title: Neuroprotective potential of the group III mGlu receptor agonist ACPT-I in animal models of ischemic stroke: In vitro and in vivo studies.
abstract: In the present study, we investigated the effect of ACPT-I [(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain-barrier permeable agonist of group III mGlu receptor, against oxygen-glucose deprivation (OGD)-evoked neuronal cell death in primary neuronal cell cultures and in the model of transient middle cerebral artery occlusion (MCAO) in rats. We found that ACPT-I (1-200 μM) in a concentration- and time-dependent way attenuated the OGD-induced neuronal cell damage, being also effective after a delayed application (30 min after OGD). The neuroprotective effects of ACPT-I were blocked by the group III mGlu receptor antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), and by the activator of cAMP-dependent PKA, 8-Bromo-cAMP, but not by an inhibitor of PI-3-K signaling pathway. Moreover, ACPT-I attenuated the OGD-induced calpain activity and glutamate release. In the in vitro study, we also demonstrated the neuroprotective potential of mGluR4 positive allosteric modulators (PAMs), PHCCC (30 μM) and VU0155041 (10 and 30 μM) and synergism in neuroprotective action of low concentrations of ACPT-I and mGluR4 PAMs suggesting an important role of mGluR4 activation in prevention of ischemic neuronal cell death. In the rat MCAO model, we demonstrated that ACPT-I (30 mg/kg) injected intraperitoneally either 30 min after starting MCAO or 30 min after beginning reperfusion not only diminished the infarction volume by about 30%, but also improved selected gait parameters (CatWalk analysis) and the mobility of animals in the open field test. In conclusion, our results indicate that ACPT-I may be not only neuroprotective against ischemic neuronal damage but may also diminish the postischemic functional deficits.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland. Electronic address: domin@if-pan.krakow.pl.
authors.forename: Helena
authors.initials: H
authors.lastname: Domin
authors.affiliation: Laboratory of Experimental Neurosurgery, Department of Neurosurgery, M. Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106 Warsaw, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Przykaza
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Jantas
authors.affiliation: Laboratory of Experimental Neurosurgery, Department of Neurosurgery, M. Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106 Warsaw, Poland; Department of Experimental and Clinical Physiology, Medical University of Warsaw, 3C Pawiński Street, 02-106 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kozniewska
authors.affiliation: Laboratory of Limbic System, Nencki Institute of Experimental Biology Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Paweł M
authors.initials: PM
authors.lastname: Boguszewski
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Śmiałowska
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D014233:Tricarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use*
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; C102718:metabotropic glutamate receptor 3; D007770:L-Lactate Dehydrogenase
keywords: Calpains; CatWalk; Glutamate; MCAO; OGD; cAMP/PKA pathway