CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathway

Huang, Chun Chih; Wu, Hao; Zhang, Honghai; Li, Ning; Yasong, Wu; Chen, Dexi

doi:10.1016/j.brainres.2008.11.088

Cited by 17 publications

(11 citation statements)

References 54 publications

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“…The balance of prosurvival and neurotoxic effects depends on the specific ligand and the activation state and proximity of surrounding glia. The EC 50 for gp120-induced synapse loss was 153 Ϯ 50 nM, in excellent agreement with previous in vitro studies (Viviani et al, 2006) and the EC 50 of 85 Ϯ 44 pM for gp120-induced cell death agreed with previous cell survival assays (Chun et al, 2009). In studies in which exogenous glutamate was applied to the culture picomolar potencies for gp120 have been reported previously (Dawson et al, 1993).…”

Section: Discussionsupporting

confidence: 90%

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Kim

Shin

Thayer³

2011

Mol Pharmacol

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HIV-1 infection of the central nervous system is associated with dendritic and synaptic damage that correlates with cognitive decline in patients with HIV-1-associated dementia (HAD). HAD is due in part to the release of viral proteins from infected cells. Because cannabinoids modulate neurotoxic and inflammatory processes, we investigated their effects on changes in synaptic connections induced by the HIV-1 envelope glycoprotein gp120. Morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). Twenty-four-hour treatment with gp120 IIIB decreased the number of PSD95-GFP puncta by 37 Ϯ 4%. The decrease was concentration-dependent (EC 50 ϭ 153 Ϯ 50 pM). Synapse loss preceded cell death as defined by retention of DsRed2 fluorescence gp120 activated CXCR4 on microglia to evoke interleukin-1␤ (IL-1␤) release. Pharmacological studies determined that sequential activation of CXCR4, the IL-1␤ receptor, and the N-methyl-D-aspartate receptor was required. Expression of alternative reading frame polypeptide, which inhibits the ubiquitin ligase murine double minute 2, protected synapses, implicating the ubiquitin-proteasome pathway. Cannabimimetic drugs are of particular relevance to HAD because of their clinical and illicit use in patients with AIDS. The cannabinoid receptor full agonist-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] (Win55,212-2) inhibited gp120-induced IL-1␤ production and synapse in a manner reversed by a cannabinoid type 2 receptor antagonist. In contrast, Win55,212-2 did not inhibit synapse loss elicited by exposure to the HIV-1 protein Tat. These results indicate that cannabinoids prevent the impairment of network function produced by gp120 and, thus, might have therapeutic potential in HAD.

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Section: Discussionsupporting

confidence: 90%

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Kim

Shin

Thayer³

2011

Mol Pharmacol

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“…In neuronal cells activation of cAMP/PKA signaling inhibited apoptosis induced by KCl in cerebella granule neurons (42) or by human immunodeficiency virus protein gp120 in the brain (43), promoting survival pathways in multiple neuronal cells (44,45); these findings are in agreement with ours (supplemental Fig. 4).…”

Section: Discussionsupporting

confidence: 82%

Differential Roles of Epac in Regulating Cell Death in Neuronal and Myocardial Cells

Suzuki

Yokoyama

Abe

et al. 2010

Journal of Biological Chemistry

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Cell survival and death play critical roles in tissues composed of post-mitotic cells. Cyclic AMP (cAMP) has been known to exert a distinct effect on cell susceptibility to apoptosis, protecting neuronal cells and deteriorating myocardial cells. These effects are primarily studied using protein kinase A activation. In this study we show the differential roles of Epac, an exchange protein activated by cAMP and a new effector molecule of cAMP signaling, in regulating apoptosis in these cell types. Both stimulation of Epac by 8-p-methoxyphenylthon-2-O-methyl-cAMP and overexpression of Epac significantly increased DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferasemediated biotin nick end-labeling)-positive cell counts in mouse cortical neurons but not in cardiac myocytes. In contrast, stimulation of protein kinase A increased apoptosis in cardiac myocytes but not in neuronal cells. In cortical neurons the expression of the Bcl-2 interacting member protein (Bim) was increased by stimulation of Epac at the transcriptional level and was decreased in mice with genetic disruption of Epac1. Epacinduced neuronal apoptosis was attenuated by the silencing of Bim. Furthermore, Epac1 disruption in vivo abolished the 3-nitropropionic acid-induced neuronal apoptosis that occurs in wild-type mice. These results suggest that Epac induces neuron-specific apoptosis through increasing Bim expression. Because the disruption of Epac exerted a protective effect on neuronal apoptosis in vivo, the inhibition of Epac may be a consideration in designing a therapeutic strategy for the treatment of neurodegenerative diseases.

