Cellular inflammatory response plays an important role in ischemic
brain injury and anti-inflammatory treatments in
stroke are beneficial. Dietary supplementation with
docosahexaenoic acid (DHA) shows anti-inflammatory and
neuroprotective effects against
ischemic stroke. However, its effectiveness and its precise modes of neuroprotective action remain incompletely understood. This study provides evidence of an alternative target for DHA and sheds light on the mechanism of its physiological benefits. We report a global inhibitory effect of 3 consecutive days of DHA preadministration on circulating and intracerebral cellular inflammatory responses in a rat model of permanent
cerebral ischemia. DHA exhibited a
neuroprotective effect against ischemic deficits by reduction of behavioral disturbance,
brain infarction,
edema and blood-brain barrier disruption. The results of enzymatic assay, Western blot, real-time
reverse transcriptase polymerase chain reaction and flow cytometric analysis revealed that DHA reduced central macrophages/microglia activation, leukocyte infiltration and pro-inflammatory
cytokine expression and peripheral leukocyte activation after
cerebral ischemia. In parallel with these immunosuppressive phenomena, DHA attenuated post-
stroke oxidative stress,
c-Jun N-terminal kinase (JNK) phosphorylation, c-Jun phosphorylation and activating protein-1 (AP-1) activation but further elevated
ischemia-induced NF-E2-related factor-2 (Nrf2) and
heme oxygenase-1 (HO-1) expression. DHA treatment also had an immunosuppressive effect in
lipopolysaccharide/
interferon-γ-stimulated glial cultures by attenuating JNK phosphorylation, c-Jun phosphorylation and
AP-1 activation and augmenting Nrf2 and HO-1 expression. In summary, we have shown that DHA exhibited neuroprotective and anti-inflammatory effects against ischemic
brain injury and these effects were accompanied by decreased oxidative stress and JNK/AP-1 signaling as well as enhanced Nrf2/HO-1 expression.