title: Group III mGlu receptor agonist, ACPT-I, exerts potential neuroprotective effects in vitro and in vivo.
abstract: Many evidence suggest that metabotropic glutamate receptors (mGluRs) may modulate glutamatergic transmission, hence, these receptors are regarded as potential targets for neuroprotective drugs. Since group III mGlu receptor agonists are known to reduce glutamatergic transmission by inhibiting glutamate release, we decided to investigate the neuroprotective potential of the group III mGlu receptor agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-I) against kainate (KA)-induced excitotoxicity in vitro and in vivo. In primary neuronal cell cultures ACPT-I (1-200 μM), applied 30 min-3 h after starting the exposure to KA (150 μM), significantly attenuated the KA-induced LDH release, increased cell viability, and inhibited caspase-3 activity both in cortical and hippocampal cell cultures. The effects were dose-, time- and structure-dependent. The neuroprotective effects of ACPT-I were reversed by (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine, a group III mGluR antagonist. In the in vivo studies, KA (2.5 nmol/1 μl) was unilaterally injected into the rat dorsal CA1 hippocampal region and the size of degeneration was examined by stereological counting of surviving neurons in the CA pyramidal layer. It was found that ACPT-I (7.5 or 15 nmol/1 μl), injected into the dorsal hippocampus 30 min, 1 or 3 h after KA in dose-dependent manner prevented the KA-induced neuronal damage. Moreover, in vivo microdialysis studies in the rat hippocampus showed that ACPT-I (200 μM) given simultaneously with KA (50 μM) significantly diminished the KA-induced glutamate release in the hippocampus. This mechanism seems to play a role in mediating the neuroprotective effect of ACPT-I.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland, domin@if-pan.krakow.pl.
authors.forename: Helena
authors.initials: H
authors.lastname: Domin
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
authors.forename: Danuta
authors.initials: D
authors.lastname: Jantas
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kamińska
authors.forename: Barbara
authors.initials: B
authors.lastname: Zięba
authors.forename: Maria
authors.initials: M
authors.lastname: Smiałowska
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D014233:Tricarboxylic Acids / Q000494:pharmacology*
chemical_list: C108242:1-aminocyclopentane-1,3,4-tricarboxylic acid; D003517:Cyclopentanes; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D014233:Tricarboxylic Acids; D018698:Glutamic Acid; D007608:Kainic Acid