Neurobehavioral effects in rats with experimentally induced glioblastoma after treatment with the mTOR-inhibitor rapamycin

Abstract

Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.