Correlation between enhancement of [3H]flunitrazepam binding and suppression of pentylenetetrazol-induced seizures by L-lysine.
L-Lysine enhanced the specific [3H]flunitrazepam (FTZ) binding of bovine brain membranes in vitro. Inhibition of specific [3H]FTZ binding to brain membranes in vitro by pentylenetetrazol (PTZ) at concentrations 0.46 mM and below was reversed by increasing L-lysine concentrations in the incubation mixture; further increase of L-lysine concentration enhanced this binding. However, inhibition of [3H]FTZ binding by PTZ higher than 2.3 mM was reversed only partially by L-lysine. L-Lysine enhanced specific [35S]t-butylbicyclophosphorothionate (TBPS) binding on mouse brain membranes in a dose-dependent manner (EC approximately 5 microM). This enhancement was inhibited by PTZ dose dependently. Inhibition of [35S]TBPS binding by PTZ was attenuated slightly by L-lysine. L-Lysine enhanced [3H]FTZ binding in intact mice in a dose- or concentration-dependent manner with an ED50 of 6 mmol/kg body weight or EC50 of 3 mumol/g brain tissue, respectively. Similar effect was observed for L-lysine in ex vivo [3H]FTZ binding study when [3H]FTZ was incubated in vitro with an ED50 of 1 mmol/kg mouse or EC50 of 0.7 mumol/g brain. PTZ not only induced seizures, but also inhibited specific [3H]FTZ binding to brain membranes in a dose-dependent manner. L-Lysine, in a dose-dependent manner, suppressed seizures caused by PTZ at 50 or 60 mg/kg, or prolonged the time of seizure onset (seizure latency) caused by higher doses of PTZ (90 or 100 mg/kg). Pretreatment with L-lysine at 1, 5, 10 or 20 mmol/kg not only reversed the inhibition of the specific [3H]FTZ binding caused by PTZ at 50, 90 or 100 mg/kg, but also enhanced this binding above control level.(ABSTRACT TRUNCATED AT 250 WORDS)
Chang
Y F
YF
Department of Biochemistry, University of Maryland, Dental School, Baltimore 21201.
Gao
X M
XM
Chen
J S
JS
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000378:metabolism*; D008239:Lysine / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D005445:Flunitrazepam; D008239:Lysine; D010433:Pentylenetetrazole