Neuroprotectin D1 upregulates Iduna expression and provides protection in cellular uncompensated oxidative stress and in experimental ischemic stroke

Abstract

Ring finger protein 146 (Iduna) facilitates DNA repair and protects against cell death induced by NMDA receptor-mediated glutamate excitotoxicity or by cerebral ischemia. Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived lipid mediator, promotes cell survival under uncompensated oxidative stress (UOS). Our data demonstrate that NPD1 potently upregulates Iduna expression and provides remarkable cell protection against UOS. Iduna, which was increased by the lipid mediator, requires the presence of the poly(ADP-ribose) (PAR) sites. Moreover, astrocytes and neurons in the penumbra display an enhanced abundance of Iduna, followed by remarkable neurological protection when DHA, a precursor of NPD1, is systemically administered 1 h after 2 h of ischemic stroke. These findings provide a conceptual advancement for survival of neural cells undergoing challenges to homeostasis because a lipid mediator, made 'on demand,' modulates the abundance of a critically important protein for cell survival.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…There is not yet a broad consensus as to whether any or all of these ligands represent authentic endogenous ligands for GPR37, and further studies in vivo will be necessary to address this important question. Nonetheless, it is intriguing to note that both prosaptide (23)(24)(25) and neuroprotectin D1 (26)(27)(28) have been shown to be protective against ischemia. Thus, the data shown here revealing that deletion of GPR37 results in greater damage in a mouse model of ischemia is consistent with a role for prosaptide or neuroprotectin D1 as modulators or agonists of GPR37.…”

“…The reported ligands for GPR37 include prosaposin and its active fragment prosaptide (17)(18)(19), an invertebrate peptide related to prosaptide known as head activator peptide (20,21), and the lipid metabolite neuroprotectin D1 (22). Intriguingly, both prosaptide (23)(24)(25) and neuroprotectin D1 (26)(27)(28) have been reported to exert protective actions in rodent models of nerve injury or stroke. Moreover, a recent study reported that deletion of the GPCR GPR37-like 1 (GPR37L1), a relative of GPR37 that is expressed mainly in astrocytes, results in increased brain damage and cell death likely because of increased extracellular glutamate concentration and NMDA receptor activation (29).…”

Neuroprotectin D1 Protects Against Postoperative Delirium-like Behaviors in Aged Mice by Regulating Neuroinflammation Induced by Surgical Trauma

“…Secondly, we only focused on the impact of NPD1 in regulating in ammation in our study, but not the signaling pathways leading to the phenomenon. It has been documented that the neuroprotection of NPD1 is elicited through NF-κB or PI3K/Akt phosphorylation signaling [22,[87][88][89], which gives the reference to illuminate the particular pathways of NPD1 in the perioperative setting.…”

Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation

“…The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38][39][40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37][38][39][40][41]. In addition, the DHA derivatives exert a range of potent neuroprotective properties that include inhibition of proinflammatory gene expression and leukocyte infiltration.…”