A college soccer player presented after a concussion for evaluation and return-to-play guidance. He asked, "Should I take fish oil? I hear it is good for the brain." Fish oil is composed of high concentrations of Ω-3 polyunsaturated fatty acids (Ω-3 PUFA). More common in the diet is Ω-6 polyunsaturated fatty acids (Ω-6 PUFA), which form arachidonic acid (AA). Ω-3 PUFA are considered essential fatty acids because the body does not make them. There are three main Ω-3 PUFA associated with disease prevention: α-linolenic acid (ALA) (C18:3), eicosapentaenoic acid (EPA) (C20:5), and docosahexaenoic acid (DHA) (C22:6). DHA has been studied the most (25). Ω-3 PUFA, from dietary fish or fish oil supplements, have been shown to be beneficial for cardiac health (13,22). The benefits of Ω-3 PUFA for combating many health problems have been reviewed in other articles (25,26). This article will address if fish oil should be used to help athletes with recovery after mild traumatic brain injury (TBI) (concussions). We will look at the animal and basic science data because clinical data in humans have not been published.
After a head injury, there is a posttraumatic depolarization and potassium efflux from cells that trigger the release of excitatory amino acids like glutamine, which in turn activate N-methyl-D-aspartate (NMDA) receptors and form a pore through which calcium enters the neuron (Fig.). A large influx of calcium into the cell triggers the lysis of AA and the formation of reactive oxygen species (ROS). NMDA or MK-801 (NMDA agonist) causes AA but not DHA levels to increase in neurons (23). Thromboxane A2 (a derivative of AA) and AA can be detected in the spinal fluid of individuals after head trauma. This has been documented in both children and adults (21,32). Higher levels of AA in the cerebrospinal fluid have been proposed to correlate with severity of injury (32). ROS-mediated damage is mainly characterized by the onset of lipid peroxidation, and this process can be detected/quantified by measuring tissue malondialdehyde (MDA). Tissue MDA levels increase 1 min after head injury in rats and peak at 2 to 3 h. Normally, MDA levels in the brain are undetectable (27). These changes after head injury can lead to neuron apoptosis.
There are many proposed mechanisms by which DHA prevents cell damage after injury. One possible mechanism of action of DHA maybe the inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-mediated channels (18). The beneficial effect of DHA on the brain could be derived from specific modulation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-mediated toxicity. DHA affects the calcium and Na ion channels in carbonic anhydrase 1 neurons. This may be one of the ways that DHA protects neurons. EPA and DHA have been shown to inhibit calcium channels in neurons (30). Moreover, DHA and EPA are competitive inhibitors of AA formation by competition with cyclooxygenase (5). Both actions would limit the damage to neurons.
DHA has a direct protective effect on the neurons. The brain uses DHA to form neuroprotectin D1 (NPD1), which acts to diminish polymorphonucleocyte infiltration. DHA and NPD1 both inhibit the increases in nuclear factor κ light chain enhancer of activated B cells binding activity and up-regulation of cyclooxygenase-2 (COX-2) mRNA after head injury. These limit ROS-mediated damage and thereby limit the size of injury (5). NPD1 inhibits oxidative stress-induced caspase-3 activation as well as interleukin-1 β-stimulated expression of COX-2 (4).
Fish Oil and Other Neurological Injuries
Seizure-induced neuronal loss is involved in the development of chronic seizures in temporal lobe epilepsy (8). Similar changes to neuronal cells are postulated to occur during neuronal damage from head injury (5). Ferrari et al. (9) investigated the effect of addition of Ω-3 PUFA to rat diets in limiting neuron loss with chronic seizures in the temporal lobe epilepsy model. Fish oil was given daily to rats in a dose of 85 mg·kg−1·d−1. They demonstrated that fish oil decreased neuron cell death in this epilepsy model. They speculated that the reduction in neuronal death in the animals given Ω-3 PUFA was due to an acute effect on ion channel modulation and anti-inflammatory action (prostaglandin E2 inhibition by blocking the formation of COX-2) (9).