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“…Indeed, our results indicate that the CaMKI and -IV inhibitor STO-609 enhanced excitotoxic death of hippocampal neurons. Such death-increasing effect of CaMKIV inhibition was also predicted by previous studies (62)(63)(64). Thus, KN93 could enhance excitotoxicity in specific situations or neuronal cell types where the toxic effect of CaMKI/IV inhibition outweighs the protective effect of CaMKII inhibition.…”

Section: Discussionsupporting

confidence: 50%

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

Vest

O’Leary

Coultrap

et al. 2010

Journal of Biological Chemistry

109

185

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Ca 2؉ /calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling involved in higher brain functions. Here, we show CaMKII involvement in pathological glutamate signaling relevant in stroke. The novel inhibitor tatCN21 was neuroprotective even when added hours after glutamate insults. By contrast, the "traditional" inhibitor KN93 attenuated excitotoxicity only when present during the insult. Both inhibitors efficiently blocked Ca 2؉ /CaM-stimulated CaMKII activity, CaMKII interaction with NR2B and aggregation of CaMKII holoenzymes. However, only tatCN21 but not KN93 blocked the Ca 2؉ -independent "autonomous" activity generated by Thr-286 autophosphorylation, the hallmark feature of CaMKII regulation. Mutational analysis further validated autonomous CaMKII activity as the drug target crucial for post-insult neuroprotection. Overexpression of CaMKII wild type but not the autonomy-deficient T286A mutant significantly increased glutamate-induced neuronal death. Maybe most importantly, tatCN21 also significantly reduced infarct size in a mouse stroke model (middle cerebral arterial occlusion) when injected (1 mg/kg intravenously) 1 h after onset of arterial occlusion. Together, these data demonstrate that inhibition of autonomous CaMKII activity provides a promising therapeutic avenue for post-insult neuro-protection after stroke.Glutamate is the most abundant excitatory neurotransmitter in the mammalian brain. However, excessive glutamate release causes Ca 2ϩ -dependent excitotoxic neuronal death in pathological situations such as focal cerebral ischemia (stroke) (for review see Refs. 1-4). Most glutamate receptors are involved in excitotoxicity, but especially important are the Ca 2ϩ -permeable ionotropic receptors such as the NMDA 4 -type glutamate receptor (NMDAR) (5-8). Extensive attempts to develop a stroke therapy by targeting glutamate receptors have resulted in disappointment (for review see Refs. 9, 10), suggesting that alternative strategies will be necessary. Currently, the only approved pharmacological treatment of stroke patients is hemolytic therapy with tissue plasminogen activator. However, less than 2% of patients actually receive tissue plasminogen activator. Although tissue plasminogen activator is effective in stroke caused by blood clots, it is actually contraindicated in hemorrhagic stroke, and diagnostic evaluation pushes most patients beyond the therapeutically effective time window (11-13).The Ca 2ϩ /calmodulin (Ca 2ϩ /CaM)-dependent protein kinase II (CaMKII) is a major physiological downstream target of glutamate-induced Ca 2ϩ signaling (for review see Refs. 14 -17) and was examined in this study for involvement in pathological excitotoxic glutamate signaling. CaMKII is highly expressed in brain where it participates in NMDAR-dependent long term potentiation and learning and memory (14 -17). CaMKII forms multimeric holoenzymes, and each kinase subunit is activated separately by Ca 2ϩ /CaM. An inter-subunit autophosphorylation at Thr-286 ...

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CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathway

Cited by 17 publications

References 54 publications

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Differential Roles of Epac in Regulating Cell Death in Neuronal and Myocardial Cells

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

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