Delta Opioid Peptide[<i>D</i>- Ala²,<i>D</i>-Leu⁵]Enkephalin Promotes Cell Survival

Abstract

By studying the hibernation in ground squirrels, a protein factor termed hibernation induction trigger (HIT) was found to induce hibernation in summer-active ground squirrels. Further purification of HIT yielded an 88-kD peptide that is enriched in winter hibernator. Partial sequence of the 88-kD protein indicates that it may be related to the inhibitor of metalloproteinase. Delta opioid [D-Ala²,D-Leu⁵]enkephalin (DADLE) also induced hibernation. HIT and DADLE were found to prolong survival of peripheral organs preserved en bloc or as a single preparation. These organs include the lung, the heart, liver and kidney. DADLE also promotes survival of neurons in the central nervous system. Methamphetamine (METH) is known to cause destruction of dopaminergic (DA) terminals in the brain. DADLE blocked and reversed the DA terminal damage induced by METH. DADLE acted against this effect of METH at least in part by attenuating the mRNA expressions of a tumor necrosis factor p53 and an immediate early gene c-fos. DADLE also blocked the neuronal damage induced by ischemia-reperfusion following a transient middle cerebral artery occlusion. In PC12 cells, DADLE blocked the cell death caused by serum deprivation in a naltrexone-sensitive manner. Thus, DADLE, and by extension the endogenous delta opioid peptides and delta opioid receptors, may play an important role in organ and neuronal survival. Here, critical developments concerning these fascinating cell protective properties of DADLE are reviewed.

The effect of the enkephalin DADLE on transcription does not depend on opioid receptors

“…DADLE has been demonstrated to induce hibernation in summer active rodents (Su 2000) and to mimic some Fig. 1 Aldehyde-OsO4-fixed, Epon-embedded samples.…”

DADLE induces a reversible hibernation-like state in HeLa cells

“…Moreover, as another major point of interest, this compound can have an effect comparable to the hibernation induction trigger (HIT) (Horton et al 1998), a factor which is believed to initiate the cascade leading the hibernating mammal to lower its body temperature and to slow down its metabolism in order to survive during the winter months (Bruce et al 1996(Bruce et al , 1997a. It has in fact been shown that DADLE induces hibernation when injected into ground squirrels in summer (Su 2000).…”

Effect of a δ Receptor Agonist on Duration of Survival during Hemorrhagic Shock

“…* of action, DADLE was chosen because of evidence in the literature demonstrating multiple mechanisms thought to attenuate ischemic insults. 10,[14][15][16]19,25 In this way, DADLE, an analogue of HIT, may mimic the comprehensive protective approach to physiologic systems used by hibernating animals. The coordination of these defensive mechanisms within the hibernating organism through the multiple physiologic and biochemical actions is still under investigation, and is presently incompletely understood.…”

“…As previously described, DADLE as a supposed analog of naturally occurring HIT has been found to ameliorate the effects of an ischemic insult by multiple mechanisms as is probable in the case of the hibernating animal. 10,15,16,19,25 The pathways of these protective mechanisms within the whole organism as well as individual tissues are as uncertain as they are diverse, and are presently under investigation by numerous researchers. 23,25 We hypothesized that DADLE, by these varied mechanisms, works in concert in the intact organism to improve overall survival during severe hemorrhagic shock.…”