The spinal cord injury (SCI) model has a similarity to concussions at the cellular level. Huang et al. (12) compared the effect of DHA given by combined intravenous and oral supplementation, oral DHA alone, and a control group on neuronal death in rats. They demonstrated in this model of SCI that significant neuroprotection could be obtained by combining an initial acute intravenous injection of DHA with a sustained dietary supplementation of DHA. The neuronal death was found to be the least in the intravenous and oral supplementation, second least in oral supplementation, and greatest in the control groups (12). King et al. (14) demonstrated that Ω-3 versus Ω-6 PUFA provides a protective effect. Ω-3 PUFA would produce anti-inflammatory protective effects, whereas Ω-6 PUFA would produce AA and inflammatory chemicals causing neuronal death. They demonstrated a striking difference in efficacy between the effects of treatment with Ω-3 and Ω-6 PUFA on the outcome of SCI. Treatment with Ω-3 PUFA was neuroprotective with reduced neuronal death, whereas Ω-6 PUFA produced more neuronal cell death than control. This study helps to demonstrate that Ω-3 PUFA may be necessary to protect neurons in an SCI model.
Fish Oil/DHA Use After Concussion
Mills et al. (19) looked at the effects of fish oil supplementation in a head injury model in rats. DHA was started on day 1 after injury (approximately 24 h after injury), in the following doses: 10 mg·kg−1·d−1 (6 mg·kg−1 of EPA and DHA per day in a 2:1 ratio) for group 1 and 40 mg·kg−1·d−1 (24 mg·kg−1 of EPA and DHA per day in a 2:1 ratio) for group 2. The number of β-amyloid precursor protein (APP)-positive axons was used to measure the level of injury. There was a significant quantitative difference of 182.2 ± 44.6 APP-positive axons in unsupplemented animals versus sham-injured animals (control animals), which had 4.1 ± 1.3 APP-positive axons per squared millimeter. Group 1 (10 mg·kg−1·d−1) and group 2 (40 mg·kg−1·d−1) animals showed only rare APP-positive axons. It is notable that Ω-3 fatty acid supplementation groups had significantly reduced numbers of APP-positive axons at 30 d after injury to levels similar to those in uninjured (sham) animals. The supplementation of 10 versus 40 mg·kg−1·d−1 started within 24 h of the head injury did not show a statistical difference in neuronal protection. Bailes and Mills (1) looked at the benefits of DHA supplementation after TBI in rats. Similar to the study of Mills et al. (19), four groups of rats were subjected to an impact acceleration injury and then received 30 d of supplementation. However, in this study, DHA instead of fish oil (which contains both DHA and EPA) was used. The supplement group received 10 or 40 mg·kg−1·d−1 of DHA. Serum fatty acid levels were determined before injury and at the end of the 30 d of DHA supplementation. APP staining was used to measure neuronal injury. Dietary supplementation with 10 or 40 mg·kg−1·d−1 of DHA for 30 d results in significantly (P < 0.05) increased DHA serum levels of 123% and 175% over baseline, respectively. The mean (±standard deviation) number of APP-positive axons per millimeter in sham-injured animals was 6.4 ± 13.9, that in animals receiving 10 mg·kg−1·d−1 of DHA dietary supplementation was 26.1 ± 5.3, that in animals receiving 40 mg·kg−1·d−1 of DHA dietary supplementation was 19.6 ± 4.7, and that in unsupplemented animals was 147.7 ± 7.1. The number of APP staining axons was much greater in the unsupplemented animals. The difference in APP-positive axons between 10 and 40 mg·kg−1·d−1 was not statistically different at 30 d.
The level of APP-positive axons is similar in both studies by Bailes and Mills and Mills et al. in the sham group. The DHA (Bailes and Mills (1)) versus fish oil supplementation (Mills et al. (19)) showed an increased number of APP-positive neurons in DHA versus fish oil (DHA and EPA). Further work needs to be done to determine whether the addition of EPA adds protective effects over DHA alone.
