Abstract
<jats:p>Combined administration of cisplatin and paclitaxel remains a cornerstone of therapy for many solid malignancies. Despite clear antitumor efficacy, this regimen is frequently accompanied by neurotoxic complications. Peripheral neuropathy induced by platinum compounds and taxanes has been widely described, whereas central nervous system involvement, especially structural alterations in specific brain regions, remains insufficiently clarified. The cerebellum has long been regarded mainly as a structure responsible for coordination of movements and maintenance of balance. Modern neurobiological studies, however, demonstrate that cerebellar circuits participate in higher cognitive integration, affective regulation, and adaptive behavioral responses. Therefore structural damage to this region during chemotherapy may contribute not only to motor impairment but also to subtle cognitive and emotional disturbances that often remain clinically underestimated. The aim of this experimental study was to determine the temporal pattern of morphological changes in the cerebellar cortex of rats after simultaneous administration of cisplatin and paclitaxel and to identify the principal stages in development of central neurotoxicity associated with this combination. The experiment involved sexually mature male white outbred rats weighing 180–220 g. Morphological and morphometric characteristics of the cerebellar cortex were evaluated on days 1, 7, 14, 28, 60, 90, and 120 after administration of the cytotoxic agents. Histological examination was performed using light microscopy. Quantitative analysis included counting Purkinje neurons, assessment of glial elements, and measurement of thickness of the molecular and granular layers. Statistical evaluation applied one way ANOVA together with the Mann–Whitney U test. The results revealed a pronounced phase dependent pattern of cerebellar injury. During the first day moderate pericellular edema, vacuolization of the neuropil, and isolated dystrophic changes in Purkinje cells were detected. By days 7–14 destructive processes intensified and were accompanied by decreased density of the ganglionic layer and evident activation of glial elements. The most severe structural disorganization occurred on the 28th day. At this stage marked disturbance of cortical lamination, extensive neuropil vacuolization, hyperchromasia of Purkinje cell nuclei, and focal neuronal loss were observed. In later periods of observation, from day 60 to day 120, partial stabilization of several structural indices was noted. Nevertheless signs of incomplete recovery persisted, including irregular thickness of the molecular layer, degeneratively altered neurons, and prolonged reactive gliosis. Thus, simultaneous exposure to cisplatin and paclitaxel induces long lasting remodeling of the cerebellar cortex with a distinct temporal sequence. These structural alterations may represent a morphological substrate for motor and cognitive deficits associated with combined chemotherapy and indicate the importance of further investigation of central neuroprotective strategies. Additional experimental data highlight the need for detailed morphological monitoring of cerebellar neurotoxicity during combined chemotherapy.</jats:p>