最近的临床前和临床研究表明,lorcaserin,一种被批准用于治疗肥胖症的5-羟色胺2C受体(5-HT2CR)优先激动剂,具有抗癫痫特性。这里,wetestedwhetherlorcaserin(1,3,5.6,10mg/kg)isproventiveagainste听源性癫痫发作(AGSs)indurifulFmr1knockoutmice,脆性X综合征(FXS)小鼠模型。MPEP(30mg/kg),非竞争性mGluR5受体拮抗剂,用作阳性对照。因为lorcaserin可能在治疗剂量下使用5-HT2AR,我们用选择性5-HT2AR拮抗剂/反向激动剂预处理一组小鼠,M100907(0.03mg/kg),单独或在施用lorcaserin(5.6mg/kg)之前,辨别5-HT2AR对AGS的推定贡献。我们还评估了lorcaserin对人(h)和小鼠(m)5-HT2CR和5-HT2AR的体外药理学及其在m5-HT2CR和m5-HT2AR的体内相互作用。MPEP显著降低AGS患病率(P=0.011)和致死率(P=0.038)。Lorcaserin,3mg/kg,AGS患病率和致死率分别降低了14%和32%,分别,然而,结果没有统计学意义(P=0.5和P=0.06);其他剂量和M100907单独或与lorcaserin一起也没有显着影响AGS。Lorcaserin对h5-HT2CRs和m5-HT2CRs表现出完全有效的激动剂活性,并且在h5-HT2ARs和m5-HT2ARs具有接近完全功效的激动剂活性;与小鼠(13倍)受体相比,人对5-HT2ARs活化的选择性更高(38倍)。Lorcaserin对拮抗剂标记的5-HT2CR和5-HT2AR表现出相对较低的亲和力,无论物种。Lorcaserin(3和5.6mg/kg)增加了小鼠(±)-2,5-二甲氧基-4-碘苯丙胺(DOI)引起的5-HT2AR依赖性头部抽搐反应(HTR)(P=0.03和P=0.02)。在3mg/kg时,单独的lorcaserin并没有引发HTR。如果用选择性5-HT2CR拮抗剂SB242084(0.5或1mg/kg)加lorcaserin(3mg/kg)治疗小鼠,观察到HTR显着增加,相对于车辆(P=0.01和P=0.03),然而,HTR远低于DOI或DOI加上lorcaserin引起的HTR。Lorcaserin,3mg/kg,运动活动显著减少,SB242084逆转了这种效应,并且在DOI之前给药时,lorcaserin也剂量依赖性地降低了运动活性(Ps<0.002)。这些数据表明,lorcaserin可能在剂量低至3mg/kg的小鼠中参与5-HT2CR以及5-HT2AR。Thesimilaractivityatm5-HT2CRsandm5-HT2ARssuggestscarefuldosingoflorcaserinisnecessarytoselectlyengage5-HT2CRsinvivo.总之,lorcaserin在预防Fmr1基因敲除小鼠的AGSs方面无效。Lorcaserin可能不是FXS癫痫发作的合适药物疗法。
Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HT2CR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HT2ARs at therapeutic doses, we pretreated one group of mice with the selective 5-HT2AR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HT2ARs to AGSs. We also assessed lorcaserin\'s in vitro pharmacology at human (h) and mouse (m) 5-HT2CRs and 5-HT2ARs and its in vivo interactions at m5-HT2CRs and m5-HT2ARs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HT2CRs and m5-HT2CRs, and near full efficacy agonist activity at h5-HT2ARs and m5-HT2ARs; selectivity for activation of 5-HT2CRs over 5-HT2ARs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HT2CRs and 5-HT2ARs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HT2AR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HT2CR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HT2CRs as well as 5-HT2ARs in mice at doses as low as 3 mg/kg. The similar activity at m5-HT2CRs and m5-HT2ARs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HT2CRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.