Wu et al. (34) studied the effects of Ω-3 PUFA supplements (8% fish oil) on the silent information regulator 2 (Sir2) (Sir2 detoxifies ROS). Mild TBI reduces the expression of Sir2α in the hippocampus, in proportion to increased levels of protein oxidation. They found that dietary supplementation of Ω-3 PUFA ameliorates protein oxidation and reverses the reduction of Sir2α level in injured rats. Energy homeostasis was determined by measuring levels of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylated AMPK. The hippocampal levels of total and phosphorylated AMPK were reduced after TBI, and levels were normalized by Ω-3 PUFA supplements. Ubiquitous mitochondrial creatine kinase (uMtCK) is an enzyme implicated in the energetic regulation of Ca2+ pumps and in the maintenance of Ca2+ homeostasis. uMtCK is a marker of cellular energy. Increased Ca2+ levels lead to increased AA and neuronal cell death. TBI reduces uMtCK, and Ω-3 PUFA supplements normalized the levels of uMtCK after injury. Wu et al. (34) postulated that TBI may compromise neuronal protective mechanisms by the action of Sir2α and other regulatory enzymes and that Ω-3 PUFA correct those abnormalities.
Fish Oil/DHA Before Treatment
Up until this point, we have reviewed studies that have looked at the use of Ω-3 PUFA (fish oil) and DHA supplementation for 30 d after injury. Other studies have investigated the effect of fish oil supplementation before head injury. Blood levels of Ω-3 PUFA (ALA, EPA, and DHA) are lower in people who eat a standard Western diet (28). Theoretically, supplementing with Ω-3 PUFA (fish oil) before injury might increase the levels of DHA and EPA in the brain and possibly provide a protective effect.
In a study by Wu et al. (33), rats were fed a regular diet or a diet supplemented with Ω-3 PUFA (8% fish oil) for 4 wk before a mild fluid percussion injury (FPI). FPI increased oxidative stress and impaired learning ability as measured by the Morris water maze. Brain-derived neurotrophic factor, synapsin I, and cyclic adenosine monophosphate responsive element-binding protein are proteins important for neuronal health and survival. FPI reduced levels of these proteins in the animals fed a regular diet. In contrast, the rats that were supplemented with Ω-3 PUFA did not have reduced levels of these proteins after FPI. The rats fed the supplemented diet also had reduced oxidative damage and less learning disability as measured by the Morris water maze. The reduction of oxidative stress indicates a beneficial effect of Ω-3 PUFA supplementation on mechanisms that maintain neuronal function and plasticity after TBI.
Bailes et al. (2) looked at the supplementation of DHA 30 d before a TBI. Five groups of rats were subjected to a TBI after having received 10 mg·kg−1·d−1 or 40 mg·kg−1·d−1 of DHA for 30 d before the TBI. The animals supplemented with either DHA dose had higher levels of serum DHA compared with those animals that were not supplemented. The rats were tested using a water maze behavioral assessment. The animals were sacrificed 1 wk after injury; APP levels, CD68, and caspase-3 levels were measured. Dietary supplementation with DHA at 40 mg·kg−1 showed significantly (P < 0.05) decreased numbers of APP-positive axons, at 1.15 axons per high-power field versus 6.78 in unsupplemented animals. Cluster of differentiation 68, caspase-3, and water maze testing all were improved significantly (P < 0.05) in the 40-mg·kg−1·d−1 dosages. The APP levels at 1 wk in the unsupplemented animals are lower than the levels found in studies where the animals were sacrificed 30 d after injury. The protection of neurons was found in the 40-mg·kg−1·d−1 DHA-supplemented group before injury. These studies of preinjury supplementation do not show an increased benefit compared with starting Ω-3 PUFA at the time of injury.
The intake of DHA seems to be important to maintain recovery from brain injury. ALA is a Ω-3 PUFA, and it is the precursor to EPA and DHA. ALA is the most common Ω-3 PUFA found in the diet. Many foods like flaxseeds, walnuts, etc., have ALA (Table 1). The difficulty with trying to increase DHA levels with ALA supplementation is that ALA is not converted effectively into DHA despite being easily converted into EPA (6). Studies have shown that dietary ALA supplementation required would be 8.3 times higher than the dietary supplementation of EPA + DHA. Hence, the efficacy of ALA is lower compared with preformed EPA + DHA in elevating Ω-3 PUFA in the brain (29,24). Therefore, taking ALA without DHA at standard doses (10 to 40 mg·kg−1) will not get the desired effect of boosting DHA levels in the brain without supplementing with exogenous DHA.
