Restoration of dietary-fat induced blood–brain barrier dysfunction by anti-inflammatory lipid-modulating agents

Pallebage-Gamarallage, Menuka; Lam, Virginie; Takechi, Ryusuke; Galloway, Susan; Clark, Karin; Mamo, John

doi:10.1186/1476-511x-11-117

Cited by 48 publications

(34 citation statements)

References 55 publications

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“…Similarly, in the meta-analysis of the discovery and replication sets, evidence of the involvement of rs10198175 in risk for BD and BE was strengthened in both the case-only and subtype analyses. APOB is a protein-coding gene for apolipoprotein B, the main component of chylomicrons and low density lipoproteins (LDL), implicated in the pathogenesis of atherosclerosis (Park et al, 2011), cardiovascular disease (Willer et al, 2008), cerebral β-amyloidosis, cognitive decline (Ramirez et al, 2011) and blood–brain barrier disruption (Pallebage-Gamarallage et al, 2012). Individual reports have implicated APOB mutations with suicide and violent behavior (Ramirez et al, 2011); on the other hand, mixed evidence has emerged, regarding a possible role in the interaction between depressive symptoms and atherogenic metabolic profiles (Hummel et al, 2011); yet its brain functional role is not completely understood (Elliott et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Winham

Cuellar-Barboza

McElroy

et al. 2014

Journal of Affective Disorders

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Background Bipolar disorder (BD) is a highly heritable disease. While genome-wide association (GWA) studies have identified several genetic risk factors for BD, few of these studies have investigated the genetic etiology of specific disease subtypes. In particular, BD is positively associated with eating dysregulation traits such as binge eating behavior (BE), yet the genetic risk factors underlying BD with comorbid BE have not been investigated. Methods Utilizing data from the Genetic Association Information Network study of BD, which included 729,454 single nucleotide polymorphisms (SNPs) genotyped in 1001 European American bipolar cases and 1034 controls, we performed GWA analyses of bipolar subtypes defined by the presence or absence of BE history, and performed a case-only analysis comparing BD subjects with and without BE history. Association signals were refined using imputation, and network analysis was performed with Ingenuity Pathway Analysis software. Based on these results, candidate SNPs were selected for replication in an independent sample of 855 cases and 857 controls. Results Top ranking SNPs in the discovery set included rs6006893 in PRR5, rs17045162 in ANK2, rs13233490 near PER4, rs4665788 and rs10198175 downstream of APOB, rs2367911 in CACNA2D1, and rs7249968 near ZNF536. Rs10198175 in APOB also demonstrated evidence of association in the replication sample and a meta-analysis of the two samples. Limitations Without information of BE history in controls, it is not possible to determine whether the observed association with APOB reflects a risk factor for BE behavior in general or a risk factor for a subtype of BD with BE. Further longitudinal and functional studies are needed to determine the causal pathways underlying the observed associations. Conclusions This study identified new potential BD-susceptibility genes, highlighting the advantages of phenotypic sub-classification in genetic research and clinical practice.

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Section: Discussionmentioning

confidence: 99%

Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Winham

Cuellar-Barboza

McElroy

et al. 2014

Journal of Affective Disorders

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“…This might happen after chronic ingestion of dietary fat with a high content of saturated fatty acids. 37 In addition, PUFA, such as arachidonic acid, can enhance oxidative stress in endothelial cells and, thereby initiate the dysfunction of the BBB. 38 …”

Section: Blood-brain Barrier Permeability and Uptake Of Fatty Acidsmentioning

confidence: 99%

Why does Brain Metabolism not Favor Burning of Fatty Acids to Provide Energy? - Reflections on Disadvantages of the Use of Free Fatty Acids as Fuel for Brain

Schönfeld

Reiser

2013

J Cereb Blood Flow Metab

370

310

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It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to b-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) b-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the b-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. Keywords: ATP generation; fatty acid; mitochondria; neural cells; oxidative stress Journal of Cerebral Blood BRAIN ENERGY METABOLISM AT A GLANCEThe minor utilization of the energy-rich long-chain fatty acids in brain energy metabolism has not been well understood. Interestingly, other organs with high energy turnover, such as the heart and kidney, largely oxidize fatty acids. The low fatty acid oxidation in the brain might be explained in terms of (i) a slow passage of fatty acids across the blood-brain barrier (BBB), (ii) a low enzymatic capacity for the fatty acid degradation and, (iii) detrimental side effects of long-chain fatty acids in the nonesterified or activated form on the mitochondrial ATP synthesis and/or on the equilibrium between the generation and the disposal of reactive oxygen species (ROS). Before going into the detailed analysis, a brief summary of the brain energy metabolism will be given.The high ATP demand in the brain tissue is impressively illustrated by the following numbers: the human brain accounts for B2% of the body mass, but consumes 20% of the total oxygen consumed by the whole body. Among the neural cells, neurons demand for most of the energy, whereas the energy consumption of astrocytes contributes to only B5% to 15% of the total energy requirement of the brain. This fact, together with the analysis of metabolites profiles supports the view that the energy metabolism of neurons is mainly aerobic and that of astrocytes mainly anaerobic glycolysis. Moreover, the largest portion of the ATP turnover occurs in the gray matter of the brain, which has a high density of excitatory glutamatergic synapses.1,2 For the rodent brain, it has been estimated that B80% of ...

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“…In line with the latter, an in vitro study using human cerebral microvascular endothelial cells showed that simvastatin and lovastatin attenuated Aβ-induced BBB dysfunction [85]. Moreover, in a mouse model of dietary- induced BBB dysfunction, we demonstrated that atorvastatin and pravastatin reversed the disruption of BBB integrity [86]. Interestingly, all studies indicated here reported the BBB protective effects of statins independent of their lipid-lowering effects but rather occurred concomitant with attenuated oxidative stress, suggesting its cerebrovascular protective action through anti-oxidative pathways.…”

Section: Antioxidants Cognitive Decline and Blood-brain Barriermentioning

confidence: 64%

Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective

2016

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A number of natural and chemical compounds that exert anti-oxidative properties are demonstrated to be beneficial for brain and cognitive function, and some are reported to reduce the risk of dementia. However, the detailed mechanisms by which those anti-oxidative compounds show positive effects on cognition and dementia are still unclear. An emerging body of evidence suggests that the integrity of the cerebrovascular blood-brain barrier (BBB) is centrally involved in the onset and progression of cognitive impairment and dementia. While recent studies revealed that some anti-oxidative agents appear to be protective against the disruption of BBB integrity and structure, few studies considered the neuroprotective effects of antioxidants in the context of cerebrovascular integrity. Therefore, in this review, we examine the mechanistic insights of antioxidants as a pleiotropic agent for cognitive impairment and dementia through a cerebrovascular axis by primarily focusing on the current available data from physiological studies. Conclusively, there is a compelling body of evidence that suggest antioxidants may prevent cognitive decline and dementia by protecting the integrity and function of BBB and, indeed, further studies are needed to directly examine these effects in addition to underlying molecular mechanisms.

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Restoration of dietary-fat induced blood–brain barrier dysfunction by anti-inflammatory lipid-modulating agents

Cited by 48 publications

References 55 publications

Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Why does Brain Metabolism not Favor Burning of Fatty Acids to Provide Energy? - Reflections on Disadvantages of the Use of Free Fatty Acids as Fuel for Brain

Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective

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