Positive Effects of DHA in Experimental Traumatic Brain Injury
Traumatic brain injury results in 53,000 deaths in the U.S. every year (Figure), with nearly twice that number suffering permanent disability, including diminished cognitive ability. Treatments with long-term benefits are few and of limited effectiveness. Progesterone may have neurological benefits and is in a Phase III clinical trial for patients with moderate-to-severe traumatic brain injury. Attention has also turned to the potential effects of DHA in preventing and ameliorating traumatic brain and spinal cord injury. DHA involvement in neuronal membrane structure and function, learning and memory, as well as neuroplasticity and synapse formation, provide a compelling rationale to investigate its potential for mitigating or preventing the damage from these events.
Evidence from animal studies suggests that DHA might be a promising therapeutic approach in neurological injury. Animals fed an omega-3 (n-3) PUFA-rich diet prior to mild fluid percussion injury were protected against the damaging effects of injury as shown by normalized levels of brain-derived neurotrophic factor (BDNF), synapsin 1 and c-AMP responsive element-binding protein and learning ability, plus reduced oxidative damage. In a study of hypoxic-ischemic encephalopathy in rats, such as might occur in hypoxia in pregnancy, females fed DHA-enriched diets during pregnancy had fewer apoptotic neuronal cells and lower 8-OHdG-immunoreactivity compared with the unenriched control group when exposed to hypoxic brain injury. A study of traumatic brain injury in animals subsequently supplemented with fish oil reported a significant reduction in β-amyloid precursor protein-positive axons and caspase-3 expression, both indicators of neuronal damage. Another study of cerebral ischemia/reperfusion injury in animals reported that pretreatment with DHA was accompanied by decreased brain infarction, less blood-brain barrier disruption and edema, reduced inflammatory cell infiltration and interleukin-6 and caspase-3 activity, all indications of neuroprotection. DHA treatment was also shown to improve histological and behavioral outcomes after spinal cord injury and to prevent white matter damage in such animals.
In a new report, Dr. Aiguo Wu and colleagues at the University of California at Los Angeles extended their studies with DHA in animals with traumatic brain injury from fluid percussion injury (FPI). They investigated the effect of a DHA-enriched (1.2%) or regular chow diet in FPI or sham-operated rats. The markers studied included brain fatty acids, cognition, BDNF, oxidative stress, intracellular phospholipase A2 and syntaxin-3 levels. The chosen markers are associated with synaptic plasticity, membrane function or learning and memory. In particular, BDNF has been linked to the regulation of synaptic plasticity, which has been described as the cellular correlate of learning and memory. BDNF is also necessary for the survival of striatal neurons, which are involved in learning and memory in the basal ganglia system.
Animals were fed the diets for 12 days immediately after surgery. Learning ability was evaluated by the Morris water maze test carried out 1 week after surgery, over 5 days. Animals were sacrificed and tissues analyzed for the markers of interest as described in the original publication.
As expected, the FPI animals fed the DHA-enriched diet accumulated more DHA in brain than either sham-operated or FPI animals fed the regular chow diet. Learning ability was assessed by the escape latency in the Morris water maze. The FPI animals fed DHA took significantly less time on each successive test day to reach the escape platform than the FPI animals on the regular diet or the sham-operated controls. On day 5 the DHA-supplemented FPI animals took approximately 21 seconds to reach the platform, whereas the FPI animals on the regular diet required nearly 30 seconds (P <0.05).
FPI resulted in a 30% decrease in BDNF in the animals fed the chow diet. However, there was no decrease in BDNF in the DHA-fed or sham-operated animals. Similar findings were obtained for the levels of calcium/calmodulin-dependent protein kinase, an enzyme involved in signaling and long-term potentiation, the strengthening of synapses thought to underlie memory.
FPI injury reduced the levels of synapsin I and cAMP-responsive element-binding protein in the hippocampus by 74 and 78%, respectively. Synapsin I is found in the membranes of synaptic vesicles and is involved in synaptogenesis and neurotransmitter release. Cyclic-AMP-responsive element-binding protein is a nuclear transcription factor involved in neuronal excitation and the formation of long-term memory. DHA-supplemented FPI animals showed no significant decrease in these markers.
Additional analyses examined the effects of the DHA-enriched diet compared with the chow diet on indicators of oxidative stress in FPI animals. The investigators measured the levels of 4-hydroxynonenal (4-HNE), a peroxidation product of n-6 PUFAs, such as arachidonic and linoleic acids, and two substances related to the control or inactivation of oxidation products, superoxide dismutase, which acts as an antioxidant factor, and Sir2, a protein with complex regulatory function in the brain. FPI animals on the regular diet had an approximately 33% higher level of 4-HNE compared with the sham-operated animals, but the DHA-enriched animals had significantly reduced 4-HNE (85% of the sham-operated controls). Similarly, injured animals on the regular diet had significantly reduced levels of superoxide dismutase (26% decrease) and Sir2 (36% decrease), but these effects were not observed in the DHA-fed animals. These responses suggested that DHA did not increase oxidative stress and may have protected against it.
For additional evidence of membrane protection, the investigators measured calcium-independent phospholipase A2 and syntaxin-3 levels in the hippocampus. Animals on the regular diet had 65% of the enzyme activity observed in the sham controls, while the DHA-enriched animals had 104% of the activity observed in the controls. Syntaxin-3 levels followed the same pattern, with a 74% reduction in the untreated animals and 97% of the control levels observed in the DHA-fed animals. A summary of these observations is shown in the Table.
Taken together, these observations suggest that the provision of dietary DHA immediately after traumatic brain injury from increased fluid pressure counteracted the deleterious effects of the injury on cognitive function, neuronal signaling, membrane integrity, synaptic function and oxidative stress. The importance of protecting neuronal membrane structure and function may be critical for the preservation of synaptic function and neurotransmission, guarding against lipid peroxidation, maintenance of learning ability and memory and reduction in the damage associated with traumatic brain injury. The authors especially note the maintenance of BDNF with the DHA-enriched diet. This neurotrophic factor facilitates synaptic transmission, is involved in intracellular signaling, regulates the expression and activation of synapsin I and affects neurite outgrowth. It also activates the cAMP-response element-binding protein, which is involved in learning and memory. The findings of Wu and colleagues provide additional support to the idea that DHA may be involved in protecting cognitive and neuronal function in traumatic brain injury and support the existing literature in animal research on the protective effects of DHA on neuronal survival and function.
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