Enhancement of glutamate uptake mediates the neuroprotection exerted by activating group II or III metabotropic glutamate receptors on astrocytes

Yao, Honghong; Ding, Jingzhong; Zhou, Fang; Wang, Fang; Hu, Lifang; Sun, Tao; Hu, Gang

doi:10.1111/j.1471-4159.2004.02937.x

Cited by 104 publications

(91 citation statements)

References 60 publications

(125 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both astroglia and microglia are known to express functional Group III mGluR; thus, speculatively, activation of either mGluR4 or 8 expressed on these cell types may contribute to neuroprotection by L-AP4 in our model in which significant gliosis occurs in response to 6-OHDA-induced cell death. In support of this concept, activation of astroglial and microglial Group III mGluR has been shown recently to be neuroprotective in vitro (Taylor et al, 2003;Yao et al, 2005). Thus, it will be important in future studies to define the exact subtype of Group III mGluR that mediates neuroprotection by L-AP4 in vivo.…”

Section: Discussionmentioning

confidence: 98%

Selective Activation of Group III Metabotropic Glutamate Receptors by l-(+)-2-Amino-4-phosphonobutryic Acid Protects the Nigrostriatal System against 6-Hydroxydopamine Toxicity in Vivo

Vernon¹,

Zbarsky²,

Datla³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Evidence from several studies suggests that the progressive degeneration of dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) may in part be due to excessive release of glutamate from subthalamic projections onto nigral DA neurones. Previous in vitro studies have demonstrated that selective activation of Group III metabotropic glutamate receptors (mGluR) negatively modulates excitatory transmission in the SNc and is neuroprotective against glutamate-mediated toxicity. Consistent with this, we have reported preliminary data indicating that the selective group III mGluR agonist L-(ϩ)-2-amino-4-phosphonobutyric acid (L-AP4) can also protect the nigrostriatal system against 6-hydroxydopamine (6-OHDA) toxicity in vivo. We have now extended these preliminary studies in this model and report here that both acute and subchronic intranigral injections of L-AP4 provide significant protection of the nigrostriatal system against 6-OHDA toxicity. This neuroprotection displays a bellshaped profile with a clear concentration-dependent relationship. In contrast, when administered to animals 7 days post-6-OHDA lesioning, L-AP4 significantly protects the functionality but not the integrity of the nigrostriatal system. We further demonstrate that neuroprotection by L-AP4 in vivo is reversed by coadministration of the selective Group III mGluR antagonist (RS)-␣-methylserine-O-phosphate, confirming a receptor-mediated mechanism of action. These data provide further compelling evidence that selective activation of Group III mGluR is neuroprotective in an in vivo experimental model of PD, a finding that may have important implications for the future treatment of this disease.Parkinson's disease (PD) is a debilitating neurodegenerative disorder that afflicts 1% of people over 65 (Lang and Lozano, 1998a). Pathologically, the disease is characterized by a progressive degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc). Currently, treatment of PD is focused on dopamine replacement therapy using the dopamine precursor levodopa (L-DOPA) and/or dopamine receptor agonists, which can provide dramatic amelioration of PD motor symptoms in the early stages of this disease (for review, see Schapira, 2005). However, prolonged use of these agents is associated with a long-term decline in efficacy and a number of severe motor and cognitive side effects (Olanow and Jankovic, 2005). Moreover, these treatments do nothing to halt the progression of nigral neuronal loss. Delaying or slowing the progression of PD would delay the need for L-DOPA therapy; therefore, the development of neuroprotective strategies may play an important role in preventing the onset and reducing the severity of L-DOPA-related adverse effects (Olanow and Jankovic, This work was supported by grants from the MRC and the Parkinson's Disease Society of the United Kingdom.Article, publication date, and citation information can be found at

show abstract

Section: Discussionmentioning

confidence: 98%

Selective Activation of Group III Metabotropic Glutamate Receptors by l-(+)-2-Amino-4-phosphonobutryic Acid Protects the Nigrostriatal System against 6-Hydroxydopamine Toxicity in Vivo

Vernon¹,

Zbarsky²,

Datla³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Cell Culture and Cell Lines-Primary rat neurons were prepared as described earlier with slight modifications (29). Briefly, hippocampus was dissected from embryonic day 18 -19 Sprague-Dawley rats and dissociated with a mild mechanical trituration.…”

Section: Methodsmentioning

confidence: 99%

Platelet-derived Growth Factor-mediated Induction of the Synaptic Plasticity Gene Arc/Arg3.1

