Govender Demi, Moloko Leila, Papathanasopoulos Maria, Tumba Nancy, Owen Gavin, Calvey Tanya
School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Front Neurosci. 2024 Jul 24;18:1378841. doi: 10.3389/fnins.2024.1378841. eCollection 2024.
Ibogaine is a psychedelic alkaloid being investigated as a possible treatment for opioid use disorder. Ibogaine has a multi-receptor profile with affinities for mu and kappa opioid as well as NMDA receptors amongst others. Due to the sparsity of research into ibogaine's effects on white matter integrity and given the growing evidence that opioid use disorder is characterized by white matter pathology, we set out to investigate ibogaine's effects on two markers of myelination, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin basic protein (MBP). Fifty Sprague Dawley rats were randomly assigned to five experimental groups of = 10; (1) a saline control group received daily saline injections for 10 days, (2) a morphine control group received escalating morphine doses from 5 to 15 mg/kg over 10 days, (3) an ibogaine control group that received 10 days of saline followed by 50 mg/kg ibogaine hydrochloride, (4) a combination morphine and ibogaine group 1 that received the escalating morphine regime followed by 50 mg/kg ibogaine hydrochloride and (5) a second combination morphine and ibogaine group 2 which followed the same morphine and ibogaine regimen yet was terminated 72 h after administration compared to 24 h in the other groups. White matter from the internal capsule was dissected and qPCR and western blotting determined protein and gene expression of CNP and MBP. Morphine upregulated CNPase whereas ibogaine alone had no effect on CNP mRNA or protein expression. However, ibogaine administration following repeated morphine administration had an immediate effect by increasing CNP mRNA expression. This effect diminished after 72 h and resulted in a highly significant upregulation of CNPase protein at 72 h post administration. Ibogaine administration alone significantly upregulated protein expression yet downregulated MBP mRNA expression. Ibogaine administration following repeated morphine administration significantly upregulated MBP mRNA expression which increased at 72 h post administration resulting in a highly significant upregulation of MBP protein expression at 72 h post administration. These findings indicate that ibogaine is able to upregulate genes and proteins involved in the process of remyelination following opioid use and highlights an important mechanism of action of ibogaine's ability to treat substance use disorders.
伊波加因是一种致幻生物碱，目前正在作为治疗阿片类药物使用障碍的一种可能疗法进行研究。伊波加因具有多受体作用模式，对μ和κ阿片受体以及N-甲基-D-天冬氨酸（NMDA）受体等具有亲和力。鉴于对伊波加因对白质完整性影响的研究较少，且越来越多的证据表明阿片类药物使用障碍的特征是白质病变，我们着手研究伊波加因对两种髓鞘形成标志物，即2',3'-环核苷酸3'-磷酸二酯酶（CNP）和髓鞘碱性蛋白（MBP）的影响。50只斯普拉格-道利大鼠被随机分为5个实验组，每组n = 10；（1）生理盐水对照组每天注射生理盐水，持续10天；（2）吗啡对照组在10天内吗啡剂量从5毫克/千克递增至15毫克/千克；（3）伊波加因对照组先接受10天生理盐水注射，然后注射50毫克/千克盐酸伊波加因；（4）吗啡与伊波加因联合组1，先接受递增的吗啡给药方案，然后注射50毫克/千克盐酸伊波加因；（5）第二个吗啡与伊波加因联合组2，采用相同的吗啡和伊波加因给药方案，但与其他组在给药后24小时处死不同，该组在给药后72小时处死。解剖内囊的白质，通过定量聚合酶链反应（qPCR）和蛋白质印迹法测定CNP和MBP的蛋白质和基因表达。吗啡上调了CNP酶，而单独使用伊波加因对CNP mRNA或蛋白质表达没有影响。然而，在重复给予吗啡后给予伊波加因可立即增加CNP mRNA表达。这种作用在72小时后减弱，并导致给药后72小时CNP酶蛋白高度显著上调。单独给予伊波加因可显著上调蛋白质表达，但下调MBP mRNA表达。在重复给予吗啡后给予伊波加因可显著上调MBP mRNA表达，该表达在给药后72小时增加，导致给药后72小时MBP蛋白质表达高度显著上调。这些发现表明，伊波加因能够上调阿片类药物使用后参与髓鞘再生过程的基因和蛋白质，并突出了伊波加因治疗物质使用障碍能力的一个重要作用机制。
