Group II metabotropic glutamate receptor activation by agonist LY379268 treatment increases the expression of brain derived neurotrophic factor in the mouse brain

Liberto, Valentina Di; Bonomo, Alessandra; Frinchi, Monica; Belluardo, Natale; Mudò, Giuseppa

doi:10.1016/j.neuroscience.2009.11.012

Cited by 37 publications

(15 citation statements)

References 55 publications

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“…In line with this observation, Di Liberto et al (2009) have shown that systemic administration of LY379268 increases BDNF mRNA levels after 3 h and BDNF protein levels after 24 h in the mouse brain. Here, gene promoter demethylation induced by LY379268 in mice pretreated with Met was already evident at 8 h, thus preceding the behavioral effect on social interaction, which was seen at 24 h. Ma et al (2009) reported that Gadd45-␤ is rapidly induced in hippocampal neurons in response to neuronal circuit activation and ionotropic glutamate receptor stimulation.…”

Section: Discussionsupporting

confidence: 55%

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

et al. 2011

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Activation of group II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently used medications exert chromatin remodeling effects. Here, we show that systemic injection of the brain-permeant mGlu2/3 receptor agonist (Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268; 0.3-1 mg/kg i.p.) increased the mRNA and protein levels of growth arrest and DNA damage 45-␤ (Gadd45-␤), a molecular player of DNA demethylation, in the mouse frontal cortex and hippocampus. Induction of Gadd45-␤ by LY379268 was abrogated by the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495; 1 mg/kg i.p.). Treatment with LY379268 also increased the amount of Gadd45-␤ bound to specific promoter regions of reelin, brain-derived neurotrophic factor (BDNF), and glutamate decarboxylase-67 (GAD67). We directly assessed gene promoter methylation in control mice and in mice pretreated for 7 days with the methylating agent methionine (750 mg/kg i.p.). Both single and repeated injections with LY379268 reduce cytosine methylation in the promoters of the three genes, although the effect on the GAD67 was significant only in response to repeated injections. Single and repeated treatment with LY379268 could also reverse the defect in social interaction seen in mice pretreated with methionine. The action of LY379268 on Gadd45-␤ was mimicked by valproate and clozapine but not haloperidol. These findings show that pharmacological activation of mGlu2/3 receptors has a strong impact on the epigenetic regulation of genes that have been linked to the pathophysiology of schizophrenia.

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Section: Discussionsupporting

confidence: 55%

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

et al. 2011

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“…Several possibilities are likely to explain the beneficial effects of LY379268 in R6/2 mice: 1) LY379268 may have opposed excitotoxic cortical and striatal injury (Kingston et al, 1999; D'Onofrio et al, 2001) by acting on mGluR2/3 receptors on cortical neuron terminals to reduce glutamate release (Battaglia et al, 1997; Cozzi et al, 1997), and/or by acting directly on neurons possessing mGluR3 receptors to diminish their excitability (Testa et al, 1994); 2) LY379268 may have increased TGF-β production by astrocytes and thereby protected against excitotoxic injury (D'Onofrio et al, 2001); and 3) LY379268 could have increased cortical BDNF production and delivery to target neurons in cortex and striatum (Di Liberto et al, 2010; Zuccato et al, 2001; Gauthier et al, 2004; Zuccato and Cattaneo 2007). These possibilities are addressed in more detail below.…”

Section: Discussionmentioning

confidence: 99%

The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

Reiner

Lafferty

Wang

et al. 2012

Neurobiology of Disease

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“…The activation of mGluR2/3 have been implicated in the production of other neurotrophic factors, such as TGFb1 in astrocytes (Bruno et al, 1998;Ciccarelli et al, 1997) and in the striatum (D'Onofrio et al, 2001), or BDNF in microglia (Matarredona et al, 2001;Venero et al, 2002), in the hippocampus (Di Liberto et al, 2010), in neuronal hippocampal cultures (Canossa et al, 2001;Wu et al, 2004;Marini et al, 1998) and in reactive astrocytes (Mudo et al, 2007;Ohishi et al, 1993Ohishi et al, , 1998. Although this proved involvement of mGluR2/3 in neurotrophic factors regulation, the present data, together with previous related findings (Battaglia et al, 2009), provide a complete demonstration for an involvement of GDNF/RET neurotrophic system in the neuroprotection observed in the mouse model of Parkinson's disease following mGluR2/3 activation.…”

Section: Discussionmentioning

confidence: 99%

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Liberto¹,

Mudò²,

Belluardo³

2011

Neuropharmacology

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Keywords:GDNF RET mGluR2/3 LY379268 Erk1/2 TrK phosphorylation a b s t r a c tIn the present study we aimed to verify if the enhancement of glial cell line-derived neurotrophic factor (GDNF) production in mouse striatum following treatment with LY379268 may also induce in the nigrostriatal system a time-related activation of RET receptor and its specific intracellular signaling. For this purpose, we have investigated the effects of LY379268 treatment on RET phosphorylation at the Tyr1062 and on downstream signaling Erk1/2, Akt and PLCg1 pathway activation. The results showed that treatment with LY379268 (3 mg/kg) induces a significant increase of GDNF levels and time-related RET and Erk1/2 phosphorylation in the striatum. These increases were detected at 24 h and 48 h following LY379268 treatment. No changes were observed in the Akt and PLCg1 phosphorylation levels. Similar results for p-Erk1/2 were observed in the substantia nigra. A complete block of LY379268 effect on striatal RET and p-Erk1/2 phosphorylation was observed in mice intrastriatal injected with anti-GDNF antibodies, suggesting a correlation between GDNF upregulation and RET activation. Overall, with present data we have shown that activation of mGluR2/3 receptors by LY379268 may be particularly promising for nigrostriatal dopaminergic system protection by enhancing striatal levels of GDNF/RET trophic system activity.

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Group II metabotropic glutamate receptor activation by agonist LY379268 treatment increases the expression of brain derived neurotrophic factor in the mouse brain

Cited by 37 publications

References 55 publications

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

Activation of Group II Metabotropic Glutamate Receptors Promotes DNA Demethylation in the Mouse Brain

The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

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