Astroglial Reaction to Delta Opioid Peptide [D-Ala2, D-Leu5] Enkephalin Confers Neuroprotection Against Global Ischemia in the Adult Rat Hippocampus

Delta opioid receptor (DOR) is essential for neuronal survival against hypoxic/ischemic damages. However, current understanding on how DOR activation affects astrocytic functions under ischemia remains incomplete. The present study investigated the astroglial responses to [d-Ala2, d-Leu5] enkephalin (DADLE) (a selective DOR agonist)-induced DOR activation after global cerebral ischemia. Adult male rats were preimplanted with intracerebral cannula and subjected to global ischemia for 10 min. The rats were divided into four groups: normal group (without any procedure), sham group (sham procedure with intracerebroventricular injection of ACSF), I/R group (ischemia procedure with intracerebroventricular injection of ACSF) and DAD-treated group (ischemia procedure with intracerebroventricular injection of DADLE). Hippocampal CA1 neuronal survival and activation of astrocytes were measured in the animals at 72 h post-ischemia. The distribution and phenotypes of p-Akt and active caspase-3 were also determined. The ischemic injury resulted in a significant neuronal loss and an increase in the dying astrocytes in the hippocampal CA1 region as compared with those in the sham animals (200.7±22.7/mm(2) vs. 6.6±3.1/mm(2), P<0.001). Improved neuronal survival in the DAD-treated animals was evident, which was accompanied by less dying astrocytes and enhanced astrocytes reaction with more active astrocytes than that in the I/R group (267.6±13.2/mm(2) vs. 157.0±18.1/mm(2), P<0.01) and a significantly increased immunoreactivity of p-Akt. However, the active caspase-3 positive cells were also evident in DAD-treated group (313.0±23.1/mm(2)) and significantly increased as compared with those of the sham group (159.0±15.8/mm(2), P<0.001) or I/R group (193.6±26.2/mm(2), P<0.01). Most of the active caspase-3-expressing cells were colabeled with glial fibrillary acidic protein (GFAP), an astrocytes marker. We conclude that the post-ischemic treatment with DADLE promotes beneficial astrocytes activation and induces astroglial apoptosis 72 h after reperfusion which may be involved in reducing their harmful effect to neurons survival.