UCB 34714, A NEW PYRROLIDONE DERIVATIVE: COMPARISON WITH LEVETIRACETAM IN HIPPOCAMPAL SLICE EPILEPSY MODELS [italic]IN VITRO[/italic]
Abstract number :
2.246
Submission category :
Year :
2003
Submission ID :
2164
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Doru-Georg Margineanu, Benoit Kenda, Philippe Michel, Alain Matagne, Henrik Klitgaard Preclinical CNS Research, UCB S.A., Pharma Sector, Braine-l[apos]Alleud, Belgium; Chemistry Research, UCB S.A., Pharma Sector, Braine-l[apos]Alleud, Belgium
ucb 34714 is a new pyrrolidone derivative, structurally related to levetiracetam (LEV; [italic]Keppra[reg][/italic]), which displays higher affinity (pKi = 7.1) than LEV (pKi = 6.1) to the LEV-binding site. This study compared the antiepileptic activities of ucb 34714 and LEV in two different [italic]in vitro[/italic] models of epilepsy.
The effects of ucb 34714 and LEV on the epileptiform responses induced by either a high K+ - low Ca2+ perfusion fluid (HKLCF), or addition to the normal perfusion milieu (ACSF) of 5[micro]M bicuculline methiodide (BMI), were assessed upon field potential recordings in the CA3 area of rat hippocampal slices. The field potentials were evoked by fimbrial stimulation with constant pulses eliciting a single population spike (PS) when in ACSF. In the HKLCF model, spontaneous bursts were also recorded at 10 min intervals.
Both HKLCF and BMI induce epileptiform field potentials in CA3 area, upon increasing PS amplitude and producing repetitive PSs evoked by single stimuli. HKLCF also regularly induces spontaneous bursts. ucb 34714, 1 [ndash] 10 [micro]M, depressed the HKLCF-induced increase in PS amplitude ([Delta]PS), and the amplitudes and number of HKLCF-induced repetitive PSs, with a U-shaped concentration-dependence with maximal effect at 3.2 [micro]M. LEV, 10 [ndash] 100 [micro]M has shown similar activities, with maximal effect at 32 [micro]M (Margineanu [amp] Klitgaard, [italic]Pharmacol. Res[/italic]. [underline]42[/underline], 281, 2000). ucb 34714, 3.2 [micro]M reduced the occurrence of spontaneous bursts, while LEV, 32 [micro]M, was inactive against this drug refractory epileptiform marker. BMI-induced [Delta]PS was inhibited by ucb 34714 even at 0.1 [micro]M, with the optimal effect observed at 3.2 [micro]M. ucb 34714, 1 and 10 [micro]M reduced the number of BMI-induced repetitive PSs. LEV also inhibited these epileptiform markers, but with a maximal effect at 32 [micro]M.
This preclinical study showed an ability of ucb 34714 to inhibit the epileptiform collective neuronal responses of rat hippocampal slices, with higher potency and efficacy than LEV, in two [italic]in vitro[/italic] epilepsy models.
[Supported by: UCB S.A., Pharma Sector]