Dynamics of hippocampal morphological changes in condition of cisplatin and paclitaxel combined administration

Combined chemotherapy regimens involving the concurrent administration of cisplatin and paclitaxel remain a standard approach for the treatment of many solid tumors; however, they are associated with a high incidence of neurotoxic complications. The central component of neurotoxicity remains insufficiently studied. The hippocampus is one of the most vulnerable structures of the central nervous system. Fragmentary data on the phasic nature, temporal dynamics, and morphofunctional correlates of central neurotoxicity with the simultaneous use of cisplatin and paclitaxel form a gap between the clinical manifestations of cognitive deficit and the results of most experimental models. The aim of this study was to characterize the temporal dynamics of morphological changes in the rat hippocampus following the concurrent administration of cisplatin and paclitaxel and to identify the key phases of central neurotoxicity development. Experimental studies were performed on adult male white inbred rats weighing 180-220 g. Morphological and morphometric changes in the hippocampus were evaluated on days 1, 7, 14, 28, 60, 90, and 120 after treatment using light microscopy and morphometric analysis of neuronal and glial elements. Statistical analysis was performed using one-way analysis of variance (ANOVA) and the Mann-Whitney U test. Concurrent administration of cisplatin and paclitaxel resulted in a phase-dependent pattern of hippocampal injury. In the early observation periods, edematous-dystrophic neuronal changes and disturbances of neuroglial interactions predominated. On days 7-14, progressive destructive processes were observed, while day 28 was characterized by the maximal level of morphological damage with pronounced disorganization of the pyramidal layer. In the late periods (60-120 days), signs of incomplete morphological repair were detected, including partial restoration of layer organization with persistent reactive glial changes. The obtained results indicate that the concurrent administration of cisplatin and paclitaxel leads to persistent structural alterations of the hippocampus, which may underlie cognitive disorders and substantiate the need for further investigation of neuroprotective strategies.