(±)-Baclofen is a lipophilic derivative of γ-aminobutyric acid (GABA), and it is an orally effective and selective agonist of the metabotropic GABAB receptor with an IC50 of 200nM [1-2]. GABA is an inhibitory neurotransmitter that functions through heteromeric ligand-gated ion channels GABAA and GABAC as well as G protein-coupled receptors GABAB [3]. (±)-Baclofen can be used as a relaxant for muscle spasms and a central nervous system inhibitor [4].
In vitro, (±)-Baclofen (25, 50, and 100μM; 24, 48, 72, and 96h) inhibited the proliferation of HepG2 cells in a dose-dependent manner, downregulated intracellular cAMP levels, and upregulated the expression and phosphorylation of p21WAF1 protein. (±)-Baclofen also caused cell cycle arrest in the G0/G1 phase without inducing cell death [3]. (±)-Baclofen (1, 10μM; 24h) significantly reduced the activity of lactate dehydrogenase (LDH) in high-density model (HD) striatal cells (HD19 and HD43), enhanced the activity of cathepsin-like proteasome in the cells and cell viability [5].
In vivo, 30 minutes before behavioral tests, intraperitoneal injection of (±)-Baclofen (0.5, 1.5, and 2.5mg/kg/d; single-dose) enhanced the alcohol consumption behavior of mice in the Vogel conflict test, which might be due to the analgesic effect of Baclofen. Mice treated with (±)-Baclofen showed similar sedative effects in other tests (i.e., reduced activity) [6]. (±)-Baclofen (4mg/kg/d; 4d; i.p.) reversed the increase in the frequency of voluntary mouth-chewing movements (VCM) induced by reserpine in mice. After repeated treatment, (±)-Baclofen reduced the spontaneous systemic activity in mice induced by reserpine. [7].
References:
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[2] Farokhnia M, Deschaine SL, Sadighi A, et al. A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation. Mol Psychiatry. 2021;26(2):545-555.
[3] Wang T, Huang W, Chen F. Baclofen, a GABAB receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. Life Sci. 2008;82(9-10):536-541.
[4] DeFalco A P. Neuromuscular blocking agents and skeletal muscle relaxants[M]//Side Effects of Drugs Annual. Elsevier, 2024, 46: 171-180.
[5] Kim W, Seo H. Baclofen, a GABAB receptor agonist, enhances ubiquitin-proteasome system functioning and neuronal survival in Huntington's disease model mice. Biochem Biophys Res Commun. 2014;443(2):706-711.
[6] Li X, Risbrough VB, Cates-Gatto C, et al. Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. Neuropharmacology. 2013; 70:156-167.
[7] Castro JP, Frussa-Filho R, Fukushiro DF, et al. Effects of baclofen on reserpine-induced vacuous chewing movements in mice. Brain Res Bull. 2006;68(6):436-441.
(±)-Baclofen是γ-氨基丁酸（GABA）的亲脂性衍生物，是一种口服有效，选择性的代谢型GABAB受体激动剂，IC50为200nM [1-2]。GABA是一种抑制性神经递质，通过异构配体门控离子通道GABAA和GABAC以及G蛋白连接接受器GABAB发挥作用 [3]。(±)-Baclofen可被用作肌肉痉挛的弛缓药和中枢神经系统抑制剂 [4]。
在体外，(±)-Baclofen（25、50和100μM; 24、48、72和96h）以剂量依赖性方式抑制了HepG2细胞的增殖，下调了细胞内cAMP水平并上调p21WAF1蛋白的表达以及磷酸化水平。(±)-Baclofen还导致细胞周期在G0/G1期停止，而不诱导细胞死亡 [3]。(±)-Baclofen（1，10μM；24h）显著降低了高密度模型（HD）纹状细胞（HD19和HD43）中乳酸脱氢酶（LDH）的活性，增强了细胞中类趋化胰蛋白酶样蛋白酶体活性和细胞活力 [5]。
在体内，行为测试前30分钟(±)-Baclofen（0.5, 1.5, and 2.5mg/kg/d; Single-dose）腹腔注射治疗加强了小鼠在Vogel冲突测试中的饮酒行为，这种现象可能是由于(±)-Baclofen的镇痛作用所致。接受(±)-Baclofen治疗的小鼠在其他测试中表现出类似镇静的效果（即活动减少）[6]。(±)-Baclofen（4mg/kg/d; 4d; i.p.）逆转了利血平诱导的小鼠空口咀嚼运动（VCM）频率的增加，在重复治疗后，(±)-Baclofen减少了利血平诱导的小鼠自发性的全身性活动 [7]。