Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders

Blanchard, H.; Taha, Ameer Y.; Rapoport, Stanley I.; Yuan, Zhi-Xin

doi:10.1016/j.plefa.2015.01.002

Cited by 21 publications

(20 citation statements)

References 63 publications

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“…Viral infections including HIV-1 usually elevate oxidative stress, which is known to promote HIV-related disease progression [41–43]. Therefore, we determined the relative levels of plasma ROS in HIV-1 Tg rats and WT.…”

Section: Resultsmentioning

confidence: 99%

“…Consistently, significantly smaller body weights were observed in HIV-1 Tg rats than the aged- and gender-matched WT (Figure A in S1 File), possibly suggesting reduced food intake and/or abnormal energy production and utilization. In addition, HIV-1 Tg rats show signs of significant behavioral and cognitive deficits when they become 5-month old [36, 37], while they are known to have increased nitroxidative stress and more susceptible to barrier dysfunction and neuronal damage [41–43, 67]. Despite many reports, the underlying molecular mechanisms for various pathological conditions are poorly understood except for general descriptions about increased inflammation, oxidative stress and the cognitive and behavioral deficits observed in 5-month old HIV-1 Tg rats compared to the corresponding control WT [36, 37].…”

Section: Discussionmentioning

confidence: 99%

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Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats

2017

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The underlying mechanisms for increased neurodegeneration and neurocognitive deficits in HIV-infected people are unclear. Therefore, this study was aimed to investigate the mechanisms of increased neurodegeneration in 5-month old male HIV-1 Transgenic (Tg) rats compared to the age- and gender-matched wild-type (WT) by evaluating histological changes and biochemical parameters of the key proteins involved in the cell death signaling and apoptosis. Histological and immunohistochemical analyses revealed decreased neuronal cells with elevated astrogliosis in HIV-1 Tg rats compared to WT. Mechanistic studies revealed that increased levels of nitroxidative stress marker proteins such as NADPH-oxidase, cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase (iNOS), the stress-activated mitogen-activated protein kinases such as JNK and p38K, activated cell-cycle dependent CDK5, hypoxia-inducible protein-1α, nitrated proteins, hyperphosphorylated tau, and amyloid plaques in HIV-Tg rats were consistently observed in HIV-1 Tg rats. Confocal microscopy and cell viability analyses showed that treatment with an antioxidant N-acetylcysteine or a specific inhibitor of iNOS 1400W significantly prevented the increased apoptosis of neuro-2A cells by HIV-1 Tat or gp120 protein, demonstrating the causal role of HIV-1 mediated nitroxidative stress and protein nitration in promoting neuronal cell death. Immunoprecipitation and immunoblot analysis confirmed nitration of Hsp90, evaluated as an example of nitrated proteins, suggesting possible involvement of nitrated proteins in neuronal damage. Further, activated p-JNK directly binds tau and phosphorylates multiple amino acids, suggesting an important role of p-JNK in tau hyperphosphorylation and tauopathy. These changes were accompanied with elevated levels of many apoptosis-related proteins Bax and cleaved (activated) caspase-3 as well as proinflammatory cytokines including TNF-α, IL-6 and MCP-1. Collectively, these results indicate that raised nitroxidative stress accompanied by elevated inflammation, cell death signaling pathway including activated p-JNK, C-terminal C99 amyloid fragment formation and tau hyperphosphorylation are responsible for increased apoptosis of neuronal cells and neurodegeneration in 5-month old HIV-Tg rats.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats

2017

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“…Within the brain microvasculature, PGE 2 promotes increased permeability and reduced BBB integrity [7,8]. The effects of increased PGE 2 within the brain are associated with a number of pathologies, including pyretic response to bacterial infection [26], HIV-and Alzheimer's disease-related microglial response and cognitive deficits [27,28], neurotoxicity in stroke and traumatic brain injury [29]. While PGE 2 is considered mostly detrimental to normal central nervous system (CNS) function it should be noted that some studies propose an anti-inflammatory role for PGE 2 in select cells within the brain [30].…”

Section: Fatty Acidmentioning

confidence: 99%

Generation of Bioactive Oxylipins from Exogenously Added Arachidonic, Eicosapentaenoic and Docosahexaenoic Acid in Primary Human Brain Microvessel Endothelial Cells

Aukema

Winter

Ravandi

et al. 2015

Lipids

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The human blood-brain barrier (BBB) is the restrictive barrier between the brain parenchyma and the circulating blood and is formed in part by microvessel endothelial cells. The brain contains significant amounts of arachidonic acid (ARA), and docosahexaenoic acid (DHA), which potentially give rise to the generation of bioactive oxylipins. Oxylipins are oxygenated fatty acid metabolites that are involved in an assortment of biological functions regulating neurological health and disease. Since it is not known which oxylipins are generated by human brain microvessel endothelial cells (HBMECs), they were incubated for up to 30 min in the absence or presence of 0.1-mM ARA, eicosapentaenoic acid (EPA) or DHA bound to albumin (1:1 molar ratio), and the oxylipins generated were examined using high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). Of 135 oxylipins screened in the media, 63 were present at >0.1 ng/mL at baseline, and 95 were present after incubation with fatty acid. Oxylipins were rapidly generated and reached maximum levels by 2-5 min. While ARA, EPA and DHA each stimulated the production of oxylipins derived from these fatty acids themselves, ARA also stimulated the production of oxylipins from endogenous 18- and 20-carbon fatty acids, including α-linolenic acid. Oxylipins generated by the lipoxygenase pathway predominated both in resting and stimulated states. Oxylipins formed via the cytochrome P450 pathway were formed primarily from DHA and EPA, but not ARA. These data indicate that HBMECs are capable of generating a plethora of bioactive lipids that have the potential to modulate BBB endothelial cell function.

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“…PUFA-derived oxylipins are synthesized via lipoxygenase (LOX) 14–16 , cyclooxygenase (COX) 15, 17, 18 , cytochrome P450 (CYP450) 19–21 or soluble epoxide hydrolase (sEH) enzymes 6, 22 following phospholipase-mediated release of fatty acids from brain membrane phospholipids 23, 24 . Oxylipin synthesis can also occur non-enzymatically 25–27 .…”

Section: Introductionmentioning

confidence: 99%

Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission

Hennebelle

Zhang

Metherel

et al. 2017

Sci Rep

Self Cite

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Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke.

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Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders

Cited by 21 publications

References 63 publications

Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats

Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats

Generation of Bioactive Oxylipins from Exogenously Added Arachidonic, Eicosapentaenoic and Docosahexaenoic Acid in Primary Human Brain Microvessel Endothelial Cells

Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission

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