Involvement of inhibitory and excitatory neurotransmitters in levofloxacin- and ciprofloxacin-induced convulsions in mice.
We studied the effects of gamma-aminobutyric acid (GABA)-benzodiazepine receptor agonists and glutamate receptor antagonists on levofloxacin (LVFX)- and ciprofloxacin (CPFX)-induced convulsions using intrathecal (i.t.) injections in mice. We also studied the effects of these agonists and antagonists on exacerbated convulsions induced by coadministration of the quinolone with 4-biphenylacetic acid (BPAA). The agonists or antagonists were injected i.t. 5 min and BPAA was administered orally 30 min before a single i.t. injection of the quinolone (10 microliters per animal). The animals were observed for clonic convulsion and death, and latency times to the appearance of convulsion were determined. Among the agonists, baclofen showed marked inhibition of both LVFX- and CPFX-induced convulsions, while other compounds such as GABA, muscimol, diazepam, and 3-aminopropylphosphonic acid had slight effects. Among the antagonists, kynurenic acid showed the strongest inhibition of convulsions caused by all doses of LVFX and CPFX and prolonged latency times; gamma-glutamyl-aminomethylsulfonic acid (GAMS) also markedly inhibited convulsions. The antagonists D-AP-5, AP-7, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) had slight effects. Additionally, GAMS, DNQX, and MK-801 significantly lowered the incidence of death in the groups treated with CPFX. The enhanced convulsive activities of LVFX or CPFX by pretreatment with BPAA were clearly blocked by baclofen, kynurenic acid, GAMS, and DNQX. D-AP-5 and AP-7 also showed clear effects on the activity of LVFX. These results suggest that LVFX has fewer effects on the brains than CPFX and that convulsions induced by these quinolones alone and by these quinolones administered with BPAA may be mediated largely through glutamate and GABA(B) rather than GABA(A) receptors in mice.
Akahane
K
K
Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Kato
M
M
Takayama
S
S
D000081:Acetamides / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists; D007275:Injections, Intravenous; D007278:Injections, Spinal; D064704:Levofloxacin; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015242:Ofloxacin / Q000008:administration & dosage / Q000633:toxicity*; D018079:Receptors, GABA / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced*
D000081:Acetamides; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D018079:Receptors, GABA; C039116:4-butoxyphenylacetamide; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D000429:Alcohol Oxidoreductases