Metabotropic Glutamate Receptors as a Drug Target in Brain Ischemia

This chapter examines whether metabotropic glutamate receptors can serve as drug target in brain ischemia. Glutamate that is released in large amounts in ischemic brain tissue activates both ionotropic receptors (NMDA, AMPA, or kainate receptors) and metabotropic receptors (mGluRs). The mGluRs form a family of eight subtypes (named mGluR1 to 8) that are tentatively classified into groups I (mGluR1 and 5), II (mGluR2 and 3), and III (mGluR4, 6, 8) on the basis of sequence homology and transduction pathways. Group I mGluRs facilitate the activation of NMDA receptors by either activating protein kinase C or producing membrane depolarization. A role for group I mGluRs in excitotoxicity have been revealed by using selective agonists for mGluR1/5. Groups II and III mGluRs are negatively coupled to either adenylyl cyclase or N-type voltage-sensitive Ca 2+ channels in heterologous expression systems. The chapter also discusses the Group II mGluR agonists that are promising drugs for the experimental therapy of stroke in which the treatment is usually initiated several hours after the onset of the ischemic insult. The results also indicate that mGluRs are promising “targets” for the development of novel neuroprotective agents which may satisfy some of the major criteria to be taken into consideration for clinical practice.