Risk of Fish Oil Use
An important question that needs to be answered before using fish oil for concussions is, "If we are uncertain about the benefits of fish oil in humans, should fish oil be avoided because of the risks?" In other words, the risks of taking fish oil supplementation should be low because we are uncertain about the benefit for concussion recovery in humans. The main side effects of fish oil include belching, bad breath, "fishy burp," heartburn, nausea, and loose stools. These gastrointestinal adverse effects are dose dependent. Fish oil has been implicated in bleeding disorders because fish oils competitively inhibit cyclooxygenase, reducing thromboxane A2 and platelet aggregation (7). Platelet-derived growth factor-like protein is decreased, and synthesis of the platelet activation factor is decreased with fish oil thereby contributing to a decrease in clinical atherothrombosis (3). Despite these in vivo findings, studies that have looked at the dosing of fish oil of up to 6 g·d−1 do not demonstrate a clinically relevant effect on bleeding (10,15,31). This is not to imply that fish oil does not have an effect on bleeding because cases of fish oil affecting international normalized ratio levels for warfarin treatment have been reported (7). The effects of DHA on lipids have mixed effects that indicate that DHA does not seem to have a negative effect on lipid profiles (16,20). Ω-3 fatty acids from fish oil supplements significantly lower triglycerides. There has been concern about Ω-3 PUFA and glucose levels. The glucose levels are not affected by the Ω-3 PUFA use in patients with type 2 diabetes (11). Despite the possible effects on clotting, it seems that Ω-3 PUFA from fish oil supplements are generally safe. Because of its effects on clotting and the potential for bleeding with head injury, cautious use would be prudent if bleeding is suspected.
There have been concerns about using fish oil in those athletes with fish allergies and in those athletes who do not eat fish. A study done on six people with an allergy to finned fish who were skin tested for reaction to fish oil after ingestion showed no allergic reaction. This is probably because a protein responsible for allergic reactions found in fish meat may not be present in fish oil supplements (17). Skin testing of the fish oil will help determine whether one's fish-allergic patient can take fish oil. The authors recommend avoiding fish oil in those allergic to fish without skin testing. Another safer option would be other sources for DHA and EPA besides fish oil. Algal oil is an algae-based Ω-3 PUFA. Fish do not make Ω-3 PUFA, and they need to ingest algae to obtain their Ω-3 PUFA.
There are many food sources of EPA and DHA (Table 2). Fish are the best source of EPA and DHA. Supplements of fish oil, krill oil, or algal oil with 10 mg·kg−1 of EPA and DHA per day in a 2:1 ratio or 10 mg·kg−1·d−1 of DHA alone seem to be sufficient if started right after a concussion (within 24 h, authors recommend 6 h) from animal studies. Supplements have varying reliability when it comes to tested levels versus label claims; look for the U.S. Pharmacopeia verification when buying a product (Table 3). Because the dosage is weight based, the total dosage would vary by the athlete's size. Larger doses (40 mg·kg−1) do not seem to produce greater benefit, and EPA may have added a benefit to the effect of DHA (further work is needed to confirm this).
The evidence in the animal model is convincing that Ω-3 PUFA especially DHA is beneficial after mild TBI. Supplementation before injury for at least 30 d seems to be helpful in rats, but it seems that the prior treatment for people would be excessive in cost and unnecessary to obtain the intended benefit compared with supplementation at the time of injury. The evidence is convincing that, if one had a pet rat and a book fell on its head, one should give it fish oil. The evidence is missing for humans. Therefore, although Ω-3 PUFA seems safe and generally well tolerated and the potential benefit seems to be greater than the risk of taking fish oil, caution should be used in prescribing fish oil. Further work is needed to determine whether the use of Ω-3 PUFA in humans, in particular DHA and EPA, produces clinically measurable benefits after concussion.
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