Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

Vana, Adam C.; Li, Shihe; Ribeiro, Rachel Bittencourt; Tchantchou, Flaubert

doi:10.1016/j.expneurol.2011.05.014

Cited by 20 publications

(16 citation statements)

References 57 publications

(85 reference statements)

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“…A recent study has shown that ALCAM is expressed in human and mouse CNS microvascular endothelium and is involved in lymphocytes and macrophage infiltration across BBB (Cayrol et al, 2008). Similar to our previous findings (Vana et al, 2011), we found that in the EAE mouse spinal cord white matter, the increased expression of ALCAM was not only observed in the endothelial cells but also in regions with inflammatory cells infiltration (Fig. 6A).…”

Section: The Increased Expression Of Activated Leukocyte Cell Adhesiosupporting

confidence: 90%

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

et al. 2015

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Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system. Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Post-symptom treatment with an ABHD6 inhibitor WWL70 increased the brain levels of 2-AG and ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules. The production of iNOS, COX-2, TNF-α and IL-1β and the phosphorylation of NF-κB were also significantly reduced by WWL70 treatment. The neuroprotective effect of WWL70 was demonstrated by increased survival of mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. The therapeutic effect of WWL70 on EAE was absent by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not afford any protection in CB2 receptor knockout mice after EAE induction. Given the increased expression of ABHD6 in microglia/macrophages, but not in T cells, we speculated that inhibition of ABHD6 might enhance 2-AG signaling particularly in microglia/macrophages to exert anti-inflammatory effects via activation of CB2 receptors. These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.

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Section: The Increased Expression Of Activated Leukocyte Cell Adhesiosupporting

confidence: 90%

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

et al. 2015

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“…Therefore, it is reasonable to consider that cPLA 2 inhibition plays an important role in preventing neurotoxicity to SH-SY5Y cells by activated microglia. These results are in agreement with other studies demonstrating the protective effects of AACOCF3 in animal models of neurological diseases, including experimental stroke (Zhang et al 2012), experimental autoimmune encephalitis for multiple sclerosis (Vana et al 2011), as well as spinal cord injury (Huang et al 2009;Liu et al 2014).…”

Section: Discussionsupporting

confidence: 93%

Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2

et al. 2016

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Microglia play a significant role in the generation and propagation of oxidative/nitrosative stress, and are the basis of neuroinflammatory responses in the central nervous system. Upon stimulation by endotoxins such as lipopolysaccharides (LPS), these cells release pro-inflammatory factors which can exert harmful effects on surrounding neurons, leading to secondary neuronal damage and cell death. Our previous studies demonstrated the effects of botanical polyphenols to mitigate inflammatory responses induced by LPS, and highlighted an important role for cytosolic phospholipase A2 (cPLA2) upstream of the pro-inflammatory pathways (Chuang et al. in J Neuroinflammation 12(1):199, 2015. doi: 10.1186/s12974-015-0419-0 ). In this study, we investigate the action of botanical compounds and assess whether suppression of cPLA2 in microglia is involved in the neurotoxic effects on neurons. Differentiated SH-SY5Y neuroblastoma cells were used to test the neurotoxicity of conditioned medium from stimulated microglial cells, and WST-1 assay was used to assess for the cell viability of SH-SY5Y cells. Botanicals such as quercetin and honokiol (but not cyanidin-3-O-glucoside, 3CG) were effective in inhibiting LPS-induced nitric oxide (NO) production and phosphorylation of cPLA2. Conditioned medium from BV-2 cells stimulated with LPS or IFNγ caused neurotoxicity to SH-SY5Y cells. Decrease in cell viability could be ameliorated by pharmacological inhibitors for cPLA2 as well as by down-regulating cPLA2 with siRNA. Botanicals effective in inhibition of LPS-induced NO and cPLA2 phosphorylation were also effective in ameliorating microglial-induced neurotoxicity. Results demonstrated cytotoxic factors from activated microglial cells to cause damaging effects to neurons and potential use of botanical polyphenols to ameliorate the neurotoxic effects.

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“…8A). As demonstrated previously, the number of CC1-positive cells in the spinal cord white matter is significantly reduced in EAE animals when compared to controls Vana et al, 2011). As anticipated, CB52 is effective in preventing the loss of these cells in the spinal cord white matter when given before (Fig.…”

Section: Cb52 Prevents Oligodendrocyte Cell Loss and Demyelination Insupporting

confidence: 79%

“…EAE was induced in 7-week-old female C57BL/6 mice (Jackson Labs, Bar Harbor, ME, USA) as we previously described Vana et al, 2011 …”

Section: Induction Of Eaementioning

confidence: 99%

Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis

Ribeiro

Wen

et al. 2013

Neuroscience

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Abstract-Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by the activation of the cannabinoid type 1 (CB1) and type 2 (CB2) receptors expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable. Although CB1 and CB2 receptors are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia. Interestingly, we found that CB52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB52 is likely due to its reduction of ERK1/2 phosphorylation and reactive oxygen species (ROS) generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset. These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that the activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS. Published by Elsevier Ltd. on behalf of IBRO.

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Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

Cited by 20 publications

References 57 publications

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2

Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis

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