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

Anastasia V Suhovskih,Olga P Molodykh,Elvira V Grigorieva,Maxim O Politko,Elena V Koldysheva,Victor S Ushakov,Dmitry K Sokolov

doi:10.3390/biomedicines8120541

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.

Highlights

Temozolomide (TMZ) is a conventional chemotherapy drug for treating various malignant tumours such as melanoma [1], metastatic adrenocortical carcinoma [2], prolactin-secreting adenoma, and carcinoma [3]
It was shown that mice treated with a regimen of TMZ similar to humans demonstrate anxiety- and depression-like behaviour [17] and behavioural and biochemical changes that have relevance to the development of depression [18]. Another important parameter of a high life quality after TMZ treatment is physical activity that might be compromised by TMZ chemotherapy
Wistar rats (9 months old), the animals were tested in the open field arena before and after the treatments

Summary

Introduction

Temozolomide (TMZ) is a conventional chemotherapy drug for treating various malignant tumours such as melanoma [1], metastatic adrenocortical carcinoma [2], prolactin-secreting adenoma, and carcinoma [3]. It was shown that mice treated with a regimen of TMZ similar to humans demonstrate anxiety- and depression-like behaviour [17] and behavioural and biochemical changes that have relevance to the development of depression [18]. Another important parameter of a high life quality after TMZ treatment is physical activity that might be compromised by TMZ chemotherapy. It cannot be ruled out that long-term use of TMZ affects motor activity, thereby reducing the life quality

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