Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats

Abstract

Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy of various malignant tumours; however, its long-term effects on patients’ health and life quality need to be further investigated. Here, we studied the effects of TMZ and/or companion drug dexamethasone (DXM) on the locomotor activity and cartilage structure of elderly Wistar rats (n = 40). Long-term TMZ treatment selectively inhibited the horizontal, but not vertical locomotor activity of the rats (6.7-fold, p < 0.01) and resulted in delamination of the superficial epiphyseal cartilage of the femoral epiphysis of knee joints, a 2-fold decrease in mean thickness of epiphyseal cartilage (p < 0.001), and changes in the proliferative and maturation cartilage zones ratio. The simultaneous use of DXM attenuated TMZ-induced changes in cartilage thickness and integrity and compensated the decrease in horizontal locomotor activity of experimental animals. Nevertheless, combined TMZ/DXM treatment still significantly affected the structure of proximal tibial, but not distal femoral epiphysis of knee joints of the rats. These changes were accompanied by the increased content of total glycosaminoglycans (GAGs) and their partial re-localisation from chondrocytes into tissue matrix, as well as the decrease in sulfated GAGs content in both compartments. Taken together, the results demonstrate that long-term treatment with TMZ results in a significant decrease in locomotor activity of elderly Wistar rats and the reorganisation of their knee joint cartilage structure, while DXM treatment attenuates those effects. So, use of DXM or chondroprotective drugs might be beneficial to maintain quality of life for TMZ-treated cancer patients.

Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans

“…A similar result was shown for rat knee joints, where DXM administration at a dose of 1 mg/kg immediately prior to TNFα injection prevented TNFα-induced degradation of CSPG aggrecan and the release of aggrecanase-generated aggrecan fragments from the articular cartilage into the synovial fluid [ 38 ]. DXM treatment at 2.5 mg/kg for five cycles for 5 consecutive days with breaks of 16 days also attenuated TMZ-induced reorganization of knee joint cartilage structure (increased content of total GAGs and their partial relocalization from chondrocytes into the tissue matrix, as well as a decrease in sulfated GAG content) in elderly Wistar rats [ 39 ]. Triamcinolone acetonide (TA) at doses of 1.25, 2.5, and 5 mg/mL increased PG loss in canine cartilage explants [ 40 ].…”

Prolonged use of temozolomide leads to increased anxiety and decreased content of aggrecan and chondroitin sulfate in brain tissues of aged rats

“…However, the effects of TMZ on the behavior of adult and elderly animals have not been sufficiently studied. In a previous conducted by the authors, it was revealed that long-term treatment with TMZ to adult Wistar rats resulted in a significant decrease in their locomotor activity ( 25 ), whereas its effects on the anxiety of the animals remained unknown.…”