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.