Abstract
BackgroundAdequate consumption of polyunsaturated fatty acids (PUFA) is vital for normal development and functioning of the central nervous system. The long-chain n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid are anti-inflammatory and neuroprotective in the models of central nervous system injury including traumatic brain injury (TBI). In the present study, we tested whether a higher brain DHA status in a mouse model on an adequate dietary α-linolenic acid (ALA) leads to reduced neuroinflammation and improved spontaneous recovery after TBI in comparison to a moderately lowered brain DHA status that can occur in humans.MethodsMice reared on diets with differing ALA content were injured by a single cortical contusion impact. Change in the expression of inflammatory cytokines was measured, and cellular changes occurring after injury were analyzed by immunostaining for macrophage/microglia and astrocytes. Behavioral studies included rotarod and beam walk tests and contextual fear conditioning.ResultsMarginal supply (0.04 %) of ALA as the sole dietary source of n-3 PUFA from early gestation produced reduction of brain DHA by 35 % in adult offspring mice in comparison to the mice on adequate ALA diet (3.1 %). The DHA-depleted group showed significantly increased TBI-induced expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the brain as well as slower functional recovery from motor deficits compared to the adequate ALA group. Despite the reduction of pro-inflammatory cytokine expression, adequate ALA diet did not significantly alter either microglia/macrophage density around the contusion site or the relative M1/M2 phenotype. However, the glial fibrillary acidic protein immunoreactivity was reduced in the injured cerebral cortex of the mice on adequate ALA diet, indicating that astrocyte activation may have contributed to the observed differences in cellular and behavioral responses to TBI.ConclusionsIncreasing the brain DHA level even from a moderately DHA-depleted state can reduce neuroinflammation and improve functional recovery after TBI, suggesting possible improvement of functional outcome by increasing dietary n-3 PUFA in human TBI.
Highlights
Adequate consumption of polyunsaturated fatty acids (PUFA) is vital for normal development and functioning of the central nervous system
The increase in docosahexaenoic acid (DHA) was mirrored by a corresponding decrease in n-6 PUFAs including arachidonic acid (AA; 20:4n-6) (8.54 ± 0.41 % vs 5.85 ± 0.45 %), n-6 docosatetraenoic acid (22:4n-6) (3.03 ± 0.14 % vs 1.53 ± 0.12 %), and Docosapentaenoic acid (DPAn-6)
The DPAn-6 level decreased from 3.51 ± 0.3 % in the brain of low adequate dietary α-linolenic acid (ALA) diet mice to a nearly undetectable level in the mice on adequate ALA diet
Summary
Adequate consumption of polyunsaturated fatty acids (PUFA) is vital for normal development and functioning of the central nervous system. Modern dietary practice has resulted in an increased consumption of n-6 polyunsaturated fatty acids (PUFA) with a corresponding deficit in n-3 PUFA. This phenomenon has skewed the n-6 to n-3 PUFA ratio, which is about 15:1 in modern diets [1]. Mice reared on adequate n-3 PUFA diet have very low levels of DPAn-6 in the brain (with the approximate DPAn-6 to DHA ratio less than 0.01), which increases in mice on low n-3 PUFA diet with a corresponding decrease in DHA [3]. Assuming that the DHA/DPAn-6 proportion in mice extrapolates to humans, this indicates that modern human brains may not have the optimum DHA levels
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