Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

Durand, Daniela Elizabeth; Carniglia, Lila; Caruso, Carla Mariana; Lasaga, Mercedes

doi:10.5772/19802

Cited by 4 publications

(7 citation statements)

References 138 publications

(138 reference statements)

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“… 4 The presence of metabotropic glutamate receptors (mGluRs) in peripheral tissues, including those not originating from neural crests, has been demonstrated in numerous studies. 5 mGluRs have been found in organs and tissues, such as: pancreas, liver, stomach mucosa, human testes and ovaries. 6-10 The presence of mGluRs in the liver has been demonstrated for the first time in 1997, when the mGluR competitive agonists 1-Amino-1,3-dicarboxycyclopentane (ACPD) and quisqualate were shown to induceinositol monophosphate formation in primary rat hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

Ferrigno¹,

Berardo²,

Pasqua³

et al. 2020

Eur J Histochem

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It has been previously found that the blockade of metabotropic glutamate receptor type 5 (mGluR5) protects against hepatic ischemia/reperfusion injury and acetaminophen toxicity. The role of mGluR5 in NAFLD has not yet been elucidated. Here, we evaluated the effects of mGluR5 blockade in an in vitro model of steatosis. HepG2 cells were pre-incubated for 12 h with an mGluR5 agonist, a negative allosteric modulator (DHPG and MPEP, respectively) or vehicle, then treated with 1.5 mM oleate/palmitate (O/P) for another 12 h. Cell viability was evaluated with the MTT assay; fat accumulation was measured using the fluorescent dye nile red; SREBP-1, PPAR-α, iNOS and Caspase-3 protein expression were evaluated by Western blot; NFkB activity was evaluated as pNFkB/NFkB ratio. mGluR5 modulation did not alter cell viability in O/P-incubated cells; MPEP prevented intracellular lipid accumulation in O/P treated cells; MPEP administration was also associated with a reversion of O/P-induced changes in SREBP-1 and PPAR-α expression, involved in free fatty acid (FFA) metabolism and uptake. No changes were observed in iNOS and Caspase-3 expression, or in NFkB activity. In conclusion, mGluR5 pharmacological blockade reduced fat accumulation in HepG2 cells incubated with O/P, probably by modulating the expression of SREBP-1 and PPAR-α.

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Section: Introductionmentioning

confidence: 99%

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

Ferrigno¹,

Berardo²,

Pasqua³

et al. 2020

Eur J Histochem

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“…Evidence of the presence of glutamate receptors in peripheral organs has been published in recent years and numerous studies have demonstrated the presence of mGluRs in peripheral cells, many of them not originating from neural crests [ 3 ]. mGluRs have been found in the pancreas [ 4 ], in the liver [ 5 ], in the stomach mucosa [ 6 ], in human testes [ 7 ], and in primate ovaries [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury

Ferrigno

Berardo

Pasqua

et al. 2018

IJMS

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2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions.

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“…GABAergic interneurons contain mGluR5 [ 20 ]. Inhibition of mGluR5 has been reported to induce decrease in inhibitory drive from GABAergic interneurons on HPA axis neurons [ 4 , 21 ]. This ultimately leads to activation of the stress hormone axis with increased ACTH and cortisol release [ 4 , 21 ], causing hyperarousal and insomnia [ 4 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…The exact underlying mechanism and implication of mGluR5 in the pathogenesis of these adverse effects remain to be verified. An overview of studies evaluating mGluR5 in preclinical and clinical settings is provided in the review papers of Gregory et al [1] and Durand et al [4]. …”

Section: Introductionmentioning

confidence: 99%

“…However, relevant mGluR5-NAM-related adverse effects including cognitive and memory impairments and psychotomimetic effects have also been reported [ 1 , 3 ].The exact underlying mechanism and implication of mGluR5 in the pathogenesis of these adverse effects remain to be verified. An overview of studies evaluating mGluR5 in preclinical and clinical settings is provided in the review papers of Gregory et al [ 1 ] and Durand et al [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Metabotropic Glutamate Receptor 5 Negative Modulation in Phase I Clinical Trial: Potential Impact of Circadian Rhythm on the Neuropsychiatric Adverse Reactions—Do Hallucinations Matter?

2014

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Metabotropic Glutamate Receptor 5 (mGluR5) negative allosteric modulators (NAMs) may play a role in some psychiatric disorders such as anxiety and depression. The pharmacokinetic profile and pharmacodynamics effects of mGluR5-NAMs have been previously reported. We performed a post hoc analysis of pharmacological and clinical data obtained from 18 young healthy female subjects who received a mGluR5-NAM in the context of a phase I drug-drug interaction study between a mGluR5 NAM and a monophasic oral contraceptive. mGluR5-NAM was administered in an escalating bidaily dose level design. There was no interaction between the OC and mGluR5-NAM. Higher morning mGluR5-NAM plasma concentrations were found compared to evening concentrations. Most of the observed clinically significant neuropsychiatric adverse reactions occurred nocturnally and included visual (pseudo) hallucinations, insomnia accompanied by secondary behavioural disorders, and cognitive dysfunction symptoms of sufficient severity to interfere with daily functioning. Circadian rhythm-related physiological variations in drug absorption and disposition may explain this pharmacokinetics-pharmacodynamics apparently disproportionate relationship. We suggest that clinical trials evaluating basic pharmacokinetic properties of psychiatric medications consider potential drug's chronopharmacokinetics. This may assist with dose optimization and minimize serious neuropsychiatric adverse reactions in the vulnerable psychiatric patient.

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Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

Cited by 4 publications

References 138 publications

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury

Metabotropic Glutamate Receptor 5 Negative Modulation in Phase I Clinical Trial: Potential Impact of Circadian Rhythm on the Neuropsychiatric Adverse Reactions—Do Hallucinations Matter?

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