TABLE 1.
Outline of preclinical studies evaluating the use of ω-3 FAs for recovery from mild traumatic brain injury1
| Results |
||||||
| Reference | mTBI model | Intervention | Timing | Pathophysiologic Events | Protective Mediators | Functional Outcomes |
| Mills et al., 2011 (57) | Impact acceleration injury | 0, 3, 12, 40 mg/kg DHA | 30 d before injury | ↓ Axonal damage (APP counts) in rats receiving high-dose DHA | — | ↓ Time latency to platform in rats receiving high-dose DHA on the Morris water maze |
| ↓ Number of apoptotic (caspase-3-positive) axons significantly reduced in rats receiving high-dose DHA | ↓ Errors in rats receiving high-dose DHA on the Morris water maze | |||||
| ↓ Inflammation (CD-68 positive cells) in rats receiving high dose DHA | ||||||
| Wu et al., 2007 (58) | Lateral fluid percussion injury | Control diet (0.9% DHA, 1% EPA) | 4 wk before injury | — | Fish oil normalized energy metabolism marker expression (SIR2, AMPK, p-AMPK, uMtCK) | — |
| Fish oil diet (12.4% DHA, 13.5% EPA) | ↓ Oxidized proteins in fish oil–fed rats | |||||
| Wu et al., 2004 (59) | Lateral fluid percussion injury | Control diet (0.9% DHA, 1% EPA) | 4 wk before injury | — | Fish oil diet normalized expression of BDNF signaling markers (synapsin I, CREB) | ↓ Time latency to platform in fish oil–fed rats on the Morris water maze |
| Fish oil diet (12.4% DHA, 13.5% EPA) | ↓ Oxidized proteins in fish oil–fed rats | |||||
| Wu et al., 2013 (65) | Lateral fluid percussion injury | 0% DHA, sedentary | 12 d after injury | ↓ Brain DHA content after injury | DHA normalized expression of BDNF signaling markers (BDNF, p-TrkB) | ↓ Slope of escape latency (↑ learning speed) after injury according to the Morris water maze test in DHA-fed rats |
| 1.2% DHA, sedentary | DHA feeding (with or without exercise) restored injury-induced reductions in brain DHA content | ↑ Antioxidant enzyme expression (SIR2) in DHA-fed rats | Exercise had an additive effect on learning performance according to the Morris water maze | |||
| 0% DHA, voluntary exercise | ↓ Lipid peroxidation (4-HHE) in DHA-fed rats | ↑ Membrane homeostasis marker expression (Acox1, 17β-HSD4, iPLA2, STX-3) in DHA-fed rats | ||||
| 1.2% DHA, voluntary exercise | Effects stronger when DHA was provided along with exercise | |||||
| Wu et al., 2014 (66) | Lateral fluid percussion injury | 0% DHA + 0 mg/kg curcumin | 14 d after injury | ↓ Brain DHA content after injury | ↑ Membrane homeostasis marker expression (17β-HSD4, FADS2) in DHA-fed rats | ↓ Time latency to complete the Barnes maze task in DHA-fed rats |
| 1.2% DHA + 0 mg/kg curcumin | DHA feeding (with or without curcumin) restored injury-induced reductions in brain DHA content | DHA normalized expression of BDNF signaling markers (BDNF, p-TrkB) | ||||
| 0% DHA + 500 mg/kg curcumin | ↓ Lipid peroxidation (4-HHE, 4-HNE) in DHA-fed rats | |||||
| 1.2% DHA + 500 mg/kg curcumin | ||||||
| Wu et al., 2011 (61) | Lateral fluid percussion injury | 0 or 1.2% DHA | 12 d after injury | — | DHA normalized expression of proteins related to learning/memory (BDNF, synapsin I, CREB, CaMKII) | ↓ Time latency to platform in DHA-fed rats on the Morris water maze |
| ↑ Antioxidant enzyme expression (SIR2, SOD) in DHA-fed rats | ||||||
| ↑ Membrane homeostasis marker expression (iPLA2, STX-3) in DHA-fed rats | ||||||
| Shin and Dixon, 2011 (62) | Controlled cortical impact injury | 1.5 mL of fish oil (360 mg/d EPA, 240 mg/d DHA) | 7 d after injury | — | Fish oil normalized dopamine release after injury | — |
| 1.5 mL of olive oil | ||||||
| Mills et al., 2011 (63) | Impact acceleration injury | 0, 10, 40 mg ⋅ kg−1 ⋅ d−1 fish oil (2:1 ratio of EPA/DHA) | 30 d after injury | ↓ Axonal damage (APP counts) in rats receiving fish oil | — | — |
| ↓ Number of apoptotic (caspase-3-positive) axons significantly reduced in rats receiving fish oil | ||||||
| Bailes and Mills, 2010 (64) | Impact acceleration injury | 0, 10, 40 mg ⋅ kg−1 ⋅ d−1 DHA | 30 d after injury | ↓ Axonal damage (APP counts) in rats receiving DHA | — | — |
| ↓ Number of apoptotic (caspase-3-positive) axons significantly reduced in rats receiving DHA | ||||||
| Wang et al., 2013 (60) | Lateral fluid percussion injury | 0 or 6% fish oil diet (0.8–1% EPA, 0.6% DHA) | 4 wk before injury and 2 wk after injury (6 wk total) | ↑ Higher density of hippocampal neurons in fish oil–fed rats (nonsignificant, P = 0.126) | — | ↑ Body weight recovery after injury in fish oil–fed rats |
| ↓ Time latency to platform in fish oil–fed rats on the Morris water maze | ||||||
| ↑ Time spent in target quadrant in fish oil–fed rats on the Morris water maze | ||||||
1
Acox1, acyl-coenzyme A oxidase 1; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; BDNF, brain-derived neurotrophic factor; CaMKII, calcium-dependent protein kinase II; CREB, cAMP response element-binding protein; FADS2, delta 6 fatty acid desaturase; iPLA2, calcium-independent phospholipase A2; mTBI: mild traumatic brain injury; p-AMPK: phosphorylated AMP-activated protein kinase; p-TrkB, p-neurotrophic tyrosine kinase receptor; SIR2, silent information regulator 2; SOD, superoxide dismutase; STX-3, syntaxin-3; uMtCK, ubiquitous mitochondrial creatine kinase; 17β-HSD4, 17β-hydroxysteroid dehydrogenase type 4; 4-HHE, 4-hydroxy-2-hexenal; 4-HNE, 4-hydroxy-2-nonenal; ↓, decreased; ↑, increased.