Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide

A Copani, V Bruno, G Battaglia, G Leanza, R Pellitteri, A Russo, S Stanzani and F Nicoletti

Institute of Pharmacology, University of Catania, Italy.

Prolonged exposure of cultured cortical cells or cultured cerebellar granule cells to the residue 25-35 fragment of beta-amyloid peptide (beta AP), beta AP(25-35), induced neuronal apoptosis, as revealed by morphological analysis, fluorescent chromatin staining, and immunodetection of oligonucleosomes released from the nucleus into the cytoplasm. beta AP(25-35)-induced apoptosis was insensitive to ionotropic glutamate receptor antagonists but was substantially attenuated by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. The neuroprotective action of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was antagonized by (RS)-alpha-methyl-4-carboxyphenylglycine and was mimicked by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (a selective agonist of mGluR2 and -3 subtypes) and by L-2-amino-4- phosphobutanoate and L-serine-O-phosphate (selective agonists of mGluR4, -6, and -7 subtypes). However, whereas all of these drugs behaved as neuroprotectants in cultured cortical cells, only L-2-amino- 4-phosphobutanoate and L-serine-O-phosphate [and not (2S,1'R,2'R,3'R)-2- (2,3-dicarboxycyclopropyl)glycine] reduced beta AP(25-35)-induced apoptosis in cultured cerebellar granule cells. The neuroprotective activity of mGluR agonists may be related to their ability to inhibit membrane Ca2+ conductance, because drugs that block voltage-sensitive Ca2+ channels, such as nimodipine or Co2+, could also attenuate beta AP(25-35)-induced apoptosis.

Volume 47, Issue 5, pp. 890-897, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				C. Corti, G. Battaglia, G. Molinaro, B. Riozzi, A. Pittaluga, M. Corsi, M. Mugnaini, F. Nicoletti, and V. Bruno The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection J. Neurosci., August 1, 2007; 27(31): 8297 - 8308. [Abstract] [Full Text] [PDF]

				Q. Jiang, Z. Yan, and J. Feng Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism. J. Neurosci., April 19, 2006; 26(16): 4318 - 4328. [Abstract] [Full Text] [PDF]

				J. P. Tyszkiewicz and Z. Yan {beta}-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons J Neurophysiol, June 1, 2005; 93(6): 3102 - 3111. [Abstract] [Full Text] [PDF]

				S.-Y. Park and A. Ferreira The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates {beta}-Amyloid-Induced Neurodegeneration J. Neurosci., June 1, 2005; 25(22): 5365 - 5375. [Abstract] [Full Text] [PDF]

				E. M. Brown and R. J. MacLeod Extracellular Calcium Sensing and Extracellular Calcium Signaling Physiol Rev, January 1, 2001; 81(1): 239 - 297. [Abstract] [Full Text] [PDF]

				A. Bond, N. M. Jones, C. A. Hicks, G. M. Whiffin, M. A. Ward, M. F. O'Neill, A. E. Kingston, J. A. Monn, P. L. Ornstein, D. D. Schoepp, et al. Neuroprotective Effects of LY379268, a Selective mGlu2/3 Receptor Agonist: Investigations into Possible Mechanism of Action In Vivo J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 800 - 809. [Abstract] [Full Text]

				C. HARMS, M. LAUTENSCHLAGER, A. BERGK, D. FREYER, M. WEIH, U. DIRNAGL, J. R. WEBER, and H. HÖRTNAGL Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures FASEB J, September 1, 2000; 14(12): 1814 - 1824. [Abstract] [Full Text]

				V. Bruno, G. Battaglia, I. Ksiazek, H. van der Putten, M. V. Catania, R. Giuffrida, S. Lukic, T. Leonhardt, W. Inderbitzin, F. Gasparini, et al. Selective Activation of mGlu4 Metabotropic Glutamate Receptors Is Protective against Excitotoxic Neuronal Death J. Neurosci., September 1, 2000; 20(17): 6413 - 6420. [Abstract] [Full Text] [PDF]

				A. COPANI, F. CONDORELLI, A. CARUSO, C. VANCHERI, A. SALA, A. M. GIUFFRIDA STELLA, P. L. CANONICO, F. NICOLETTI, and M. A. SORTINO Mitotic signaling by {beta}-amyloid causes neuronal death FASEB J, December 1, 1999; 13(15): 2225 - 2234. [Abstract] [Full Text]

				F. Gasparini, V. Bruno, G. Battaglia, S. Lukic, T. Leonhardt, W. Inderbitzin, D. Laurie, B. Sommer, M. A. Varney, S. D. Hess, et al. (R,S)-4-Phosphonophenylglycine, a Potent and Selective Group III Metabotropic Glutamate Receptor Agonist, Is Anticonvulsive and Neuroprotective In Vivo J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1678 - 1687. [Abstract] [Full Text]

				K. Imaizumi, T. Morihara, Y. Mori, T. Katayama, M. Tsuda, T. Furuyama, A. Wanaka, M. Takeda, and M. Tohyama The Cell Death-promoting Gene DP5, Which Interacts with the BCL2 Family, Is Induced during Neuronal Apoptosis Following Exposure to Amyloid beta  Protein J. Biol. Chem., March 19, 1999; 274(12): 7975 - 7981. [Abstract] [Full Text] [PDF]

				V. Bruno, G. Battaglia, G. Casabona, A. Copani, F. Caciagli, and F. Nicoletti Neuroprotection by Glial Metabotropic Glutamate Receptors Is Mediated by Transforming Growth Factor-beta J. Neurosci., December 1, 1998; 18(23): 9594 - 9600. [Abstract] [Full Text] [PDF]

				V. Bruno, F. X. Sureda, M. Storto, G. Casabona, A. Caruso, T. Knopfel, R. Kuhn, and F. Nicoletti The Neuroprotective Activity of Group-II Metabotropic Glutamate Receptors Requires New Protein Synthesis and Involves a Glial-Neuronal Signaling J. Neurosci., March 15, 1997; 17(6): 1891 - 1897. [Abstract] [Full Text] [PDF]

				M. A. Pappolla, M. Sos, R. A. Omar, R. J. Bick, D. L. M. Hickson-Bick, R. J. Reiter, S. Efthimiopoulos, and N. K. Robakis Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide J. Neurosci., March 1, 1997; 17(5): 1683 - 1690. [Abstract] [Full Text] [PDF]