Prolonged hypoxic/ischemic stress may cause cortical injury and clinically manifest as a neurological disability. Activation of the δ-
opioid receptor (DOR) may induce cortical protection against hypoxic/ischemic insults. However, the mechanisms underlying DOR protection are not clearly understood. We have recently found that DOR activation modulates the expression of
microRNAs (
miRNAs) in the kidney exposed to
hypoxia, suggesting that DOR protection may involve a
miRNA mechanism. To determine if the
miRNAs expressed in the cortex mediated DOR neuroprotection, we examined 19
miRNAs that were previously identified as
hypoxia- and DOR-regulated
miRNAs in the kidney, in the rat cortex treated with
UFP-512, a potent and specific DOR agonist under hypoxic condition. Of the 19
miRNAs tested, 17 were significantly altered by
hypoxia and/or DOR activation with the direction and amplitude varying depending on hypoxic duration and times of DOR treatment. Expression of several
miRNAs such as
miR-29b, -101b, -298, 324-3p, -347 and 466b was significantly depressed after 24 hours of
hypoxia. Similar changes were seen in normoxic condition 24 hours after DOR activation with one-time treatment of
UFP-512. In contrast, some
miRNAs were more tolerant to hypoxic stress and showed significant reduction only with 5-day (e.g., miR-31 and -186) or 10-day (e.g., miR-29a, let-7f and -511) exposures. In addition, these
miRNAs had differential responses to DOR activation. Other
miRNAs like miRs-363* and -370 responded only to the combined exposure to
hypoxia and DOR treatment, with a notable reduction of >70% in the 5-day group. These data suggest that cortical
miRNAs are highly yet differentially sensitive to
hypoxia. DOR activation can modify, enhance or resolve the changes in
miRNAs that target HIF, ion transport, axonal guidance,
free radical signaling, apoptosis and many other functions.