A PRECLINICAL STUDY EXPLORING THE PHARMACOLOGICAL INTERACTION BETWEEN TEMOZOLOMIDE CHEMOTHERAPY AND ANTIDEPRESSANT TREATMENTS IN A RAT GLIOBLASTOMA MODEL

In the context of cancer-depression comorbidity, temozolomide, the gold standard drug used for the treatment of glioblastoma, is known to affect healthy brain proliferating cells, inhibiting the first stages of hippocampal neurogenesis. Given that most antidepressant drugs mediate their beneficial effect through this process, and since a large proportion of glioblastoma patients present depressive symptoms, this preclinical study aimed to evaluate the interaction between temozolomide chemotherapy and three pharmacological agents with different mechanisms of action. Male Fisher 344 rats were intracranially implanted with syngen RG2 cells and treated with temozolomide (25 mg/kg) in the morning for 5 days. Additionally, animals received injections with fluoxetine (10 mg/kg), cannabidiol (30 mg/kg) or metformin (100 mg/kg) 3 hours after temozolomide treatment. Antidepressant-like responses were assessed under the stress of forced-swim test 1-day post-treatment. The next day, rats were sacrificed, and brain and blood samples were taken for biochemical analyses. Data was analyzed with two-way ANOVAs (independent variables: pretreatment x treatment). The main results showed no drug interactions between temozolomide and the drugs tested at any levels analyzed. In fact, the expected antidepressant-like responses of the drugs evaluated were not present, probably due to the need of adjusting the doses and duration of treatment given the presence of the brain tumor. Interestingly, both fluoxetine and cannabidiol reduced corticosterone levels suggesting some improvements independently of the concomitant temozolomide treatment. Evaluations of tumor volume and adult hippocampal neurogenesis will provide further information that may explain the behavioral data.