Phospholipases A2 and Inflammatory Responses in the Central Nervous System

Sun, Grace Y.; Shelat, Phullara B.; Jensen, Marina Bergen; He, Yan; Sun, Albert Y.; Simonyi, Ágnes

doi:10.1007/s12017-009-8092-z

Cited by 180 publications

(126 citation statements)

References 165 publications

(196 reference statements)

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…glutamate excitotoxicity) can exacerbate inflammatory processes and oxidative stress. In turn, these can promote neurological disorders such as Alzheimer's disease, Parkinson's disease, and traumatic brain injuries [68]. In glioblastoma cells, cPLA2a activity is likely to be upregulated in response to chemotherapeutic intervention, allowing cancer cells to stock up in energy and adapt their metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Zhang

Cui

Amiri

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

a b s t r a c tIncreased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Zhang

Cui

Amiri

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

show abstract

“…In particular, phospholipase A2 (PLA2) may play a key role in brain inflammation and thus neurodegeneration [90]. CBD has been reported to act upon Naja naja venom PLA2, while it has no effect on N-acylphosphatidyl-ethanolamines-hydrolyzing phospholipase D, monoacylglycerol lipase, or diacylglycerol lipase-α ( Table 2).…”

Section: Effect Of Cbd On Phospholipasesmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

447

323

View full text Add to dashboard Cite

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

show abstract

“…Neuronal cells express at least 2 types of phospholipases A 2 : (1) the calcium-independent membrane-associated enzyme (iPLA 2 ) that is thought to be involved in the metabolism of docosahexaenoic acid, the major n-3 long-chain polyunsaturated fatty acid in the brain; and (2) the calciumdependent cytosolic enzyme (cPLA 2 ) that displays a strong selectivity for the AA-containing phospholipids (for review, see Sun et al, 2010). This latter 85-kDa enzyme, which is also referred to as GIVA-PLA 2 (Schaloske and Dennis, 2006), is activated and translocated to membranes after calcium influx and phosphorylation by mitogen-activated protein (MAP) kinases or other kinases (Clark et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

View full text Add to dashboard Cite

Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

show abstract

Phospholipases A2 and Inflammatory Responses in the Central Nervous System

Cited by 180 publications

References 165 publications

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Molecular Targets of Cannabidiol in Neurological Disorders

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Contact Info

Product

Resources

About