Peng

Yao

Bai

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Platelet-derived growth factor (PDGF) is a pleiotropic protein with critical roles in both developmental as well as pathogenic processes. In the central nervous system specifically, PDGF is critical for neuronal proliferation and differentiation and has also been implicated as a neuroprotective agent. Whether PDGF also plays a role in synaptic plasticity, however, remains poorly understood. In the present study we demonstrated that in the rat hippocampal neurons PDGF regulated the expression of Arc/ Arg3.1 gene that has been implicated in both synapse plasticity and long term potentiation. Relevance of these findings was further confirmed in vivo by injecting mice with intracerebral inoculations of PDGF, which resulted in a rapid induction of Arc in the hippocampus of the injected mice. PDGF induced long term potentiation in rat hippocampal slices, which was abolished by PDGF receptor-tyrosine kinase inhibitor STI-571. We also present evidence that PDGF-mediated induction of Arc/Arg3.1 involved activation of the MAPK/ERK (MEK) pathway. Additionally, induction of Arc/Arg3.1 also involved the upstream release of intracellular calcium stores, an effect that could be blocked by thapsigargin but not by EGTA. Pharmacological approach using inhibitors specific for either MAPK/ERK phosphorylation or calcium release demonstrated that the two pathways converged downstream at a common point involving activation of the immediate early gene Egr-1. Chromatin immunoprecipitation assays demonstrated the binding of Egr-1, but not Egr-3, to the Arc promoter. These findings for the first time, thus, suggest an additional role of PDGF, that of induction of Arc.

show abstract

“…Glutamate uptake determination was performed according to the procedure as described (Yao et al, 2005 (190 nM, final concentration) to reaction flasks covered with astrocytes, and incubated for 15 min at 371C in 24-well plates. Nonspecific uptake was determined from samples incubated in the presence of the Na + -free buffer, and these values were subtracted from the total.…”

Section: Assays Of Glutamate Uptakementioning

confidence: 99%

KATP Channel Openers Facilitate Glutamate Uptake by GluTs in Rat Primary Cultured Astrocytes

Sun

Zeng

Zhou

et al. 2007

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Increasing evidence, including from our laboratory, has revealed that opening of ATP sensitive potassium channels (K ATP channels) plays the neuronal protective roles both in vivo and in vitro. Thus K ATP channel openers (KCOs) have been proposed as potential neuroprotectants. Our previous studies demonstrated that K ATP channels could regulate glutamate uptake activity in PC12 cells as well as in synaptosomes of rats. Since glutamate transporters (GluTs) of astrocytes play crucial roles in glutamate uptake and K ATP channels are also expressed in astrocytes, the present study showed whether and how K ATP channels regulated the function of GluTs in primary cultured astrocytes. The results showed that nonselective KCO pinacidil, selective mitochondrial KCO diazoxide, novel, and blood-brain barrier permeable KCO iptakalim could enhance glutamate uptake, except for the sarcolemmal KCO P1075. Moreover pinacidil, diazoxide, and iptakalim reversed the inhibition of glutamate uptake induced by 1-methyl-4-phenylpyridinium (MPP + ). These potentiated effects were completely abolished by mitochondrial K ATP blocker 5-hydroxydecanoate. Furthermore, either diazoxide or iptakalim could inhibit MPP + -induced elevation of reactive oxygen species (ROS) and phosphorylation of protein kinases C (PKC). These findings are the first to demonstrate that activation of K ATP channel, especially mitochondrial K ATP channel, improves the function of GluTs in astrocytes due to reducing ROS production and downregulating PKC phosphorylation. Therefore, the present study not only reveals a novel pharmacological profile of KCOs as regulators of GluTs, but also provides a new strategy for neuroprotection.

show abstract

Enhancement of glutamate uptake mediates the neuroprotection exerted by activating group II or III metabotropic glutamate receptors on astrocytes

Cited by 104 publications

References 60 publications

Selective Activation of Group III Metabotropic Glutamate Receptors by l-(+)-2-Amino-4-phosphonobutryic Acid Protects the Nigrostriatal System against 6-Hydroxydopamine Toxicity in Vivo

Selective Activation of Group III Metabotropic Glutamate Receptors by l-(+)-2-Amino-4-phosphonobutryic Acid Protects the Nigrostriatal System against 6-Hydroxydopamine Toxicity in Vivo

Platelet-derived Growth Factor-mediated Induction of the Synaptic Plasticity Gene Arc/Arg3.1

KATP Channel Openers Facilitate Glutamate Uptake by GluTs in Rat Primary Cultured Astrocytes

Contact Info

Product

Resources

About