Neuroprotective activity of metabotropic glutamate receptor ligands.
Metabotropic glutamate receptors form a family of currently eight subtypes (mGluR1-8), subdivided into three groups (I-III). Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) has been established to be neuroprotective in vitro and in vivo. In contrast, group-I mGluRs (mGluR1 and -5) need to be antagonized in order to evoke protection. Initially, all neuroprotective mGluR ligands were analogues of L-glutamate. Those compounds were valuable to demonstrate protection in vitro, but showed limited applicability in animal models, particularly in chronic tests, due to low blood-brain-barrier penetration. Recently, systemically active and more potent and selective ligands became available, e.g., the group-II mGluR agonists LY354740 and LY379268 or group-I antagonists like MPEP (mGluR5-selective) and BAY36-7620 (mGluR1-selective). This new generation of pharmacological agents allows a more stringent assessment of the role of individual mGluR-subtypes or groups of receptors in various nervous system disorders, including ischaemia-induced brain damage, traumatic brain injury, Huntington's and Parkinson's-like pathology or epilepsy. Moreover, the use of genetically modified animals (e.g., knock-out mice) is starting to shed light on specific functions of mGluR-subtypes in experimental neuropathologies.
Flor
Peter J
PJ
Novartis PharmaAG, Nervous System Research, Basel, Switzerland.
Battaglia
Giuseppe
G
Nicoletti
Ferdinando
F
Gasparini
Fabrizio
F
Bruno
Valeria
V
D000818:Animals; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid