Abstract
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.
Highlights
Hypoxic/ischemic stress causes cortical neural injury that may result in serious neurological disorders and disability
Owing to a higher density of d-opioid receptors (DOR) in the cortex, it is not surprising that the miRNAs profiled in the cortex are more affected by DOR activation with UFP-512 than in the kidney
DOR activation accelerates the resolution of hypoxiainduced changes in miR-29b, -347 and -324-3p expression in the cortex
Summary
Hypoxic/ischemic stress causes cortical neural injury that may result in serious neurological disorders and disability. We have previously shown that the activation and/or expression of the d-opioid receptors (DOR) is neuroprotective against hypoxic, ischemic and excitotoxic insults [1,2,3,4,5,6,7,8,9,10,11,12]. Substantial evidence from various independent laboratories have reaffirmed that DOR is neuroprotective against hypoxic/ischemic stress [13,14,15,16,17,18,19,20] in part by increasing the antioxidant activity [21], and partly through regulation of survival and death signaling [3,10]. The exact mechanisms underlying DOR neuroprotection are still unclear
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