[Leu5]-Enkephalin

Protective effect of delta opioid receptor agonist (D-Ala2, D-Leu5) enkephalin on permanent focal cerebral ischemia in rats.[Pubmed:27232517]

Neuroreport. 2016 Jul 6;27(10):749-54.

To investigate the effect of delta opioid receptor agonist (D-Ala, D-Leu) enkephalin (DADLE) on the permanent focal cerebral ischemia in rats. Thirty four male Sprague-Dawley rats were assigned randomly into three groups: sham group (group Sham, n=10), artificial cerebrospinal fluid group (group ACSF, n=12), and DADLE group (group DADLE, n=12). Permanent middle cerebral artery occlusion was performed to induce permanent focal cerebral ischemia in rats. Then, the animals in group DADLE and group ACSF were treated with DADLE or ACSF by an intracerebroventricular injection at 45 min after ischemia. Neurologic deficit scores were assessed according to the Garcia criterion at 24 h after ischemia. Infarct volume was determined using the 2,3,5-triphenyltetrazolium chloride staining method. The histological analysis was used to evaluate the extent of cerebral injury. Compared with the control group, the Garcia scores were significantly higher (P=0.000) and the infarct volumes (P=0.018) were significantly smaller in the DADLE treatment group at 24 h after ischemia. These neurologic changes were closely correlated with the outcome of the infarct volumes. In addition, the histological examination showed more intact neurons in rats treated with DADLE than those treated with ACSF at 24 h after ischemia (P=0.000). DADLE by intracerebroventricular administration at 45 min after ischemia can improve neurologic outcome and mitigate cortical neuronal injury induced by permanent focal cerebral ischemia in rats.

Increase in antinociceptive effect of [leu5]enkephalin after intrathecal administration of mixture of three peptidase inhibitors.[Pubmed:23868737]

Tokai J Exp Clin Med. 2013 Jul 20;38(2):62-70.

OBJECTIVE: Previous in vitro studies have shown that the degradation of [Leu5]enkephalin during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors such as amastatin, captopril, and phosphoramidon. The present in vivo study was performed to examine the antinociceptive effect of [Leu5]enkephalin administered intrathecally under pretreatment with these three peptidase inhibitors. METHODS: A tail-flick test was used to determine the nociceptive threshold after administration of [Leu5]enkephalin. The time-course profiles of the latency to flick the tail and the area under the time response curve were evaluated for the antinociceptive action of the drug. RESULTS: The antinociceptive effect of [Leu5]enkephalin administered intrathecally on the tail-flick test was increased more than 100-fold under i.t. pretreatment with three peptidase inhibitors. The antinociceptive effect produced by [Leu5]enkephalin in rats pretreated with any single peptidase inhibitor increased antinociception compared to that with saline. The antinociceptive potency of [Leu5]enkephalin under pretreatment with any combination of two peptidase inhibitors was smaller than that in rats pretreated with three peptidase inhibitors together. These results indicate that any residual single peptidase inactivates significant amounts of [Leu5]enkephalin. CONCLUSION: The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in the inactivation of [Leu5]enkephalin administered intrathecally in rat.

Protection of rat intestinal epithelial cells from ischemia/reperfusion injury by (D-Ala2, D-Leu5)-enkephalin through inhibition of the MKK7-JNK signaling pathway.[Pubmed:26126577]

Mol Med Rep. 2015 Sep;12(3):4079-4088.

Previous studies have demonstrated that (DAla2, DLeu5)enkephalin (DADLE) protects rats from hepatic ischemia/reperfusion (I/R) injury. In the present study, DADLE was also observed to alleviate IRinduced intestinal epithelial cell injury in rats by inhibiting mitogenactivated protein kinase kinase 7 (MKK7)cJun Nterminal kinase (JNK) pathway signaling. To investigate the protective effect of DADLE on hypoxia/reoxygenation injury in rat intestinal epithelial cells, rat intestinal epithelial cells were treated with different concentrations of DADLE, following which the cell survival rate was determined using a tetrazolium (MTT) colorimetric assay, and apoptosis was determined using flow cytometry. To confirm whether the protective effect of DADLE was due to its effect on MKK7JNK signaling, the phosphorylation levels of MKK7 and JNK were analyzed using western blot analysis following treatment with different concentrations of DADLE. The results demonstrated that, following treatment with DADLE, the survival rate of the rat intestinal cells subjected to I/Rinduced injury increased significantly and the apoptotic rate decreased in a concentrationdependent manner. In addition, the levels of phosphorylated MKK7 and JNK decreased in a concentrationdependent manner following treatment with DADLE. Silencing the gene expression of MKK7 using small interfering RNA prior to DADLE treatment resulted in a reduction in the protective effects of DADLE on the rat intestinal epithelial cells subjected to I/R injury. Collectively, the results of the present study demonstrated that the protective effects of DADLE in I/R injury in rat intestinal cells occurred through inhibition of the MKK7JNK pathway.

