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

Abstract

Introduction: This study intended to assess the histomorphology characteristics of hippocampal structures and determine the severity of seizures after treatment with the tyrosine kinase B inhibitor axitinib and diazepam in fully developed and postponed period in PTZ-kindled rats. Methods and materials: Wistar rats were given PTZ for 21 days until fully developed convulsions were achieved. Two protocols were explored: assessment of seizures immediately after the completion of the kindling (early kindling) and after a two-week post-kindling PTZ-free period. Treatment with axitinib and diazepam was performed before early and postponed kindling seizures assessment, with the consequent collection of brains for histomorphology. Results: Axitinib and diazepam effectively reduced seizure severity at the early and postponed periods of kindling. Axitinib’s antiseizure effectiveness was reduced in the postponed stage of kindling period compared with the early one (P = 0.039), while diazepam’s effectiveness was maintained at a similar level (P > 0.05). Stereological quantification of neuronal hippocampus changes revealed an increase in the total volume of the stratum radiatum, while a decrease of the dentate gyrus, in postponed compared with early kindling (P < 0.05). The positivity of collagen type IV, which is present in the blood-brain barrier, increased and was more pronounced in the postponed period in hippocampal structures (CA1-CA3). Conclusion: The antiseizure effect of tyrosine kinase B inhibition with a specific antagonist of VEGF axitinib is particularly pronounced in the early phase of PTZ kindling. Opposite to axitinib, diazepam demonstrated a similar antiseizure action in both periods of kindling. These results suggest a more pronounced contribution of angiogenesis compared with the neuronal degenerative hippocampal damage to the development of PTZ-kindled chronic epileptogenesis.