Retracted: Neuroprotection mediated by glial group‐II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol‐3‐kinase pathways

Abstract

The mGlu2/3 receptor agonists 4-carboxy-3-hydroxyphenylglycine (4C3HPG) and LY379268 attenuated NMDA toxicity in primary cultures containing both neurons and astrocytes. Neuroprotection was abrogated by PD98059 and LY294002, which inhibit the mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI-3-K) pathways, respectively. Cultured astrocytes lost the ability to produce transforming growth factor-b1 (TGF-b1) in response to mGlu2/3 receptor agonists when co-incubated with PD98059 or LY294002. As a result, the glial medium was no longer protective against NMDA toxicity. Activation of the MAPK and PI-3-K pathways in cultured astrocytes treated with 4C3HPG or LY379268 was directly demonstrated by an increase in the phosphorylated forms of ERK-1/2 and Akt. Similarly to that observed in the culture, intracerebral or systemic injections of mGlu2/3 receptor agonists enhanced TGF-b1 formation in the rat or mouse caudate nucleus, and this effect was reduced by PD98059. PD98059 also reduced the ability of LY379268 to protect striatal neurons against NMDA toxicity. These results suggest that activation of glial mGlu2/3 receptors induces neuroprotection through the activation of the MAPK and PI-3-K pathways leading to the induction of TGF-b. Keywords: astrocytes, MAP kinase, mGlu receptors, neuroprotection, phosphatidylinositol-3-kinase, TGF-b1.The low success of ionotropic glutamate receptor antagonists in clinical trials (reviewed by Lee et al. 1999) has switched the interest toward metabotropic glutamate (mGlu) receptors as targets for neuroprotective drugs. These receptors form a family of eight subtypes divided into three groups on the basis of sequence homology, pharmacological pro®le and transduction mechanisms. Group-I includes mGlu1 and -5 receptors, which are coupled to polyphosphoinositide hydrolysis and selectively activated by 3,5-dihydroxyphenylglycine (DHPG). Group-II includes mGlu2 and -3 receptors, which are coupled to G i proteins in heterologous expression systems. Compounds are now available that activate these two receptor subtypes with high potency and selectivity, such as (1)-2- Abbreviations used: l-AP4, l-2-amino-4-phosphonobutanoate; 4C3HPG, 4-carboxy-3-hydroxyphenylglycine; DHPG, 3,5-dihydroxyphenylglycine; DIV, days in vitro; GAD, glutamate decarboxylase; GCM, glial conditioned medium; LY354740, (1)-2-aminobicyclo[3,1,0]hexane-2,6-dicarboxylic acid; LY379268, (±)-2-oxa-4-aminobicyclo[3,1,0]hexane-4,6-dicarboxylic acid; LY389795, (±)-2-thia-4-aminobicyclo[3,1,0]hexane-4,6-dicarboxylic acid; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; mGlu, metabotropic glutamate; MAPK, mitogen activated protein kinase; MS, medium stock; PI-3-K, phosphatidylinositol-3-kinase; PPG, 4-phosphonophenylglycine; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; TGF-b1, transforming growth factor-b1. R e t r a c t e d

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

“…Activation of mGluR3 on presynaptic neurons by NAAG decreases glutamate release (37)(38)(39), potentially promoting the survival of neurons crucial to cognitive function. Additionally, activation of mGluR3 on astrocytes stimulates the release of transforming growth factor beta, a cytokine with demonstrated in vitro neuroprotective effects (40,41). It is possible that one or both of these NAAG-mediated pathways regulates cognitive function in MS, requiring future studies to elucidate the exact mechanism.…”

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

“…This offers the advantage to examine the respective contribution of astrocytic and neuronal mGlu2 and mGlu3 receptors to processes of neurodegeneration/neuroprotection. Neuroprotection by mGlu2/3 receptor agonists in mixed cortical cultures involves a mechanism of glial-neuronal interaction mediated by the production of transforming growth factor-␤ (Bruno et al, 1997(Bruno et al, , 1998bD'Onofrio et al, 2001). This mechanism was dem- onstrated by transferring the medium collected from astrocyte cultures treated with mGlu2/3 receptor agonists to recipient mixed cultures challenged with NMDA (Bruno et al, 1997).…”

“…We have shown previously that activation of group II mGlu receptors in astrocytes promotes neuroprotection via a paracrine mechanism mediated by TGF-␤ and perhaps other neurotrophic factors (Bruno et al, 1997(Bruno et al, , 1998bCiccarelli et al, 1999;D'Onofrio et al, 2001). We therefore examined whether the medium collected from pure cultures of astrocytes prepared from wt or mGlu3 Ϫ/Ϫ mice treated or not with LY379268 affected neuronal death in recipient mixed cultures challenged with NMDA prepared from a-wt/n-wt or a-mGlu3…”

“…Data obtained with more potent and selective "second generation" agonists of mGlu2 and mGlu3 receptors, such as (1S, 2S, 5R, 6S)-(ϩ)-2-aminobicylco[3.1.0]-hexane-2,6-dicarboxylic acid (LY354740) and (Ϫ)-2-oxa-4-aminocyclo [3.1.0]hexane-4,6-dicarboxylic acid (LY379268), are less convincing. These drugs protect cultured neurons against excitotoxic death, but at concentrations that are 10-to 100-fold higher than the reported EC 50 values for mGlu2 and mGlu3 re-ceptors (Battaglia et al, 1998;Behrens et al, 1999;Kingston et al, 1999a,b;D'Onofrio et al, 2001). Although LY354740 and LY379268 are systemically active, their efficacy as neuroprotectants in in vivo studies is restricted to a few models of neurodegeneration.…”

“…One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by NMDA or AMPA receptor antagonists, such as sedation, ataxia, and severe learning impairment Bruno et al, 2001). Of the eight known mGlu receptor subtypes, mGlu2 and mGlu3 receptors are the best candidates as "neuroprotective receptors," because their activation inhibits glutamate release (Lovinger, 1991;Lovinger and McCool, 1995;Battaglia et al, 1997;Cozzi et al, 1997), inhibits voltage-gated calcium channels (for review, see Pin and Duvoisin, 1995), positively modulates potassium channels (Sharon et al, 1997), and stimulates the production of neurotrophic factors in astrocytes and microglia (Bruno et al, 1997(Bruno et al, , 1998bCiccarelli et al, 1999;D'Onofrio et al, 2001;Matarredona et al, 2001). Early in vitro studies have shown that first generation agonists of mGlu2 and mGlu3, such as (2S,1ЈS,2ЈS)-2-(carboxycyclopropyl)glycine and (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine, are protective against excitotoxicity and other neuronal insults (Pizzi et al, 1993;Bruno et al, 1994Bruno et al, , 1995Ambrosini et al, 1995;Buisson and Choi, 1995;Thomsen et al, 1996).…”