Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice

Battaglia, Giuseppe; Busceti, Carla L.; Molinaro, Gemma; Biagioni, Francesca; Storto, Marianna; Fornai, Francesco; Nicoletti, Ferdinando; Bruno, Valeria

doi:10.1523/jneurosci.3831-03.2004

Cited by 116 publications

(77 citation statements)

References 70 publications

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“…A reduced proliferation of NPCs may limit the endogenous repair mechanisms when mGlu5 receptor antagonists are used as neuroprotective agents in neurodegenerative disorders. 42,43 Materials and Methods …”

Section: Discussionmentioning

confidence: 99%

“…NPCs were isolated from the forebrain of C57 black wild-type mice or from mGlu5 receptor knockout mice (purchased from Jackson Laboratories, Bar Harbor, ME, USA) 43 at embryonic day 20 (E20). Briefly, the brain tissue was collected in HBSS, mechanically dissociated to a single cell suspension and then resuspended in serum-free medium in the presence of 20 and 10 ng/ml of human recombinant EGF and bFGF, respectively.…”

Section: Cultures Of Npcsmentioning

confidence: 99%

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Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

et al. 2005

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The use of neural progenitor cells (NPCs) is limited by the incomplete knowledge of the extracellular signals regulating their proliferation and survival. We report that cultured mouse NPCs express functional mGlu3 and mGlu5 metabotropic glutamate receptors. Pharmacological blockade of both receptors reduced NPC proliferation and survival, whereas activation of mGlu5 receptors substantially enhanced cell proliferation. Adult mice lacking mGlu5 receptors or treated with mGlu5 or mGlu3 receptor antagonists showed a dramatic reduction in the number of dividing neuroprogenitors present in the subventricular zone and in the dentate gyrus of the hippocampus. These data disclose a novel function of mGlu receptors and offer new potential strategies for the optimization of cell replacement therapy in neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Cultures Of Npcsmentioning

confidence: 99%

Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

et al. 2005

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“…Recent evidence suggests that mGlu receptors are involved in mechanisms of neurodegeneration/ neuroprotection in mice challenged with MPTP. Knock-out mice lacking mGlu5 receptors are partially protected against MPTP toxicity, as are mice treated with mGlu1 or mGlu5 receptor antagonists (Aguirre et al, 2001;Battaglia et al, 2004). Pharmacological activation of mGlu2/3 receptors is also protective, whereas mGlu2/3 receptor blockade amplifies MPTP neurotoxicity (Matarredona et al, 2001;Battaglia et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

et al. 2006

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We examined whether selective activation of mGlu4 metabotropic glutamate receptors attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in mice. C57BL mice were treated with a single dose of MPTP (30 mg/kg, i.p.) preceded, 30 min earlier, by a systemic injection of the mGlu4 receptor enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). PHCCC was injected either subcutaneously in cremophor EL or intraperitoneally in saline containing 50% DMSO. PHCCC treatment (3 or 10 mg/kg) significantly reduced MPTP toxicity, as assessed by measurements of the striatal levels of dopamine and its metabolites and by tyrosine hydroxylase, dopamine transporter, and glial fibrillary acidic protein immunostaining in the corpus striatum and substantia nigra. In another set of experiments, a higher cumulative dose of MPTP (80 mg/kg divided into four injections with 2 h of interval) was injected to mGlu4 Ϫ/Ϫ mice and their Sv129/CD1 wild-type controls. A higher dose was used in these experiments because Sv129/CD1 mice are less sensitive to MPTP toxicity. Systemic administration of PHCCC was protective in wild-type mice but failed to affect nigrostriatal damage in mGlu4 Ϫ/Ϫ mice. Finally, unilateral infusion of PHCCC in the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity. These data support the view that mGlu4 receptors are potential targets for the experimental treatment of parkinsonism.

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“…Interestingly, mGluR5 and A 2A receptor antagonists exert synergistic antiparkinsonian effects in rat models of PD (Coccurello et al, 2004). It is noteworthy that MPEP and MTEP are also neuroprotective toward degeneration of midbrain dopaminergic neurons in mice and monkey models of PD (Flor et al, 2002;Battaglia et al, 2004;Masilamoni et al, 2011). In MPTP-treated nonhuman primates, MTEP also protects locus coeruleus noradrenergic neurons from degeneration (Masilamoni et al, 2011).…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice

Abstract: We combined the use of knock-out mice and subtype-selective antagonists [2-methyl-6-(phenylethynyl)pyridine (

Cited by 116 publications

References 70 publications

Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

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