Compound-Specific Isotope Analysis as a Potential Approach for Investigation of Cerebral Accumulation of Docosahexaenoic Acid: Previous Milestones and Recent Trends

Abstract

Docosahexaenoic acid (DHA, C22:6 n-3), a predominant omega-3 polyunsaturated fatty acid in brain, plays a vital role in cerebral development and exhibits functions with potential therapeutic effects (synaptic function, neurogenesis, brain inflammation regulation) in neurodegenerative diseases. The most common approaches of studying the cerebral accretion and metabolism of DHA involve the use of stable or radiolabeled tracers. Although these methods approved kinetic modeling of ratios and turnovers for fatty acids, they are associated with excessive costs, restrictive studies, and singular dosing effects. Compound-specific isotope analysis (CSIA) is recognized as a cost-effective alternative approach for investigating DHA metabolism in vitro and in vivo. This method involves determining variations in ¹³C content to identify the sources of specific compounds. This review comprehensively discusses a summary of different methods and recent advancements in CSIA application in studying DHA turnover in brain. Following, the ability and applications of CSIA by using gas-chromatography combined with isotope ratio mass-spectrometry to differentiate between natural endogenous DHA in brain and exogenous DHA are also highlighted. In general, the efficiency of CSIA has been demonstrated in utilizing natural ¹³C enrichment to distinguish between the incorporation of newly synthesized or pre-existing DHA into the brain and other body tissues, eliminating the need of tracers. This review provides comprehensive knowledge, which will have potential applications in both academia and industry for advancing the understanding in neurobiology and enhancing the development of nutritional strategies and pharmaceutical interventions targeting brain health.

Keywords: Bioavailability, Neurological disorders; Brain; CSIA; Docosahexaenoic acid; GC-IRMS.

Fig. 1

A Biosynthetic conversion pathway of ALA to DHA [16]. B Uptake of DHA into the brain [5]. Abbreviations (LysoPL-DHA, lysophospholipids-docosahexaenoic acid; Mfsd2a, a sodium-dependent lysophosphatidylcholine symporter responsible for docosahexaenoic acid uptake into the brain; NE-DHA, non-esterified DHA; Rc, receptor; FABP, fatty acid-binding proteins; LPLAT, lysophosphatidylcholine acyltransferases; ACSL, acyl CoA synthetase long chain; CoA, coenzyme A; PLA₂, phospholipase A₂; SPM, specialized pro-resolving mediator)

Fig. 2

Relationship between DHA levels in the human brain and various neurodegenerative diseases. Data adapted from [65, 74, 77, 81, 83, 85, 86]

Fig. 3

A GC-IRMS systematic diagram [148]. B GC-IRMS trace of fatty acids methyl esters derived from rat brain total lipids extract. The upper plot displays the signal ratio for mass/charge 45 and mass/charge 44. The lower plot displays the signal for mass/charge 45 for the duration of IRMS run. The detonated peak, A, emphasizes the complete baseline resolution of DHA from surrounding peaks. STD indicates signal peaks from the admitted calibrating CO₂ reference gas, > 10 pulses of calibrant were acknowledged before each run [116]