Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, indicated for treatment of chorea associated with Huntington's disease[1,3,4]. It reversibly inhibits central vesicular monoamine transporter (VMAT) transporter type 2 which acts on the various monoaminergic systems in the brain, e.g., dopamine, serotonin and noradrenaline[5] Tetrabenazine binds predominately to VMAT2 and has been shown to reversibly inhibit monoamine uptake in pre-synaptic vesicles, resulting in monoamine depletion of serotonin, dopamine, and nor-epinephrine [6] thereby reducing chorea[7].
In Neuro-2a neuroblastoma cell line, Tetrabenazine loaded nanoemulsion showed 100.00±1.23%, 100.00±2.01% and 100.00±2.09% cell viability when treated at the dose of 4.8ng/mL, 2.4ng/mL and 9.6ng/Ml[2]. When used bovine chromaffin cells (BCCs) challenged with repeated pulses of high K+ Upon repeated K+ pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to tetrabenazine, responses were mildly augmented and decay rate delayed[8].
In rat, The superiority of tetrabenazine nanoemulsion for delivering of tetrabenazine via intranasal route bypassing BBB[2]. In mice, Cold-water immersion-induced acute stress diminished the locomotor activity, exploratory behaviour, motor activity and social behaviour along with increase in the plasma corticosterone levels. Administration of tetrabenazine (1 and 2 mg/kg, i.p.), abolished the acute stress-induced behavioural and biochemical changes in a dose-dependent manner[9].
References:
[1]. Peter D, Vu T, et,al.Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine. J Biol Chem. 1996 Feb 9;271(6):2979-86. doi: 10.1074/jbc.271.6.2979. PMID: 8621690.
[2]. Arora A, Kumar S, et,al. Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study. Chem Phys Lipids. 2020 Aug;230:104917. doi: 10.1016/j.chemphyslip.2020.104917. Epub 2020 May 19. PMID: 32439327.
[3]. Kenney C, Hunter C, et,al. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov Disord. 2007 Jan;22(1):10-3. doi: 10.1002/mds.21161. PMID: 17078062.
[4]. Mestre TA, Ferreira JJ. An evidence-based approach in the treatment of Huntington's disease. Parkinsonism Relat Disord. 2012 May;18(4):316-20. doi: 10.1016/j.parkreldis.2011.10.021. Epub 2011 Dec 16. PMID: 22177624.
[5]. Thibaut F, Faucheux BA, et,al. Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine. Brain Res. 1995 Sep 18;692(1-2):233-43. doi: 10.1016/0006-8993(95)00674-f. PMID: 8548309.
[6]. Pettibone DJ, Totaro JA, et,al. Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants. Eur J Pharmacol. 1984 Jul 20;102(3-4):425-30. doi: 10.1016/0014-2999(84)90562-4. PMID: 6489435.
[7]. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72. doi: 10.1212/01.wnl.0000198586.85250.13. PMID: 16476934.
[8]. de Pascual R, álvarez-Ortego N,et,al. Tetrabenazine Facilitates Exocytosis by Enhancing Calcium-Induced Calcium Release through Ryanodine Receptors. J Pharmacol Exp Ther. 2019 Oct;371(1):219-230. doi: 10.1124/jpet.119.256560. Epub 2019 Jun 17. PMID: 31209099.
[9].Kumar M, Singh N, et,al. Exploring the anti-stress effects of imatinib and tetrabenazine in cold-water immersion-induced acute stress in mice. Naunyn Schmiedebergs Arch Pharmacol. 2020 Sep;393(9):1625-1634. doi: 10.1007/s00210-020-01862-w. Epub 2020 Apr 14. PMID: 32291496.
丁苯那嗪是美国食品和药物管理局唯一批准的亨廷顿舞蹈病药物,适用于治疗与亨廷顿舞蹈病相关的舞蹈症[1,3,4]。它可逆地抑制 2 型中央囊泡单胺转运蛋白 (VMAT) 转运蛋白,后者作用于大脑中的各种单胺能系统,例如多巴胺、5-羟色胺和去甲肾上腺素[5] Tetrabenazine 主要与 VMAT2 结合并已被证明可逆地抑制突触前小泡中的单胺摄取,导致血清素、多巴胺和去甲肾上腺素的单胺消耗[6],从而减少舞蹈病[7]。\n
在 Neuro-2a 神经母细胞瘤细胞系中,负载 Tetrabenazine 的纳米乳剂以 4.8ng/mL、2.4ng/mL 和 9.6ng/mL 的剂量处理时显示出 100.00±1.23%、100.00±2.01% 和 100.00±2.09% 的细胞活力毫升[2]。当使用重复的高 K+ 脉冲攻击牛嗜铬细胞 (BCC) 时 在重复 K+ 脉冲下,胞吐儿茶酚胺释放反应逐渐衰减。然而,当细胞暴露于丁苯那嗪时,反应会轻度增强,衰减速率会延迟[8]。
在大鼠中,丁苯那嗪纳米乳剂通过鼻内途径绕过 BBB 递送丁苯那嗪的优势[2]。在小鼠中,冷水浸泡引起的急性应激会降低运动活动、探索行为、运动活动和社交行为,同时血浆皮质酮水平也会升高。施用丁苯那嗪（1 和 2 mg/kg,腹腔注射）,以剂量依赖性方式消除急性应激诱导的行为和生化变化[9]。