Reduced acute neuroinflammation and improved functional recovery after traumatic brain injury by α-linolenic acid supplementation in mice

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.

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…Restriction of ω-3 PUFA levels in male mice from pregnancy onset until 4 months of age resulted in greater GFAP + coverage in response to traumatic brain injury, an effect that was diminished when ω-3 levels were restored (Desai et al, 2016). Treatment of cultured astrocytes with DHA was able to prevent a CORT-induced stress response as measured by increased glutamate uptake, increased GS levels, and Together these results show that undernutrition lastingly impacts GFAP expression in astrocytes.…”

“…Another model of early‐life malnutrition entails restriction of essential nutrients (nutrients that need to be obtained by the diet). Restriction of ω‐3 PUFA levels in male mice from pregnancy onset until 4 months of age resulted in greater GFAP + coverage in response to traumatic brain injury, an effect that was diminished when ω‐3 levels were restored (Desai et al, ). Treatment of cultured astrocytes with DHA was able to prevent a CORT‐induced stress response as measured by increased glutamate uptake, increased GS levels, and altered GFAP cytoskeletal morphology (Champeil‐Potokar, Hennebelle, Latour, Vancassel, & Denis, ).…”

Role of neuroinflammation in ischemic stroke

“…[45] The positive role associated with neuroinflammation is only present for a brief, controlled inflammatory situations and responses and this can be considered as performing a protective function to the host organism. [46][47][48] For example, during low transient inflammation that may occur during infections, the immune cell signals to the brain by increasing the expression of interleukin (IL)-1 cytokine, this then increasing the 'survellience' role of glia cells in the brain if infected. [49,50] The transient inflammation of traumatic CNS injury, following the expression of IL-4, has been shown to promote injury recovery and axonal regrowth.…”

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

“…In one study delivering recombinant IL-4 after stroke in IL-4 knockout mice, repeated measures were not accounted for and wild-type mice were not tested (52). A variety of other approaches to TBI that promote an M2-like response have also observed improvement in behavioral outcomes (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (31)(32)(33)(34)(35)(36). However, in many of these studies, behavior is not (or could not be) assessed prior to treatment to ensure the absence of accidental bias.…”