Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice.
Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice.
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DOI：
10.1016/j.eplepsyres.2021.106677
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发表时间：
2021-09
影响因子：
2.2
通讯作者：
Canal CE
中科院分区：
文献类型：
--
作者：
Saraf TS;Felsing DE;Armstrong JL;Booth RG;Canal CE
最近的临床前和临床研究表明，氯卡色林，一种被批准用于治疗肥胖症的优先5-羟色胺2C受体（5-HT 2CR）激动剂，具有抗癫痫特性。在这里，我们测试了氯卡色林（1，3，5.6，10毫克/公斤）是否是预防听源性癫痫发作（AGS）在幼年Fmr 1基因敲除小鼠，小鼠模型脆性X综合征（FXS）。使用MPEP（30 mg/kg）（一种非竞争性mGluR 5受体拮抗剂）作为阳性对照。由于氯卡色林可能在治疗剂量下与5-HT 2AR结合，我们单独或在给予氯卡色林（5.6 mg/kg）之前用选择性5-HT 2AR拮抗剂/反向激动剂M100907（0.03 mg/kg）预处理一组小鼠，以辨别5-HT 2AR对AGS的推定贡献。我们还评估了氯卡色林对人（h）和小鼠（m）5-HT 2CR和5-HT 2AR的体外药理学及其对m5-HT 2CR和m5-HT 2AR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）。氯卡色林3 mg/kg可使AGS患病率和致死率分别降低14%和32%，但结果无统计学显著性（P=0.5和P=0.06）;其他剂量和M100907单独给药或与氯卡色林联合给药对AGS无显著影响。氯卡色林对h5-HT 2CR和m5-HT 2CR表现出完全有效的激动剂活性，对h5-HT 2AR和m5-HT 2AR表现出接近完全有效的激动剂活性;与小鼠（13倍）受体相比，人（38倍）对5-HT 2AR的活化选择性更高。无论种属如何，氯卡色林对拮抗剂标记的5-HT 2CR和5-HT 2AR的亲和力相对较低。氯卡色林（3和5.6 mg/kg）可增加（±）-2，5-二甲氧基-4-碘苯丙胺（DOI）引起的小鼠5-HT 2AR依赖性甩头反应（HTR）（P=0.03和P=0.02）。在3 mg/kg剂量下，氯卡色林单独给药未引起HTR。如果用选择性5-HT 2CR拮抗剂SB 242084（0.5和1 mg/kg）加氯卡色林（3 mg/kg）处理小鼠，则观察到HTR相对于媒介物显著增加（P=0.01和P=0.03），然而，HTR远低于DOI或DOI加氯卡色林引起的HTR。氯卡色林（3 mg/kg）自身显著降低运动活动，SB 242084逆转了该效应，并且在DOI前给药时，氯卡色林也剂量依赖性地降低运动活动（Ps<0.002）。这些数据表明，在小鼠中，低至3 mg/kg的剂量下，氯卡色林与5-HT 2CR以及5-HT 2AR结合。对m5-HT 2CR和m5-HT 2AR的相似活性表明，氯卡色林的谨慎给药对于在体内选择性地接合5-HT 2CR是必要的。总之，氯卡色林在预防Fmr 1基因敲除小鼠中的AGSs方面无效。氯卡色林可能不是FXS癫痫发作的合适药物治疗。
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 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 SB242084 (0.5 and 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 SB242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin engages 5-HT2CRs as well as 5-HT2ARs at doses as low as 3 mg/kg in mice. 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.
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影响因子：
2.7
作者：
Serafine, Katherine M.;Rice, Kenner C.;France, Charles P.
通讯作者：
France, Charles P.
影响因子：
64.8
作者：
Cameron LP;Tombari RJ;Lu J;Pell AJ;Hurley ZQ;Ehinger Y;Vargas MV;McCarroll MN;Taylor JC;Myers-Turnbull D;Liu T;Yaghoobi B;Laskowski LJ;Anderson EI;Zhang G;Viswanathan J;Brown BM;Tjia M;Dunlap LE;Rabow ZT;Fiehn O;Wulff H;McCorvy JD;Lein PJ;Kokel D;Ron D;Peters J;Zuo Y;Olson DE
通讯作者：
Olson DE
影响因子：
4.3
作者：
Olaghere da Silva UB;Morabito MV;Canal CE;Airey DC;Emeson RB;Sanders-Bush E
通讯作者：
Sanders-Bush E
影响因子：
2.8
作者：
Garcia-Cairasco, N
通讯作者：
Garcia-Cairasco, N
影响因子：
30.8
作者：
Brennan, TJ;Seeley, WW;Tecott, LH
通讯作者：
Tecott, LH