Evaluation of the Possible Anticonvulsant Effect of Δ(9)-Tetrahydrocannabinolic Acid in Murine Seizure Models.
Evaluation of the Possible Anticonvulsant Effect of Δ(9)-Tetrahydrocannabinolic Acid in Murine Seizure Models.
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DOI：
10.1089/can.2020.0073
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发表时间：
2022-03
影响因子：
3.8
通讯作者：
Arnold JC
中科院分区：
文献类型：
--
作者：
Benson MJ;Anderson LL;Low IK;Luo JL;Kevin RC;Zhou C;McGregor IS;Arnold JC
简介：大麻素Δ9-tetrahydrocannabinolic酸（Δ9-THCA）长期以来在评论文章和轶事报道中被认为是抗惊厥药；然而，支持这一观点的证据很少。本研究的目的是探讨Δ9-THCA在多种癫痫发作模型中的抗惊厥潜能——Dravet综合征的Scn1a+/−小鼠模型、精神运动性癫痫的6 hz模型和全身性强直-阵挛性癫痫的最大电击（MES）模型。材料和方法：我们研究了急性Δ9-THCA治疗对高热诱发癫痫发作的影响，以及亚慢性治疗对Scn1a+/−小鼠自发性癫痫发作和生存的影响。我们还研究了急性Δ9-THCA治疗对6 hz和MES测试中临界电流阈值的影响。研究中使用高纯度的Δ9-THCA或Δ9-THCA和Δ9-THC的混合物。结果：我们观察到Δ9-THCA在癫痫发作模型中的抗惊厥和促惊厥混合作用。高纯度Δ9-THCA对Scn1a+/−小鼠的高热诱导癫痫发作没有影响。在6赫兹阈值测试中，Δ9-THCA/Δ9-THC混合物具有抗惊厥作用，但纯化的Δ9-THCA和Δ9-THC没有作用。相反，单独给药Δ9-THCA和Δ9-THC在MES阈值测试中都是前惊厥药，但当Δ9-THCA/Δ9-THC混合给药时没有效果。然而，Δ9-THCA/Δ9-THC混合物增加了Scn1a+/−小鼠的自发性癫痫发作严重程度和死亡率。讨论：Δ9-THCA的抗惊厥特征是可变的，这取决于所使用的癫痫发作模型和Δ9-THC的存在。由于Δ9-THCA的不稳定性，在没有稳定的情况下，通过正式的抗惊厥药物开发进一步探索Δ9-THCA是有问题的。未来的研究可能会更好地集中于确定Δ9-THCA和Δ9-THC联合改变癫痫发作阈值的机制，因为这可能会发现控制难治性部分癫痫发作的新靶点。
Introduction: The cannabinoid Δ9-tetrahydrocannabinolic acid (Δ9-THCA) has long been suggested in review articles and anecdotal reports to be anticonvulsant; yet, there is scant evidence supporting this notion. The objective of this study was to interrogate the anticonvulsant potential of Δ9-THCA in various seizure models—the Scn1a+/− mouse model of Dravet syndrome, the 6-Hz model of psychomotor seizures and the maximal electroshock (MES) model of generalized tonic-clonic seizures. Materials and Methods: We examined the effect of acute Δ9-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the Scn1a+/− mice. We also studied the effect of acute Δ9-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ9-THCA was used in the studies or a mixture of Δ9-THCA and Δ9-THC. Results: We observed mixed anticonvulsant and proconvulsant effects of Δ9-THCA across the seizure models. Highly pure Δ9-THCA did not affect hyperthermia-induced seizures in Scn1a+/− mice. A Δ9-THCA/Δ9-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ9-THCA and Δ9-THC had no effect. Conversely, both Δ9-THCA and Δ9-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ9-THCA/Δ9-THC mixture. The Δ9-THCA/Δ9-THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a+/− mice. Discussion: The anticonvulsant profile of Δ9-THCA was variable depending on the seizure model used and presence of Δ9-THC. Because of the unstable nature of Δ9-THCA, further exploration of Δ9-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ9-THCA and Δ9-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.
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影响因子：
3.8
作者：
McPartland, John M.;MacDonald, Christa;Glass, Michelle
通讯作者：
Glass, Michelle
影响因子：
2.2
作者：
Barton, ME;Klein, BD;White, HS
通讯作者：
White, HS
影响因子：
4.5
作者：
Hawkins, Nicole A.;Zachwieja, Nicole J.;Kearney, Jennifer A.
通讯作者：
Kearney, Jennifer A.
影响因子：
5.1
作者：
Anderson, Lyndsey L.;Low, Ivan K.;Arnold, Jonathon C.
通讯作者：
Arnold, Jonathon C.
影响因子：
2.6
作者：
Press, Craig A.;Knupp, Kelly G.;Chapman, Kevin E.
通讯作者：
Chapman, Kevin E.