Medical Research: What are the main findings of your study?
Dr. Collins: There were several:
- First, we found that a cadre of neuroinflammatory proteins which promote or are stimulated by increased oxidative stress were significantly altered in a brain neurodegeneration model involving high alcohol binges in adult (male) rats. Most surprising was that the alterations were selectively evident in the three brain regions that contain a lot of dying neurons, and not in regions lacking neurodamage.
- Additionally, in an alcohol-binged adult rat brain cultures, the same neuroinflammatory protein alterations, along with the neuronal damage, were replicated.
- We further observed that binging the cultures depleted a key omega-3 fatty acid, termed DHA, in brain membranes. When these binged brain cultures were then supplemented with DHA, the neuroinflammatory protein changes and the neurodegeneration were largely or completely inhibited.
- The results link specific oxidative stress-associated neuroinflammatory routes to the brain neuronal demise arising from high binge alcohol exposures.
- They also reveal that supplementation with an omega-3 fatty acid reported to be neuroprotective with respect to other insults may be effective as well in suppressing the brain-damaging effects of excessive alcohol binges.
Medical Research: Were any of the findings unexpected?
Dr. Collins: There were several also, but to answer this, some details are necessary. Basically two polyunsaturated fatty acid families are essential for animal survival and have to be taken into the body via the diet, to be mainly chemically bound into cell membrane complex lipids—one is the omega-3 class already mentioned, and the second is the omega-6 group. Unlike omega-3’s however, too much “freeing up” of omega-6’s from these complex lipids can trigger oxidative stress and even cellular degeneration.
The second detail which is related is the kinds of neuroinflammatory proteins that we observed being changed by alcohol. When they are enhanced, several are capable of releasing too much omega-6 fatty acid, while another is the principal water channel in brain membranes that, when excessively elevated, can cause swelling of brain cells (we see this in alcohol-binged cultures, or in brain edema in the rats) and then trigger increases in the enzymes above that release omega-6’s. These findings were not entirely surprising based on our previous work; however, what was unexpected was another protein to be increased by alcohol, called PARP. This nuclear protein is amplfied by oxidative damage to DNA, but when increased too much, it can cause neuronal cell death, perhaps by signaling pathways that might involve the proteins mentioned above. It is possible, then, that oxidative breaks in DNA, perhaps via initial oxidative stress from alcohol itself, may start the whole cascade that could lead to even more oxidative stress—a sort of feed-forward mechanism.
A second somewhat unexpected finding was the all-encompassing nature of the protection against alcohol exhibited by omega-3 DHA in our brain culture study. We did not expect such potency.
Medical Research: What should clinicians and patients take away from your report?
Dr. Collins: It should be emphasized that levels/concentrations of alcohol we used are only achieved in chronic binging alcoholics. Most clinicians and many patients are aware that cognitive dysfunction and dementia are relatively common in chronic alcoholic individuals. As with other dementias, the loss of neurons, their axons and dendrites, and synapses on these brain structures in large measure underlies the cognitive impairments in the addiction. Some level of neuroprotection against these deficits might be achieved by intake of agents such as omega-3 fatty acid (DHA). Of course, reduction in or elimination of alcohol intake is the first step, but this is difficult in alcohol addiction.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Collins: Whereas the association between neuroinflammatory proteins and neurodegeneration were observed in intact adult male rats and in vitro in rat brain slice cultures, the protective effects of DHA were shown in the latter, so omega-3 supplementation studies are needed with adult male and female rats. We also want to examine the descrete molecular mechanisms promoted by DHA. Of course, if confirmed in vivo, it should be possible to design and carry out translational cognitive function studies with DHA in alcohol abusing individuals, basically mirroring the promising omega-3 fatty acid supplementation studies in numerous other neurological and cardiological reports.
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