δ-opioid Receptor, Microglia and Neuroinflammation

Abstract

Neuroinflammation underlies the pathophysiology of multiple age-related neurological disorders. Microglia, the resident immune cells of the central nervous system, are critically involved in neuroinflammatory regulation and neural survival. Modulating microglial activation is thus a promising approach to alleviate neuronal injury. Our serial studies have revealed a neuroprotective role of the δ-opioid receptor (DOR) in several acute and chronic cerebral injuries by regulating neuroinflammation and cellular oxidative stress. More recently, we found an endogenous mechanism for the inhibition of neuroinflammation is closely related to DOR’s modulation of microglia. Our recent studies showed that DOR activation could strongly protect neurons from hypoxia- and lipopolysaccharide (LPS)-induced injury by inhibiting microglial pro-inflammatory transformation, while knocking-down DOR or restraining DOR activity promoted microglia activation and the relevant inflammatory events with an aggravation of cell injury. This novel finding highlights a therapeutic potential of DOR in numerous age-related neurological disorders through the modulation of neuroinflammation by targeting microglia. This review summarized the current data regarding the role of microglia in neuroinflammation, oxidative stress, and age-related neurological diseases focusing on the pharmacological effects and signaling transduction of DOR in microglia.

RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway

“…Numerous studies had provided evidence that an elevation in M2 phenotype microglia following SAH was linked to a more favorable neurological outcome, which indicated that a promising approach for microglia-mediated neuroinflammation in SAH was regulating microglial phenotype from M1 to M2 [ 18 , 50 , 51 ]. However, the specific mechanisms and modulators were not completely understood [ 52 ]. To further evaluate the microglial response status following SAH, we utilized skeleton analysis and fractal analysis with immunofluorescence for Iba1 to assess microglial morphology.…”

SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis

“…This signaling pathway also mediated the neuroprotective effects of SNC-121 and biphalin in the retinal ganglion of glaucoma models and in the brain of a neonatal cerebral ischemia model, respectively [66,72]. Although the mechanism of signal activation by DOR has not been clearly identified [73], it is possible that DOR agonists exert their effects via a signal distinct from that of the cAMP pathway. The second hypothesis is that SYK-623 potentiates the action of endogenous agonists through its receptor-upregulating effects, a commonly observed property of inverse agonists [18].…”

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation

“…Recent reviews have summarized advances in the dynamics of the extracellular matrix and the regulation of intracellular transcription factors [ 129 , 130 ]. A growing body of research has shifted focus toward the role of neuroinflammation, providing novel insights that could potentially impede or inhibit the progression of such age-related brain disorders [ 131 , 132 ]. MSCs, particularly the MSCs-based cell-free therapy, have emerged as a potent therapeutic strategy.…”