Pharmacological Blockade of Group II Metabotropic Glutamate Receptors Reduces the Incidence of Brain Tumors Induced by Prenatal Exposure to N-ethyl-N-nitrosourea in Rats.

Abstract

The study demonstrates that pharmacological blockade of type 3 metabotropic glutamate (mGlu3) receptors at the time of tumor induction significantly reduces the incidence of brain gliomas in rats. The overall survival of patients with high-grade brain gliomas is 14-20 months after current multimodal therapy, including surgery, radiotherapy, and adjuvant chemotherapy. To demonstrate in this experimental model that pharmacological blockade of group II metabotropic glutamate receptors reduces the incidence of brain tumors induced by prenatal exposure to N- ethyl-N-nitrosourea (ENU) in rats. Dams received a single injection of ENU (40 mg/kg, e.v.) at day 20 of pregnancy, combined with 5 daily injections of either saline or the mGlu2/3 receptor antagonist, LY341495 (10 mg/kg) (from day 15 to day 21 of pregnancy). Assessment of brain tumors in the offspring at 5 months of age showed the presence of mixed gliomas (astrocytomas/oligodendrogliomas) in 70% of the ENU + saline group of rats and only in 30% of the ENU + LY341495 group. Tumors in both groups of rats showed a moderate/high expression of the astrocyte marker, GFAP, and the oligodendrocyte marker, OLIG-2, and a low expression of the proliferation marker, Ki-67. However, tumors of the ENU + LY341495 group showed a reduced density of Iba-1+ cells, suggesting a lower extent of neuroinflammation in the tumor microenvironment. These findings strengthen the hypothesis that mGlu3 receptors are candidate drug targets for the treatment of malignant gliomas.