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Review
. 2012 Feb 10;87(2-3):154-71.
doi: 10.1016/j.brainresbull.2011.12.001. Epub 2011 Dec 9.

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

Mireille Basselin  1 , Epolia Ramadan, Stanley I Rapoport
Affiliations
Review

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

Mireille Basselin et al. Brain Res Bull. .

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 A(2) (PLA(2)) 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 M(1,3,5), serotonergic 5-HT(2A/2C), dopaminergic D(2)-like (D(2), D(3), D(4)) 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.

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Conflict of interest statement

No author has a financial or other conflict of interest related to this work.

Figures

Figure 1
Figure 1
Model explaining PLA2 activation and arachidonic acid signaling in response to muscarinic, dopaminergic, or serotonergic drugs. Activation of M1,3,5, D2-like (D2, D3, D4), 5-HT2A/2C receptors by acetylcholine (ACh), dopamine (DA) or serotonin (5-HT), or an appropriate agonist, arecoline, quinpirole or DOI, activates G protein and stimulates cytosolic phospholipase A2 (cPLA2) thereby initiating rapid release of arachidonic acid (AA) from membrane phospholipid (PL). Then AA is converted to eicosanoids such as prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) via cyclooxygenases (COX).
Figure 2
Figure 2
Model explaining PLA2 activation and AA signaling in response to NMDA. Activation of glutamatergic NMDA receptors by glutamate or an appropriate agonist, NMDA, gates a cation channel that is permeable to Ca2+ and Na+. Influx of Ca2+ stimulates cytosolic phospholipase A2 (cPLA2), thereby initiating rapid release of arachidonic acid (AA) from membrane phospholipid (PL). Then AA is converted to eicosanoids such as prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) via cyclooxygenases (COX). The NMDA receptor channel is blocked by the selective non-competitive NMDA antagonist, MK-801.
Figure 3
Figure 3
Coronal autoradiographs of brain showing effects of NMDA (25 mg/kg, i.p.) and MK-801 (0.3 mg/kg, s.c.) on regional [1-14C] arachidonic acid and [1-14C] docosahexaenoic acid incorporation coefficients k* in rats. Values of k* are given on a color scale. AA, arachidonic acid; DHA, docosahexaenoic acid; NMDA, N-methyl-D-aspartate. From (Basselin et al., 2006a; Ramadan et al., 2011b).
Figure 4
Figure 4
Mood stabilizers downregulate NMDA and D2-like induced arachidonic acid signal. Coronal autoradiographs of brain showing effects of the four mood stabilizers on NMDA and D2-like signal on regional [1-14C]arachidonic acid incorporation coefficients k* in rats. NMDA, N-methyl-D-aspartate; ND, not determined. From (Basselin et al., 2005a; Basselin et al., 2006a; Basselin et al., 2007a; Basselin et al., 2008a; Basselin et al., 2008b; Ramadan et al., 2011a; Ramadan et al., 2011b).
Figure 5
Figure 5
Increased incorporation coefficients k* of arachidonic acid after 6-day LPS infusion and in HIV-1 transgenic rat. Coronal autoradiographs of brain after 6-day LPS infusion (0.5 ng/h) and in HIV-1 transgenic rats on regional [1-14C]arachidonic acid incorporation coefficients k* in rats. Values of k* are given on a color scale. aCSF, artificial cerebrospinal fluid; LPS, lipopolysaccharide. From (Basselin et al., 2007c; Basselin et al., 2011b).
Figure 6
Figure 6
Increased incorporation coefficients k* of arachidonic acid in 5-HTT-deficient but not in DAT-deficient mice, and decreased k* of docosahexaenoic acid in iPLA2β-deficient mice Coronal autoradiographs of brain showing effects of 5-HTT, DAT, and iPLA2β genotype on regional [1-14C]arachidonic acid or [1-14C]docosahexaenoic acid incorporation coefficients k* in mice. Values of k* are given on a color scale. From (Basselin et al., 2009a; Basselin et al., 2010b) and Ramadan et al. (unpublished data).
Figure 7
Figure 7
Horizontal PET brain images of significant increments in incorporation coefficients k* for arachidonic acid comparing Alzheimer’s disease patients and healthy controls. From (Esposito et al., 2008).
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