The Experts below are selected from a list of 16152 Experts worldwide ranked by ideXlab platform
Toru Nakazawa - One of the best experts on this subject based on the ideXlab platform.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1β and TNF-α, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18–/–) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1beta and TNF-alpha, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18(-/-)) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.
Ali Hafezimoghadam - One of the best experts on this subject based on the ideXlab platform.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1β and TNF-α, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18–/–) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1beta and TNF-alpha, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18(-/-)) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.
Demaw Chuang - One of the best experts on this subject based on the ideXlab platform.
-
neuroprotective effects of the mood stabilizer lamotrigine against glutamate Excitotoxicity roles of chromatin remodelling and bcl 2 induction
The International Journal of Neuropsychopharmacology, 2013Co-Authors: Yan Leng, Emily Bame Fessler, Demaw ChuangAbstract:Lamotrigine (LTG), a phenyltriazine derivative and anti-epileptic drug, has emerged as an effective first-line treatment for bipolar mood disorder. Like the other mood stabilizers lithium and valproate, LTG also has neuroprotective properties but its exact mechanisms remain poorly defined. The present study utilized rat cerebellar granule cells (CGCs) to examine the neuroprotective effects of LTG against glutamate-induced Excitotoxicity and to investigate potential underlying mechanisms. CGCs pretreated with LTG were challenged with an excitotoxic dose of glutamate. Pretreatment caused a time- and concentration-dependent inhibition of glutamate Excitotoxicity with nearly full protection at higher doses (≥ 100 μm), as revealed by cell viability assays and morphology. LTG treatment increased levels of acetylated histone H3 and H4 as well as dose- and time-dependently enhanced B-cell lymphoma-2 (Bcl-2) mRNA and protein levels; these changes were associated with up-regulation of the histone acetylation and activity of the Bcl-2 promoter. Importantly, lentiviral-mediated Bcl-2 silencing by shRNA reduced both LTG-induced Bcl-2 mRNA up-regulation and neuroprotection against glutamate Excitotoxicity. Finally, the co-presence of a sub-effective concentration of LTG (10 μm) with lithium or valproate produced synergistic neuroprotection. Together, our results demonstrate that the neuroprotective effects of LTG against glutamate Excitotoxicity likely involve histone deacetylase inhibition and downstream up-regulation of anti-apoptotic protein Bcl-2. These underlying mechanisms may contribute to the clinical efficacy of LTG in treating bipolar disorder and warrant further investigation.
-
neuroprotective effects of lithium in cultured cells and animal models of diseases
Bipolar Disorders, 2002Co-Authors: Demaw Chuang, Renwu Chen, Elzbieta Chaleckafranaszek, Ming Ren, Ryota Hashimoto, Vladimir V Senatorov, Hirohiko Kanai, Christopher J Hough, Toyoko HiroiAbstract:Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate Excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which Excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
-
lithium protection against glutamate Excitotoxicity in rat cerebral cortical neurons involvement of nmda receptor inhibition possibly by decreasing nr2b tyrosine phosphorylation
Journal of Neurochemistry, 2002Co-Authors: Ryota Hashimoto, Christopher J Hough, Takanobu Nakazawa, Tadashi Yamamoto, Demaw ChuangAbstract:The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects of lithium against Excitotoxicity in cultured cerebral cortical neurons. Glutamate-induced Excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre-treatment of cortical neurons with LiCl time-dependently suppressed Excitotoxicity with maximal protection after 6 days of pre-treatment. Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2–1.6 mm LiCl with almost complete protection at 1 mm. Neuroprotection was␣also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition␣of␣NMDA receptor-mediated calcium influx. Lithium pre-treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and Excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against Excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar patients.
-
lithium activates the serine threonine kinase akt 1 and suppresses glutamate induced inhibition of akt 1 activity in neurons
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Elzbieta Chaleckafranaszek, Demaw ChuangAbstract:This report describes a modulatory action of lithium and glutamate on the activity of serine/threonine kinase Akt-1. Lithium is most commonly used to treat bipolar disorder, but the mechanism of its therapeutic action remains unknown. We have recently demonstrated that lithium protects against glutamate-induced Excitotoxicity in cultured brain neurons and in an animal model of cerebral ischemia. This study was undertaken to investigate the role of Akt-1, activated by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating glutamate Excitotoxicity and lithium protection in cerebellar granule cells. High levels of phosphorylation and activity of Akt-1 were detected in cerebellar neurons cultured in the presence of serum. Protracted treatment with selective PI 3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced neuronal death that could be reduced by long-term lithium pretreatment. Exposure of cells to glutamate induced a rapid and reversible loss of Akt-1 phosphorylation and kinase activity. These effects were closely correlated with Excitotoxicity and caspase 3 activation and were prevented by phosphatase inhibitors, okadaic acid and caliculin A. Long-term lithium pretreatment suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery toward the control levels. Lithium treatment alone induced rapid increase in PI 3-K activity, and Akt-1 phosphorylation with accompanying kinase activation, which was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt. Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of glutamate Excitotoxicity and lithium neuroprotection.
Daryl A Bosco - One of the best experts on this subject based on the ideXlab platform.
-
the rna binding protein fus tls undergoes calcium mediated nuclear egress during excitotoxic stress and is required for gria2 mrna processing
Journal of Biological Chemistry, 2019Co-Authors: Maeve Tischbein, Desiree M Baron, Yenchen Lin, Katherine V Gall, John Landers, Claudia Fallini, Daryl A BoscoAbstract:Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between Excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that Excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by Excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely Excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.
-
fus tls undergoes calcium mediated nuclear egress during excitotoxic stress and is required for gria2 mrna processing
bioRxiv, 2018Co-Authors: Maeve Tischbein, Desiree M Baron, Yenchen Lin, Katherine V Gall, John Landers, Claudia Fallini, Daryl A BoscoAbstract:Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between Excitotoxicity, RBP function and pathology have not been explored. Here, we found that Excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by Excitotoxicity include TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS translocation occurs through a calcium-dependent mechanism and coincides with striking alterations in nucleocytoplasmic transport. Further, glutamate-induced upregulation of Gria2 in neurons was dependent on FUS expression, consistent with a functional role for FUS under excitotoxic stress. These findings reveal a link between prominent factors in neurodegenerative disease, namely Excitotoxicity, disease-associated RBPs and nucleocytoplasmic transport.
Kazuaki Nishijima - One of the best experts on this subject based on the ideXlab platform.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1β and TNF-α, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18–/–) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.
-
pitavastatin prevents nmda induced retinal ganglion cell death by suppressing leukocyte recruitment
Journal of Neurochemistry, 2007Co-Authors: Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali HafezimoghadamAbstract:Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1beta and TNF-alpha, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18(-/-)) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced Excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against Excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in Excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.