Suppression of Glutamate Carboxypeptidase II Ameliorates Neuronal Apoptosis from Ischemic Brain Injury

Zhang, Weiqiao; Zhang, Zhijie; Wu, Liping; Qiu, Yongming; Lin, Yingying

doi:10.1016/j.jstrokecerebrovasdis.2015.10.035

Cited by 14 publications

(14 citation statements)

References 17 publications

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“…In our experiments, a significant decrease in HI enhanced Bax, and an increase in Bcl-2 expression was observed after agonist application at both time points before HI. A similar effect was observed in GCPII knockout mice subjected to traumatic brain injury [43] and in the rat model of ischemia/reperfusion when GCPII was inhibited by injection of Id2-siRNA one day before MCAO [42]. The only report on the effect of LY379268 on Bax concentration concerns cultured rat astrocytes subjected to NO exposure.…”

Section: Discussionsupporting

confidence: 52%

“…The direct antiapoptotic effect of NAAG was observed in glucose-induced cell death [41]. The antiapoptotic effect of increasing NAAG concentration by inhibiting glutamate carboxypeptidase (GCPII), the enzyme that mediates the hydrolysis of NAAG into glutamate and N-acetyl-aspartate, was also previously observed in the ischemia/reperfusion model in adult rats [42].…”

Section: Discussionmentioning

confidence: 77%

“…The effect of NAAG on HI-increased caspase-9 and caspase-3 is less questionable, as a decrease in the activity of these enzymes was reported in a rat model of focal ischemia [38] and glucose-induced neuronal death [41]. Increasing NAAG levels by inhibiting GCPII activity 1 day before ischemia in rats also resulted in decreased caspase-9 and caspase-3 activity [42]; moreover, an increase in cleaved caspase-3 level in a mouse model of traumatic brain injury was attenuated in the GCPII knockout mice [43].…”

Section: Discussionmentioning

confidence: 98%

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Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia‐Ischemia in Neonatal Rat Brains

Bratek-Gerej

Bronisz

Ziembowicz

et al. 2021

Oxidative Medicine and Cellular Longevity

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Hypoxia-ischemia (HI) in an immature brain results in energy depletion and excessive glutamate release resulting in excitotoxicity and oxidative stress. An increase in reactive oxygen species (ROS) production induces apoptotic processes resulting in neuronal death. Activation of group II mGluR was shown to prevent neuronal damage after HI. The application of agonists of mGluR3 (N-acetylaspartylglutamate; NAAG) or mGluR2 (LY379268) inhibits the release of glutamate and reduces neurodegeneration in a neonatal rat model of HI, although the exact mechanism is not fully recognized. In the present study, the effects of NAAG (5 mg/kg) and LY379268 (5 mg/kg) application (24 h or 1 h before experimental birth asphyxia) on apoptotic processes as the potential mechanism of neuroprotection in 7-day-old rats were investigated. Intraperitoneal application of NAAG or LY379268 at either time point before HI significantly reduced the number of TUNEL-positive cells in the CA1 region of the ischemic brain hemisphere. Both agonists reduced expression of the proapoptotic Bax protein and increased expression of Bcl-2. Decreases in HI-induced caspase-9 and caspase-3 activity were also observed. Application of NAAG or LY379268 24 h or 1 h before HI reduced HIF-1α formation likely by reducing ROS levels. It was shown that LY379268 concentration remains at a level that is required for activation of mGluR2 for up to 24 h; however, NAAG is quickly metabolized by glutamate carboxypeptidase II (GCPII) into glutamate and N-acetyl-aspartate. The observed effect of LY379268 application 24 h or 1 h before HI is connected with direct activation of mGluR2 and inhibition of glutamate release. Based on the data presented in this study and on our previous findings, we conclude that the neuroprotective effect of NAAG applied 1 h before HI is most likely the result of a combination of mGluR3 and NMDA receptor activation, whereas the beneficial effects of NAAG pretreatment 24 h before HI can be explained by the activation of NMDA receptors and induction of the antioxidative/antiapoptotic defense system triggered by mild excitotoxicity in neurons. This response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 98%

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Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia‐Ischemia in Neonatal Rat Brains

Bratek-Gerej

Bronisz

Ziembowicz

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Despite the apparent variation in postischemic GCPII levels, the neuroprotective effect of increasing NAAG through either decreased degradation or increased synthesis is less controversial. In the CoCl 2 in vitro model of ischemia, GCPII knock-down was protective against neuronal apoptosis [81]. This antiapoptotic effect could be replicated in the rat MCAO model in vivo, where a local injection of small-interfering RNA (siRNA) for GCPII resulted in a lower number of apoptotic cells in the penumbra area.…”

Section: Naag In Strokementioning

confidence: 85%

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

Morland

Nordengen

2022

IJMS

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N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels.

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“…Increased inflammation may also increase GCPII uptake into neurons. For example, GCPII labeling of neurons was increased in both cell cultures exposed to hypoxia, and in rat cortical neurons following ischemic injury ( Zhang W. et al, 2016 ). Thus, neuronal GCPII labeling may be related to the degree of exposure to inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance

Datta

Leslie

Woo

et al. 2021

Front. Aging Neurosci.

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Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation.

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Suppression of Glutamate Carboxypeptidase II Ameliorates Neuronal Apoptosis from Ischemic Brain Injury

Abstract: Our results highlighted the roles of GCPII in the ischemia brain injury, and might provide an important target in therapeutic implications.

Cited by 14 publications

References 17 publications

Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia‐Ischemia in Neonatal Rat Brains

Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia‐Ischemia in Neonatal Rat Brains

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance

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