The pharmacological manipulation of glutamate receptors and neuroprotection

Stone, T.W.; Addae, Jonas I.

doi:10.1016/s0014-2999(02)01851-4

Cited by 101 publications

(53 citation statements)

References 153 publications

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“…14) Severe stress response will release large amounts of glutamate to excessively activate NMDA receptor, and then neurons will be damaged to the death with intracellular calcium overload, finally produces neuro-toxicity. 15,16) Indoleamine 2,3-dioxygenase (IDO) widely exists in the brain endothelial cells, astrocytes and microglia cells, which is activated by inflammatory cytokines such as interleukins-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). 17,18) IDO can decompose tryptophan (TRP) into kynurenine (KYN).…”

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confidence: 99%

Prevention of Postoperative Fatigue Syndrome in Rat Model by Ginsenoside Rb1 <i>via</i> Down-Regulation of Inflammation along the NMDA Receptor Pathway in the Hippocampus

Chen

Liu

Chen

et al. 2015

Biological & Pharmaceutical Bulletin

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Postoperative fatigue syndrome (POFS) is a common complication which decelerates recovery after surgery. The present study investigated the anti-fatigue effect of ginsenoside Rb1 (GRb1) through the inflammatory cytokine-mediated N-methyl-D-aspartate (NMDA) receptor pathway. A POFS rat model was created by major small intestinal resection and assessed with an open field test. Real-time quantitative polymerase chain reaction, western blot analysis, high performance liquid chromatography and a transmission electron microscopic analysis were used to determine typical biochemical parameters in the hippocampus. Our results showed that POFS rats exhibited fatigue associated with an increased expression of inflammatory cytokines and NMDA receptor 1, higher (kynurenine)/(tryptophan) and (kynurenine)/(kynurenic acid) on postoperative days 1 and 3, and an increased expression of indoleamine 2,3-dioxygenase (IDO) on postoperative day 1. Degenerated neurons were found in the hippocampus of POFS rats. The NMDA receptor antagonist MK801 had a significant effect on central fatigue on postoperative day 1. GRb1 had no effect on IDO or tryptophan metabolism, but exhibited a significant effect on POFS by inhibiting the expression of inflammatory cytokines and NMDA receptor 1. These data suggested that inflammatory cytokines could activate tryptophan metabolism to cause POFS through the NMDA receptor pathway. GRb1 had an anti-fatigue effect on POFS by reducing inflammatory cytokines and NMDA receptors.

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confidence: 99%

Prevention of Postoperative Fatigue Syndrome in Rat Model by Ginsenoside Rb1 <i>via</i> Down-Regulation of Inflammation along the NMDA Receptor Pathway in the Hippocampus

Chen

Liu

Chen

et al. 2015

Biological & Pharmaceutical Bulletin

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“…[20][21][22] Overstimulation of NMDA receptors leads to neuronal damage. 23 Neurotoxicity of KYN and its metabolites has been demonstrated in animal studies 19,20,24 and studies using human cell cultures. 25,26 KYN is able to pass the BBB 27 and human microglia have been shown capable of metabolizing this substance into its toxic metabolites.…”

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confidence: 99%

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

et al. 2004

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Studies show that administration of interferon (IFN)-a causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-a-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-a treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-a treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-a-induced depressive symptoms, through its induction of neurotoxic KYN metabolites. Molecular Psychiatry (2005) 10, 538-544.

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“…Consequently, a mechanism capable of preventing glutamate receptors from being overly stimulated seems essential for maintaining the normal physiological condition of the brain (12,13). Brain KYNA levels are abnormal in the progression of diseases such as Huntington's disease (14 -16) and schizophrenia (17)(18)(19), which suggest that variations in brain KYNA, acting as an endogenous modulator of glutamatergic and cholinergic neurotransmission, may be functionally significant.…”

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confidence: 99%