Pentylenetetrazole is a non-selective antagonist of the γ-aminobutyric acid (GABA) A receptor[1]. The GABAA receptor, a major inhibitory neurotransmitter receptor widely present in the central nervous system, mediates the fast inhibitory effects of GABA by increasing the permeability of the cell membrane to chloride ions, causing hyperpolarization and thus inhibiting neuronal excitability[2]. Pentylenetetrazole is often used to study the mechanism of epileptic seizures, screen antiepileptic drugs, and investigate oxidative stress and neuroinflammatory responses[3][4].
In vivo, Pentylenetetrazole (35mg/kg; i.p.; every other day for 14 times) induced epileptic seizures, increased levels of oxidative stress markers (e.g., malondialdehyde, MDA), decreased the activities of antioxidant enzymes (e.g., glutathione, GSH; superoxide dismutase, SOD; catalase, CAT) , elevated the levels of inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α), and led to neuroinflammatory responses and neuronal damage in mice model[5]. Intraperitoneal injection of Balb-c mice with Pentylenetetrazole (60mg/kg; i.p.; 24h) significantly decreased protein thiols (PSH), cysteine (CSH), and non-protein mixed disulfides (NPSSC), while increasing protein symmetric disulfides (PSSP), non-protein symmetric disulfides (NPSSR), lipid peroxidation, and protein oxidation levels in the mouse hippocampus[6]. Pentylenetetrazole (35mg/kg; i.p.; three times a week) induced kindling in rats, significantly increased the hippocampal concentrations of alanine, arginine, glutamate, aspartate, and taurine, while decreasing GABA levels, leading to an over fourfold increase in the Glu/GABA ratio[7].
References:
[1] Huang RQ, Bell-Horner CL, Dibas MI, Covey DF, Drewe JA, Dillon GH. Pentylenetetrazole-induced inhibition of recombinant gamma-aminobutyric acid type A (GABA(A)) receptors: mechanism and site of action. J Pharmacol Exp Ther. 2001;298(3):986-995.
[2] Lambert JJ, Belelli D, Hill-Venning C, Peters JA. Neurosteroids and GABAA receptor function. Trends Pharmacol Sci. 1995;16(9):295-303.
[3] Shimada T, Yamagata K. Pentylenetetrazole-Induced Kindling Mouse Model. J Vis Exp. 2018;(136):56573.
[4] Monteiro ÁB, Alves AF, Ribeiro Portela AC, et al. Pentylenetetrazole: A review. Neurochem Int. 2024;180:105841.
[5] Younis NS, Almostafa MM, Mohamed ME. Geraniol Ameliorates Pentylenetetrazol-Induced Epilepsy, Neuroinflammation, and Oxidative Stress via Modulating the GABAergic Tract: In vitro and in vivo studies. Drug Des Devel Ther. 2024;18:5655-5672.
[6] Patsoukis N, Zervoudakis G, Panagopoulos NT, Georgiou CD, Angelatou F, Matsokis NA. Thiol redox state (TRS) and oxidative stress in the mouse hippocampus after pentylenetetrazol-induced epileptic seizure. Neurosci Lett. 2004;357(2):83-86.
[7] Szyndler J, Maciejak P, Turzyńska D, et al. Changes in the concentration of amino acids in the hippocampus of pentylenetetrazole-kindled rats. Neurosci Lett. 2008;439(3):245-249.
Pentylenetetrazole是一种γ-氨基丁酸（GABA）A受体的非选择性拮抗剂[1]。GABAA受体是中枢神经系统中广泛存在的主要抑制性神经递质受体，通过增加细胞膜对氯离子的通透性来介导GABA的快速抑制作用，导致细胞膜超极化，从而抑制神经元的兴奋性[2]。Pentylenetetrazole常用于研究癫痫发作的机制、筛选抗癫痫药物以及研究氧化应激和神经炎症反应[3][4]。
在体内实验中，Pentylenetetrazole（35mg/kg; 腹腔注射; 每两天一次，共14次）诱导了小鼠的癫痫发作，增加了氧化应激标志物（如丙二醛，MDA）的水平，降低了抗氧化酶（如谷胱甘肽，GSH；超氧化物歧化酶，SOD；过氧化氢酶，CAT）的活性，提高了炎症因子（如IL-1β、IL-6、TNF-α）的水平，并导致了神经炎症反应和神经元损伤[5]。对Balb-c小鼠进行腹腔注射Pentylenetetrazole（60mg/kg; 24小时）显著降低了蛋白硫醇（PSH）、半胱氨酸（CSH）和非蛋白混合二硫化物（NPSSC）的水平，同时增加了蛋白对称二硫化物（PSSP）、非蛋白对称二硫化物（NPSSR）、脂质过氧化和蛋白质氧化水平[6]。Pentylenetetrazole（35mg/kg; 腹腔注射; 每周三次）在大鼠中诱导了癫痫发作，显著增加了海马区的丙氨酸、精氨酸、谷氨酸、天冬氨酸和牛磺酸的浓度，同时降低了GABA水平，导致谷氨酸与GABA比值（Glu/GABA）增加了四倍以上[7]。