gms | German Medical Science

Objective: Neuropsychiatric comorbidities, e.g. depression or anxiety, are frequently seen in glioblastoma (GBM) patients restricting patients’ quality of life. However, the underlying pathophysiology is still unclear. Dysfunction of mTOR signaling has been implicated in the development of neurobehavioral disorders. Coincidently, activation of mTOR signaling is a key driver of GBM progression and, therefore, has emerged as an attractive molecular target for treating this tumor, although clinical approaches to target the mTOR pathway have not been successful. In the current study, we first investigated whether neurobehavioral alterations may arise in an orthotopic rat model of experimentally induced GBM. Moreover, possible modulatory effects of the mTOR inhibitior rapamycin on tumor growth, behavior and protein expression in the hippocampus were analyzed.

Methods: Male Fisher rats (n=40) were sham operated or received intracranial implantation of RG2 cells. Animals were treated with rapamycin (3mg/kg) for 7 days following surgery. Anxiety- and depressive-related behavior was assessed by the elevated plus maze (EPM) and by the forced swim test (FST). Subsequently, brain tissue and blood samples were taken for biochemical analyses.

Results: Systemic treatment with rapamycin inhibited RG2 cell proliferation in vivo. While compared to SHAM controls, RG2 implanted rats displayed increased depressive-related behaviors in the FST, whereas a reduction in these behaviors was observed in RG2 rats treated with rapamycin. Concomitantly, rapamycin treated RG2 animals showed increased anxiety-related behavior in the EPM test. The behavioral alterations correlated with neuromolecular changes in the hippocampus reflected by decreased protein expression of glucocorticoid receptors (GR) and brain derived neurotrophic factor (BDNF) compared to sham and untreated RG2 rats.

Conclusion: Our findings indicate that alterations in mood and anxiety-related behavior that arise in an experimental model of GBM can be modulated by systemic rapamycin treatment. Since no peripheral neuroendocrine changes were detected we hypothesize that the observed impact of rapamycin on behavior was mediated by mTOR together with GR regulated mechanism(s) in the hippocampus rather than by stress. Together, these findings provide novel insights in the pathophysiology of neurobehavioral comorbidities of GBM and the central effects of systemic rapamycin treatment in subjects with a neurological disorder.