Oxidation of DHA to neuroprostanes is associated with synaptic loss. Further oxidation produces a toxic end-product, 4-hydroxyhexenal, that contributes to neuron death Tubacin MM and defective uptake of glucose by neurons and glutamate by astrocytes. Clinical studies demonstrate that similar dosing with marine n-3 fatty acids (polyunsaturated fatty acids with a double bond at the third carbon), including DHA, can deplete vitamin E and increase some peripheral measures of oxidative damage, particularly with dosing up to 6 months [16]. Because DHA is enriched in the brain where oxidative damage is already increased in AD patients, antioxidant supplements optimized for AD brain appear crucial. Even though marine n-3 fatty acids can deplete vitamin E, high dose vitamin E (900 IU) did not reduce measures of lipid peroxidation in human plasma [17], so vitamin E supplementation is probably not sufficient.

In mice the lipophilic phenolic antioxidant food additive butylhydroxytoluene attenuated measures of lipid peroxidation in plasma after high intake of fish oil [18]. The preclinical studies with DHA in AD mouse models require encapsulation of DHA in the chow to minimize oxidation [10,11]. Also, using the US Food and Drug Administration’s equation to estimate the human equivalent doses, the clinical trial dose was three-fold higher than the efficacious preclinical dose in mice [10,11], and twice as high as in the MIDAS trial [7], raising questions about whether the dose may have been too high, potentially exacerbating oxidative damage.

Possible cognitive benefits in patient subgroups (pharmacogenomic or otherwise) would be strengthened by evidence of a biomarker response, arguing for the need to validate neuroimaging, cerebrospinal fluid or plasma biomarker responses Carfilzomib in preclinical studies going forward. MRI was performed in a small subset of subjects, showing that volumentrics of the left hippo-campus in the DHA group showed trends to be smaller than in the placebo group (P = 0.17), which may indicate brain shrinkage. In the AN1792 active A?? vaccination, MRI shrinkage was attributed to plaque clearance. Since drugs may only work in a subset of patients, it would be helpful in large selleck inhibitor studies where neuroimaging or cerebrospinal fluid biomarker analysis are less feasible to identify likely responders with plasma biomarkers. A difficult task at hand is to design future DHA or other trials with earlier intervention to include validated surrogate and/or diagnostic biomarkers that have shown DHA responses in animal models. For tracking adverse effects of DHA, it is important to measure blood vitamin E depletion and lipid peroxides (thiobarbituric acid reactive substances, malondialdehyde, or the specific byproduct of DHA oxidation, 4-hydroxyhexenal).