Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans

Abstract

The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A2 (PLA2) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M1,3,5, serotonergic 5-HT2A/2C, dopaminergic D2-like (D2, D3, D4) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics.

ESI–MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts

“…From a translational standpoint, our observation raises the possibility of DHA as a predictive measure of BM-hMSC homing efficacy (17). DHA radiotracers ( 11 C) have been used recently to image DHA metabolism in the brain by positron emission tomography (PET) (67). More recently, longer-lived 18 F-fluoro tracers have been developed to measure DHA content within the brain.…”

Challenges to determining whether DHA can protect against age-related cognitive decline

“…DHA kinetics in the brain are therefore clearly different from those of the whole-body, because the latter is estimated to be 32 days in carriers of APOE4 and 140 days in noncarriers of APOE4 [93]. The study of brain DHA homeostasis using PET imaging may therefore provide some useful information on genotype-and diet-related modifications to DHA during aging [102]. Postmortem studies of brain from AD patients show a linear relationship between apoE and DHA concentrations [103], suggesting a role of apoE protein and indirectly in APOE4 genotype, in the maintenance of DHA concentrations within the brain.…”

Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo

“…1). Multiplying k* by the unlabeled plasma unesterified DHA concentration gives incorporation rates, J in , of unlabeled unesterified DHA (where the asterisk identifies labeled DHA) [33, 50], $$k^{\ast }=\frac{c_{\mathit{brain}\left(\mathit{DHA}\right)}^{\ast }}{{\int }_0^T{c}_{\mathit{plasma}\left(\mathit{DHA}\right)}^{\ast }dt}$$ …”