Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons

Giuseppe Battaglia, Gemma Molinaro, Barbara Riozzi, Marianna Storto, Carla L. Busceti, Paola Spinsanti, Domenico Bucci, Valentina Di Liberto, Giuseppina Mudò, Corrado Corti, Mauro Corsi, Ferdinando Nicoletti, Natale Belluardo, Valeria Bruno

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.

Original languageEnglish (US)
Article numbere6591
JournalPLoS One
Volume4
Issue number8
DOIs
StatePublished - Aug 12 2009

Fingerprint

Glial Cell Line-Derived Neurotrophic Factor
Corpus Striatum
LY 379268
neurotrophins
neuroglia
Neurons
neurons
Chemical activation
cell lines
receptors
Metabotropic Glutamate Receptors
mice
Knockout Mice
agonists
tyrosine 3-monooxygenase
antagonists
LY 341495
Phosphatidylinositol 3-Kinase
injection
Excitatory Amino Acid Agonists

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Battaglia, G., Molinaro, G., Riozzi, B., Storto, M., Busceti, C. L., Spinsanti, P., ... Bruno, V. (2009). Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons. PLoS One, 4(8), [e6591]. https://doi.org/10.1371/journal.pone.0006591

Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons. / Battaglia, Giuseppe; Molinaro, Gemma; Riozzi, Barbara; Storto, Marianna; Busceti, Carla L.; Spinsanti, Paola; Bucci, Domenico; Di Liberto, Valentina; Mudò, Giuseppina; Corti, Corrado; Corsi, Mauro; Nicoletti, Ferdinando; Belluardo, Natale; Bruno, Valeria.

In: PLoS One, Vol. 4, No. 8, e6591, 12.08.2009.

Research output: Contribution to journalArticle

Battaglia, G, Molinaro, G, Riozzi, B, Storto, M, Busceti, CL, Spinsanti, P, Bucci, D, Di Liberto, V, Mudò, G, Corti, C, Corsi, M, Nicoletti, F, Belluardo, N & Bruno, V 2009, 'Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons', PLoS One, vol. 4, no. 8, e6591. https://doi.org/10.1371/journal.pone.0006591
Battaglia, Giuseppe ; Molinaro, Gemma ; Riozzi, Barbara ; Storto, Marianna ; Busceti, Carla L. ; Spinsanti, Paola ; Bucci, Domenico ; Di Liberto, Valentina ; Mudò, Giuseppina ; Corti, Corrado ; Corsi, Mauro ; Nicoletti, Ferdinando ; Belluardo, Natale ; Bruno, Valeria. / Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons. In: PLoS One. 2009 ; Vol. 4, No. 8.
@article{27e84f93d7414e469530bfa132c24a70,
title = "Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons",
abstract = "Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.",
author = "Giuseppe Battaglia and Gemma Molinaro and Barbara Riozzi and Marianna Storto and Busceti, {Carla L.} and Paola Spinsanti and Domenico Bucci and {Di Liberto}, Valentina and Giuseppina Mud{\`o} and Corrado Corti and Mauro Corsi and Ferdinando Nicoletti and Natale Belluardo and Valeria Bruno",
year = "2009",
month = "8",
day = "12",
doi = "10.1371/journal.pone.0006591",
language = "English (US)",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons

AU - Battaglia, Giuseppe

AU - Molinaro, Gemma

AU - Riozzi, Barbara

AU - Storto, Marianna

AU - Busceti, Carla L.

AU - Spinsanti, Paola

AU - Bucci, Domenico

AU - Di Liberto, Valentina

AU - Mudò, Giuseppina

AU - Corti, Corrado

AU - Corsi, Mauro

AU - Nicoletti, Ferdinando

AU - Belluardo, Natale

AU - Bruno, Valeria

PY - 2009/8/12

Y1 - 2009/8/12

N2 - Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.

AB - Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.

UR - http://www.scopus.com/inward/record.url?scp=68949151921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68949151921&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0006591

DO - 10.1371/journal.pone.0006591

M3 - Article

C2 - 19672295

AN - SCOPUS:68949151921

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e6591

ER -