Protective effect of delta opioid agonist [D-Ala2, D-Leu5] enkephalin on spinal cord ischemia reperfusion injury by regional perfusion into abdominal aorta in rabbits.[Pubmed:25283992]

Neurosci Lett. 2015 Jan 1;584:1-6.

[D-Ala(2), D-Leu(5)] enkephalin (DADLE) has been reported to exhibit protective effects against hypoxic or ischemic induced brain insult. However its efficacy on the spinal cord ischemia-reperfusion injury remains unclear. Here we investigate whether DADLE could attenuate ischemia and reperfusion induced neural injury in the rabbit spinal cord. New Zealand white rabbits were subjected to spinal cord ischemia by infrarenal aortic occlusion for 30 min. In the period of spinal cord ischemia, DADLE 0.5 mg/kg or NS were infused continuously into the distal clamped abdominal aorta. The heart rate, blood pressure, and core temperature were monitored continuously during the whole experimental procedure. Then the neurological behavioral function was assessed with Tarlov scale system at 1h, 6h, 24h, 48 h after reperfusion, and neuronal injury evaluation in the ventral horn of gray matter was measured by counting the normal motor neurons at 48 h after reperfusion. Comparing with the control group, the Tarlov scores were significantly higher and the incidences of paraplegia were significantly lower in the DADLE group at four time-point recorded. In addition, the normal neurons numbers in the DADLE group were significant more than those in the control group at 48 h after reperfusion. These results suggested that DADLE infused into the abdominal aorta during ischemia period could attenuate behavioral retardation and the loss of normal motor neuron induced by ischemia-reperfusion in rabbits.

Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effect of conformational constraints on opiate receptor selectivity.[Pubmed:6296388]

J Med Chem. 1982 Dec;25(12):1432-8.

Using a combination of solid-phase and solution methods, we synthesized a series of cyclic [Leu5]enkephalin analogues by substitution of D-alpha, omega-diamino acids in position 2 of the enkephalin sequence and cyclization of the omega-amino group to the C-terminal carboxy group of leucine. Cyclic analogues containing D-alpha, beta-diaminopropionic acid (1), D-alpha, gamma-diaminobutyric acid (2), D-ornithine (3), or D-lysine (4) in position 2 and the [D-Leu5] and [des-Leu5] analogues of 4 (5 and 6) showed, in general, high potency in the guinea pig ileum (GPI) assay and low potency in the mouse vas deferens (MVD) assay. IC50 (MVD)/IC50 (GPI) ratios ranging from 3.1 to 29.4 were obtained, indicating the preference of the cyclic analogues for mu receptors over delta receptors. With two exceptions, preferential affinity for mu receptors is reflected in the Ki ratios determined in parallel binding assays using [3H]naloxone and [3H] [D-Ala2, D-Leu5]enkephalin as mu and delta receptor selective radioligands, respectively. Comparison of the pharmacological profiles of the cyclic analogues 1-4 with those of their corresponding open-chain analogues, [D-Ala2, Leu5]enkephalinamide (1a), [D-Abu2, Leu5]enkephalinamide (2a), [D-Nva2, Leu5]enkephalinamide (3a), and [D-Nle2, Leu5]enkephalinamide (4a), revealed that the pronounced mu character of compounds 1-4 is a direct consequence of the conformational constraints introduced by cyclization. This finding is in agreement with the concept of different conformational requirements of mu- and delta-opiate receptors and raises the possibility of manipulating opiate receptor selectivity by varying the type and degree of conformational restriction.

[Leu5]-Enkephalin is a pentapeptides with morphine like properties. [Leu5]-Enkephalin is a five amino acid endogenous peptide that acts as an agonist at opioid receptors.

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