Abstract
Background. Paclitaxel is well known for its neurotoxicity, which affects both the peripheral and central nervous systems. In the hippocampus, this cytostatic agent disrupts neuroplasticity, induces glial activation, and may lead to cognitive impairment. Because in clinical practice most patients receive treatment against the background of already established neurological disorders, the search for agents capable of correcting post-toxic changes remains highly relevant.Vortioxetine, a multimodal serotonin modulator, influences synaptic transmission, neuroplasticity, and glutamatergic networks, making it potentially useful for restoring structures damaged by chemotherapy. At the same time, the effects of therapeutic administration of vortioxetine specifically after paclitaxel-induced toxicity in central nervous system regions remain insufficiently studied.
Aim: To evaluate morphological changes in the rat hippocampus under conditions of therapeutic administration of vortioxetine after paclitaxel-induced neurotoxicity.
Materials and Methods. The study was performed on sexually mature male inbred white rats (180–220 g) housed under standard vivarium conditions. Neurotoxicity was induced by paclitaxel administration (2 mg/kg, intraperitoneally, four injections every other day). The therapeutic effect was assessed following intragastric administration of vortioxetine (5 mg/kg, daily for 14 days), initiated after completion of the paclitaxel course. Functional status was evaluated using behavioral tests of mechanical and thermal sensitivity. Morphological and morphometric changes in the hippocampus (CA1 and CA3 regions) were analyzed on days 14, 28, 60, 90, and 120 using light microscopy after hematoxylin and eosin staining with digital morphometry. Statistical analysis was performed using ANOVA or the Mann-Whitney U test at p<0.05. All procedures complied with international ethical standards for laboratory animal research.
Results. Therapeutic administration of vortioxetine after paclitaxel-induced neurotoxicity reduced the severity of hippocampal morphological damage and modified the temporal dynamics of recovery processes. As early as day 14, partial preservation of the pyramidal layer architecture in CA1-CA3 was observed against a background of moderate edema and limited glial reaction. During the peak toxic phase (day 28), the depth of tissue destruction was lower than in untreated animals, with preservation of neuronal nuclei and reduced areas of tissue homogenization. On days 60–90, reparative changes predominated, manifested by restoration of perikaryon contours, stabilization of glial elements, and gradual recovery of laminar organization. By day 120, nearly complete morphological repair of the hippocampus was observed. Morphometric analysis confirmed attenuation of toxic alterations: in the CA1 and CA3 regions, the areas of neuronal perikarya and nuclei were significantly increased, the nucleus-to-cytoplasm ratio was partially normalized, and neuronal density was higher compared with the untreated toxic group (p<0.05). Functional tests demonstrated that paclitaxel induced a persistent motor-sensory deficit. Under vortioxetine treatment, the severity of motor and sensory impairments was significantly lower, with partial compensation in later time points, consistent with morphological signs of the drug’s neuroprotective and reparative effects.
Conclusions. Therapeutic administration of vortioxetine reduces toxic damage to the hippocampus and accelerates reparative processes after paclitaxel exposure. The drug may be considered a promising agent for post-toxic correction of central manifestations of chemotherapy-induced neurotoxicity.