Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models

Kohara, Atsuyuki; Takahashi, M; Yatsugi, Shin-ichi; Tamura, Shinzo; Shitaka, Yoshitsugu; Hayashibe, S.; Kawabata, Sueo; Okada, Masamichi

doi:10.1016/j.brainres.2007.11.035

Cited by 58 publications

(35 citation statements)

References 36 publications

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“…106,107 Microglia expression of glutamate receptor subtypes in vivo has not been extensively characterized, but protein expression of mGluR1, mGLuR2/3, and mGluR8 has been reported in microglia surrounding human multiple sclerosis lesions, 113 and expression of ionotropic glutamate receptors has been detected in reactive microglia in damaged areas of the hippocampus following ischemia. 114 The acute administration of an mGluR5 agonist after experimental stroke or spinal cord injury is neuroprotective, 115,116 and an mGluR5 agonist was also shown to reduce microglial activation in the spinal cord injury study, 116 suggesting that the neuroprotective effect of these agents may be attributable to the suppression of microglial activation.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Section: Glutamate Receptorsmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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“…Many preclinical studies have demonstrated that mGluR1 antagonists were neuroprotective in brain ischemia in adult and developing animals [4,15,19,23,35]. However, contradictory data have been reported concerning the neuroprotective effects of mGluR5 antagonists.…”

Section: Introductionmentioning

confidence: 99%

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

Makarewicz

Słomka²,

Danysz³

et al. 2015

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A b s t r a c t In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.5 h after the insult. The number of apoptotic neurons in the immature rat brain was evaluated after 24 h. The wet weight of both hemispheres was determined 14 days after H-I, and its loss was used as an indicator of brain damage. In the vehicle-treated groups, H-I reduced the weight of the ipsilateral (ischemic

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“…These allosteric mGluR1 antagonists exhibit high selectivity to mGluR1, in contrast to orthosteric antagonists, which lack sufficient selectivity between mGluR1 and mGluR5 (2 -9). An increasing body of animal studies using these mGluR1-selective allosteric antagonists indicate that blockade of mGluR1 could ameliorate CNS disorders such as neuropathic pain (10 -12), stroke (13,14), epilepsy (15,16), and psychiatric diseases (17 -20). On the other hand, behavioral studies using mGluR1 knockout mice or some mGluR1 antagonists suggest that inhibition of mGluR1 might elicit adverse effects such as deficits in motor functions (9,18,21,22).…”

Section: Introductionmentioning

confidence: 99%

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

et al. 2009

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Abstract. The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [ H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.

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Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models

Cited by 58 publications

References 36 publications

Microglial Activation in Stroke: Therapeutic Targets

Microglial Activation in Stroke: Therapeutic Targets

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

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