GLA had a beneficial effect on the course of diabetic neuropathy.

Eribis peptide 94 (EP 94) is a novel enkephalin derivative which binds with high potency to μ and δ opioid receptors with less affinity for the κ opioid receptor. This compound has recently been shown to produce an acute reduction in myocardial infarct size in the anesthetized pig and rat partially via an eNOS- and KATP channel-dependent mechanism. EP 94 also was found to produce a chronic reduction in infarct size 24 hrs post drug administration via the upregulation of iNOS in rats. In spite of these findings, no data have emerged in which the opioid receptor subtype responsible for cardioprotection has been identified and the site of action, heart, other peripheral organs or the CNS have not been addressed. In the current study, EP 94, was administered in 2 divided doses (0.5 ug/kg, iv) at 5 and 10 min into the ischemic period and the opioid antagonists were administered 10 min prior to the onset of the 30 min ischemic period. The selective antagonists used were the μ receptor antagonist CTOP, the δ receptor antagonists, naltrindole and BNTX and the κ receptor antagonist, nor-BNI. Surprisingly, only CTOP completely blocked the cardioprotective effect of EP 94, whereas, naltrindole, BNTX and nor-BNI had modest but nonsignificant effects. Since there is controversial evidence suggesting that μ receptors may be absent in the adult rat myocardium, it was hypothesized that the protective effect of EP 94 may be mediated by an action outside the heart, perhaps in the CNS. To test this hypothesis, rats were pretreated with the nonselective opioid antagonist, naloxone HCl (NAL), which penetrates the blood brain barrier (BBB) or naloxone methiodide (NME), the quaternary salt of NAL, which does not penetrate the BBB prior to EP 94 administration. In support of a CNS site of action for EP 94, NAL completely blocked its cardioprotective effect, whereas, NME had no effect. These results suggest that EP 94 reduces IS/AAR in the rat primarily via activation of central μ opioid receptors.

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Background/Aims: Eribis peptide 94 (EP 94) is a new enkephalin derivative which potently binds to the µ- and δ-opioid receptor. In this study, we determined the effects of EP 94 and potential mechanism(s) involved in cardioprotection of the rat heart. Methods and Results: An acute (5 and10 min into ischemia) and a chronic (24 h prior to ischemia) EP 94 administration produced a similar 30–40% reduction in infarct size/area at risk and the effects were blocked by the K_ATP channel antagonists, HMR 1098 and 5-HD. The cardioprotective effects were blocked by a nonselective nitric oxide synthase (NOS) inhibitor (L-NAME) following acute administration and by a selective iNOS inhibitor (1400W) following chronic administration. Conclusion: These results suggest that EP 94 may have potential for the treatment of ischemic heart disease via a nitric oxide (NO)-K_ATP-mediated mechanism.