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.

in Current neuropharmacology by Antonietta Arcella, Marika Alborghetti, Anna Traficante, Maria Antonietta Oliva, Sabrina Staffieri, Veronica Russo, Matteo Caridi, Giuseppe Battaglia

TLDR

  • Pharmacological blockade of mGlu3 receptors at the time of tumor induction significantly reduces the incidence of brain gliomas in rats, suggesting a potential therapeutic target for the treatment of malignant gliomas.

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.

Overview

  • The study aimed to investigate the effect of mGlu3 receptor blockade on the incidence of brain gliomas in rats.
  • Pregnant rats were injected with ENU to induce brain tumors, while some received a mGlu2/3 receptor antagonist, LY341495, to block mGlu3 receptors.
  • The study aimed to determine the effect of mGlu3 receptor blockade on the incidence and growth of brain gliomas in rats.

Comparative Analysis & Findings

  • The study found that pharmacological blockade of mGlu3 receptors at the time of tumor induction significantly reduced the incidence of brain gliomas in rats.
  • Rats that received the LY341495 treatment had a lower incidence of gliomas (30%) compared to those that did not receive the treatment (70%).
  • Tumors in both groups showed similar levels of expression for astrocyte and oligodendrocyte markers, but tumors in the LY341495 group showed reduced neuroinflammation.

Implications and Future Directions

  • The study suggests that mGlu3 receptors may be a potential therapeutic target for the treatment of malignant gliomas.
  • Future studies should investigate the efficacy and safety of mGlu3 receptor blockade in humans with gliomas.
  • The study provides a foundation for further investigations into the role of mGlu3 receptors in gliomagenesis and potential therapeutic applications.
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