Suemaru Katsuya, Yoshikawa Misato, Aso Hiroaki, Watanabe Masahiko
School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.
Epilepsy Res. 2018 Sep;145:153-159. doi: 10.1016/j.eplepsyres.2018.06.016. Epub 2018 Jul 3.
Acetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown.
This study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models.
Repeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect.
These findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol-kindled mouse models and TRPV1 mediates the anticonvulsant action.
对乙酰氨基酚是最常用的解热镇痛药之一。据报道，对乙酰氨基酚在多种癫痫动物模型中具有抗惊厥作用。对乙酰氨基酚的一种活性代谢产物AM404可抑制内源性大麻素花生四烯乙醇胺的摄取。然而，对乙酰氨基酚抗惊厥作用的机制尚不清楚。
本研究旨在检测对乙酰氨基酚是否能预防小鼠戊四氮诱导的点燃效应，并使用完全点燃的小鼠模型研究对乙酰氨基酚抗惊厥作用的精确机制。
反复给予对乙酰氨基酚可显著延缓戊四氮诱导的癫痫严重程度的进展。此外，对乙酰氨基酚对完全由戊四氮点燃的癫痫发作表现出剂量依赖性的抗惊厥活性。AM404在完全点燃的动物中也表现出剂量依赖性的抗惊厥活性。对乙酰氨基酚的抗惊厥活性被辣椒素受体1（TRPV1）拮抗剂辣椒平及AMG9810拮抗。然而，锚蛋白1型瞬时受体电位（TRPA1）拮抗剂HC030031及CB1受体拮抗剂AM251对此没有影响。
这些发现表明，对乙酰氨基酚在戊四氮点燃的小鼠模型中具有抗惊厥作用，且TRPV1介导了该抗惊厥作用。
