Clinical Pharmacy Department, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Int J Mol Sci. 2023 Jun 28;24(13):10773. doi: 10.3390/ijms241310773.
One prevalent neurological disorder is epilepsy. Modulating GABAergic/glutamatergic neurotransmission, Nrf2/HO-1, PI3K/Akt, and TLR-4/NF-B pathways might be a therapeutic strategy for epilepsy. Eight-week-old BALB/c mice were administered 12.5, 25, or 50 mg/kg (-) pseudosemiglabrin orally one hour before inducing epilepsy with an i.p. injection of 360 mg/kg pilocarpine. (-) Pseudosemiglabrin dose-dependently alleviated pilocarpine-induced epilepsy, as revealed by the complete repression of pilocarpine-induced convulsions and 100% survival rate in mice. Furthermore, (-) pseudosemiglabrin significantly enhanced mice's locomotor activities, brain GABA, SLC1A2, GABARα1 levels, glutamate decarboxylase activity, and SLC1A2 and GABARα1mRNA expression while decreasing brain glutamate, SLC6A1, GRIN1 levels, GABA transaminase activity, and SLC6A1 and GRIN1 mRNA expression. These potentials can be due to the suppression of the TLR-4/NF-κB and the enhancement of the Nrf2/HO-1 and PI3K/Akt pathways, as demonstrated by the reduction in TLR-4, NF-κB, IL-1β, TNF-α mRNA expression, MDA, NO, caspase-3, Bax levels, and Bax/Bcl-2 ratio, and the enhancement of Nrf2, HO-1, PI3K, Akt mRNA expression, GSH, Bcl-2 levels, and SOD activity. Additionally, (-) pseudosemiglabrin abrogated the pilocarpine-induced histopathological changes. Interestingly, the (-) pseudosemiglabrin intervention showed a comparable effect to the standard medication, diazepam. Therefore, (-) pseudosemiglabrin can be a promising medication for the management of epilepsy.
一种流行的神经障碍是癫痫。调节 GABAergic/glutamatergic 神经递质、Nrf2/HO-1、PI3K/Akt 和 TLR-4/NF-B 途径可能是治疗癫痫的一种策略。将 8 周龄 BALB/c 小鼠用 12.5、25 或 50 mg/kg 的 (-) pseudosemiglabrin 灌胃，在腹腔注射 360 mg/kg 匹罗卡品诱导癫痫发作前 1 小时给药。(-) pseudosemiglabrin 剂量依赖性地缓解匹罗卡品诱导的癫痫发作，表现为完全抑制匹罗卡品诱导的惊厥和 100%的小鼠存活率。此外，(-) pseudosemiglabrin 显著增强了小鼠的运动活性、大脑 GABA、SLC1A2、GABARα1 水平、谷氨酸脱羧酶活性以及 SLC1A2 和 GABARα1mRNA 表达，同时降低了大脑谷氨酸、SLC6A1、GRIN1 水平、GABA 转氨酶活性以及 SLC6A1 和 GRIN1mRNA 表达。这些潜力可能是由于抑制 TLR-4/NF-κB 并增强 Nrf2/HO-1 和 PI3K/Akt 途径，这表现为 TLR-4、NF-κB、IL-1β、TNF-αmRNA 表达、MDA、NO、caspase-3、Bax 水平和 Bax/Bcl-2 比值降低，Nrf2、HO-1、PI3K、Akt mRNA 表达、GSH、Bcl-2 水平和 SOD 活性增强。此外，(-) pseudosemiglabrin 阻断了匹罗卡品诱导的组织病理学变化。有趣的是，(-) pseudosemiglabrin 的干预与标准药物地西泮具有相当的效果。因此，(-) pseudosemiglabrin 可能是治疗癫痫的一种有前途的药物。
