GHB (γ-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier
GHB (γ-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier
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DOI：
10.1124/jpet.104.069682
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发表时间：
2004-10-01
影响因子：
3.5
通讯作者：
Boje, KMK
中科院分区：
文献类型：
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作者：
Bhattacharya, I;Boje, KMK
羟丁酸钠是一种被批准的治疗发作性睡病猝倒的药物。GHB被广泛滥用为一种合成代谢剂、快乐剂和枣子油菜药物。娱乐性滥用或过量服用GHB(或其前体伽马丁内酯或1，4-丁二醇)会导致剂量依赖的中枢神经系统(CNS)效应(呼吸抑制、意识丧失、昏迷和死亡)以及耐受性和戒断。了解GHB的中枢神经系统转运机制可能有助于对过量治疗方法的深入了解。使用大鼠原位脑灌流技术验证了GHB经历载体介导的跨血脑屏障转运的假设。利用多种药理药物对转运蛋白的药理特性进行了研究。GHb表现出与高容量、低亲和力转运体一致的载体介导的跨血脑屏障转运；平均脑区参数为V-max=709+/-214nmol/min/g，K-m=11.0+/-3.56 mm，CLns=0.019+/-0.003 cm(3)/min/g。短链单羧酸(丙酮酸、乳酸和β-羟基丁酸)、中链脂肪酸(己酸和丙戊酸)和有机阴离子(丙磺舒、苯甲酸、水杨酸和α-氰基-4-羟基肉桂酸)显著抑制GHb的流入35%至90%。二元酸(琥珀酸和戊二酸)和γ-氨基丁酸不抑制GHB的血脑屏障转运。观察到GHB和苯甲酸之间的相互抑制，苯甲酸是众所周知的单羧酸转运体MCT1的底物。这些结果提示GHB通过MCT异构体穿过血脑屏障。这些关于GHB血脑屏障转运的新发现为治疗GHB过量提供了潜在的治疗方法。我们目前正在进行“概念验证”研究，涉及在GHB中毒期间使用GHB脑转运抑制剂。
gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V-max=709+/-214 nmol/min/g, K-m=11.0+/-3.56 mM, and CLns=0.019+/-0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.