Dadle

[D-Ala2, D-Leu5] enkephalin, commonly referred to as DADLE, is a synthetic delta-opioid peptide with a range of biological effects. It has been shown to induce a hibernation-like state in mammals and has protective properties in various tissues subjected to ischemic conditions. The interest in DADLE spans across multiple fields due to its potential therapeutic applications, particularly in ischemia-reperfusion injury, cell protection, and modulation of cellular metabolism123456910.

DADLE exerts its effects primarily through the activation of the delta-opioid receptor (DOR). Activation of DOR leads to a cascade of intracellular events, including the phosphorylation of pro-survival kinases such as Akt and ERK. This signaling pathway is crucial for the protective effects of DADLE against ischemic injury. For instance, in the context of heart ischemia, DADLE's protective effects are mediated by the transactivation of the epidermal growth factor receptor (EGFR), which in turn activates Akt and ERK, leading to reduced infarct size2. Similarly, in the brain, DADLE postconditioning can protect hippocampal neurons from ischemic injury through the Akt pathway4. Moreover, DADLE has been shown to induce autophagy in astrocytes, which contributes to its cytoprotective effects9. Interestingly, some studies suggest that DADLE's effects on transcription and cell metabolism do not solely depend on opioid receptors, indicating additional mechanisms of action610.

Ischemia-Reperfusion Injury

DADLE has demonstrated significant protective effects against ischemia-reperfusion (I-R) injury in various organs. In the liver, DADLE administration before ischemia reduced serum glutamic-pyruvic transaminase levels and liver tissue malondialdehyde concentrations, indicating protection against hepatocyte I-R injury1. In the heart, DADLE reduced infarct size when administered at reperfusion, with its effects being dependent on pro-survival kinase activation2. Additionally, DADLE postconditioning has been shown to protect neurons from transient forebrain ischemia, improving behavioral and cognitive outcomes in rats4.

Cell Protection and Metabolism

DADLE enhances the viability and anti-inflammatory effects of human mesenchymal stem cells (MSCs) under serum-starved conditions, which is partly mediated by the DOR/PI3K/AKT pathway5. It also induces a reversible hibernation-like state in HeLa cells, decreasing transcription and proliferation, which resumes upon removal of DADLE3. Furthermore, DADLE can inhibit cellular transcription in neurons without causing cell injury, suggesting a potential therapeutic strategy for neuroprotection10.

Neuroprotection

In the context of neuronal injury, DADLE has been shown to reduce oxygen-glucose deprivation-caused neuronal injury through the MAPK pathway, balancing the activation of ERK and p388. It also exerts a cytoprotective effect in astrocytes exposed to oxygen-glucose deprivation by inducing autophagy and inhibiting apoptosis9.

Other Potential Applications

While not directly related to DADLE's biological effects, it is worth noting that research has also been conducted on improving action recognition accuracy in computational models by using descriptors inspired by kinematic fields, which are named after DADLE due to their discriminative properties7. This highlights the broad influence of DADLE's concept beyond biomedical research.