On different mechanisms of axitinib and diazepam antiseizure action in pentylenetetrazol-induced kindling model

The present work aimed to evaluate the histomorphology characteristics of hippocampal structures and determine the severity of seizures after treatment with the tyrosine kinase B axitinib inhibitor in fully developed and postponed periods in PTZ-kindled rats. Considering that benzodiazepines cause antiseizure effects via GABAA receptors (Nicholson et al., 2018), while inhibitors of Tyr-kinase inhibit them (Dunne et al., 1998) we have also studied antiseizure effectiveness of diazepam at both stages of PTZ-kindling.
Axitinib treatment (10.0 mg/kg, p.o.) performed at the early phase of kindling resulted in complete protection from generalized tonic-clonic seizures and a significant reduction of seizures compared to the control (H=10.988, P=0.001). PTZ testing (35.0 mg/kg, i.p.) in a postponed period caused generalized seizures in all animals and with repeated character in most (6 out of 7) of them. Seizure severity was higher when compared with fully developed kindling (H=4.116, P=0.042). Treatment with axitinib prevented generalized tonic-clonic seizures in most rats (5 out of six) and significantly reduced seizure severity (H=5.989, P=0.014) . At the same time, seizure severity in the postponed period exceeded such one in the early phase of kindling in axitinib-treated rats (H=4.275, P=0.039).
Diazepam (1.0 mg/kg, i.p.) prevented generalized tonic-clonic seizures in 5 out of 6 rats and reduced seizure severity in fully developed kindling in comparison with the control (H=7.773, P<0.005) (Fig. 3, C). Testing PTZ administration caused tonic-clonic seizures in all rats with repeated fits in 5 out of 6 animals in postponed periods. Diazepam administration (1.0 mg/kg, p.o.) did not prevent generalized seizures in 2 out of 7 rats but reduced seizure severity compared with the control (H=6.647, P=0.01). Seizure severity was not significantly different from those registered after diazepam treatment in the early period of kindling (H=1.114, P=0.291).
Immunohistochemical, light and elctron micropscopy data revealed neurodegeneration in CA1 hippocampal zone along with the accumulation collagen IV - marker of angiogenesis.

本研究旨在评估海马结构在给予酪氨酸激酶B抑制剂阿昔替尼治疗后，在完全发展期和推迟期PTZ诱导的鼠模型中，其组织形态学特征以及癫痫发作的严重程度。鉴于苯二氮䓬类药物通过GABAA受体产生抗癫痫作用（Nicholson等人，2018年），而酪氨酸激酶抑制剂则抑制其作用（Dunne等人，1998年），本研究亦探讨了地西泮在PTZ诱导的两阶段中的抗癫痫效果。阿昔替尼治疗（10.0 mg/kg，口服）在诱导早期阶段实施，能完全防止全面性强直-阵挛性癫痫发作，与对照组相比，癫痫发作显著减少（H=10.988，P=0.001）。在推迟期进行PTZ测试（35.0 mg/kg，腹腔注射）导致所有动物发生全面性癫痫发作，其中大多数（6/7）表现为反复发作。与完全发展期诱导相比，癫痫发作的严重程度更高（H=4.116，P=0.042）。阿昔替尼治疗防止了大多数鼠（6只中的5只）发生全面性强直-阵挛性癫痫发作，并显著降低了癫痫发作的严重程度（H=5.989，P=0.014）。同时，在推迟期，阿昔替尼治疗组鼠的癫痫发作严重程度超过了诱导早期阶段的水平（H=4.275，P=0.039）。地西泮（1.0 mg/kg，腹腔注射）防止了6只鼠中的5只发生全面性强直-阵挛性癫痫发作，并与对照组相比在完全发展期诱导中降低了癫痫发作的严重程度（H=7.773，P<0.005）（图3，C）。PTZ给药测试导致所有鼠发生强直-阵挛性癫痫发作，其中推迟期有5只动物出现反复发作。地西泮口服给药（1.0 mg/kg）未能防止7只鼠中的2只发生全面性癫痫发作，但与对照组相比降低了癫痫发作的严重程度（H=6.647，P=0.01）。与诱导早期阶段的地西泮治疗相比，癫痫发作的严重程度没有显著差异（H=1.114，P=0.291）。免疫组化、光镜和电子显微镜数据揭示了海马CA1区域的神经退行性变，以及血管生成标志物胶原蛋白IV的积累。