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.