4-Aminopyridine; C004639:cyclothiazide