Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-Dependent Mechanism

Jiang, Qian; Yan, Zhen; Feng, Jian

doi:10.1523/jneurosci.0118-06.2006

Cited by 45 publications

(34 citation statements)

References 38 publications

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“…These data are consistent with previous reports of a neuroprotective action of L-AP4 against glutamate-mediated toxicity both in vitro and in vivo (Lafon-Cazal et al, 1999a;Bruno et al, 2000) and very recent data reported by Jiang et al (2006), who demonstrated that L-AP4 is neuroprotective against rotenone toxicity in vitro, providing evidence for a neuroprotective effect of selective Group III mGluR activation in an experimental model of PD. To our knowledge, the current study is the first to document such an action for L-AP4 in an experimental model of PD in vivo.…”

Section: Discussionsupporting

confidence: 93%

“…In support of this, selective activation of Group III mGluR has been reported to attenuate excitatory amino acid-mediated excitotoxic neuronal death both in vitro and in vivo (LafonCazal et al, 1999b;Bruno et al, 2000). Furthermore, L-(ϩ)-2-amino-4-phosphonobutyric acid (L-AP4) has been reported recently to be neuroprotective in vitro against the pesticide toxin rotenone, which has been strongly implicated in the pathogenesis of PD (Jiang et al, 2006). We have reported previously preliminary data suggesting that L-AP4 is neuroprotective against 6-hydroxydopamine (6-OHDA) toxicity in vivo (Vernon et al, 2005).…”

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confidence: 97%

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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. 2007

The Journal of Pharmacology and Experimental Therapeutics

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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

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 97%

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. 2007

The Journal of Pharmacology and Experimental Therapeutics

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“…It has been shown that rotenone, a commonly used inhibitor of complex I, interferes with CD8 ϩ T-cell function (70) and activation-induced CD95L expression (7). Nevertheless, rotenone inhibits, in addition, spindle microtubule formation and tubulin assembly, leading to cell cycle arrest, disassembly of the Golgi apparatus, disturbance of the cytoskeleton, and tubulin-dependent cell-signaling events (4,5,8,16,32,44,52). Therefore, it is likely that rotenone interferes with formation of the immunological synapse and movement of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Complex I was blocked by rotenone, a commonly used inhibitor. However, rotenone is also known to interfere with a couple of cellular pathways, including tubulindependent signaling events (8,16,32,52). Thus, we also used a second, more specific inhibitor, piericidin A (13, 28).…”

Section: Tcr-induced Ros Generation Depends On the Proximal Tcr Signamentioning

confidence: 99%

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Kamiński

Kießling

Süss

et al. 2007

Molecular and Cellular Biology

124

153

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Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domaincontaining leukocyte protein of 76 kDa), PLC␥1 (phospholipase C␥1), and PKC (protein kinase C), are crucial for ROS production. PKC is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKC-dependent ROS generation by mitochondrial complex I is essential for AICD.Because CD95L expression is crucial for the induction of activation-induced T-cell death (AICD), efforts have been made to explore the connection between T-cell receptor (TCR) signaling and regulation of CD95L transcription. Following TCR engagement, ZAP70 (zeta chain-associated protein kinase 70) is activated (11). ZAP70 phosphorylates the adaptor protein LAT (linker of activated T cells) (19), which recruits PLC␥1 (phospholipase C␥1) subsequently. The activation of PLC␥1 results in the generation of inositol 3,4,5-triphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 mediates an increase in cytosolic calcium (Ca 2ϩ ), whereas DAG activates protein kinase C (PKC). The rise in cytosolic Ca 2ϩ causes activation of the transcription factor NF-AT (nuclear factor of activated T cells) (69), one of the key regulators of CD95L expression (41). In addition, reactive oxygen species (ROS) are shown to be crucial for activation-induced CD95L expression (7,15,25), possibly via the ROS-inducible transcription factors NF-B and AP-1 (17). Recently, we demonstrated that a hydrogen peroxide (H 2 O 2 )-mediated signal combined with simultaneous Ca 2ϩ influx into the cytosol constitutes the minimal requirement for CD95L expression (25). However, the molecular source of TCR-induced ROS remains largely unclear. Aerobic organisms produce ROS by several means: in mitochondria as a by-product of respiration (63), at the endoplasmic reticulum by cytochrome P450 (50), in the cytoplasm by xanthine oxidase (20), at the plasma membrane by NADPH oxidases (35, 46) and phospholipases (54), and in peroxisomes (56). Recently, the phagocytic NADPH oxidase (NOX2) was shown to be one source for TCR-triggered ROS. However,...

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“…al. (72) found that the mechanism for this stems from L-AP-4 (an mGluRIII agonist) stimulation of ERK that depends on dynamin, β-arrestin2, and c-Src. The β-arrestin-activated ERK stabilizes microtubules, which protects DA neurons from rotenone toxicity (72) and prevents Parkinson's-like symptoms.…”

Section: Erk: the Archetype For β-Arrestin Signalingmentioning

confidence: 99%

β-Arrestins and Cell Signaling

DeWire

Ahn

Lefkowitz

et al. 2007

Annu. Rev. Physiol.

1,282

992

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Upon their discovery, β-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows that β-arrestins can also function to activate signaling cascades independently of G protein activation. By serving as multiprotein scaffolds, the β-arrestins bring elements of specific signaling pathways into close proximity. β-Arrestin regulation has been demonstrated for an everincreasing number of signaling molecules, including the mitogenactivated protein kinases ERK, JNK, and p38 as well as Akt, PI3 kinase, and RhoA. In addition, investigators are discovering new roles for β-arrestins in nuclear functions. Here, we review the signaling capacities of these versatile adapter molecules and discuss the possible implications for cellular processes such as chemotaxis and apoptosis.

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Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-Dependent Mechanism

Cited by 45 publications

References 38 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

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

β-Arrestins and Cell Signaling

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