N,N-Dimethyl-3β-hydroxycholenamide attenuates neuronal death and retinal inflammation in retinal ischemia/reperfusion injury by inhibiting Ninjurin 1

Abstract

Background Retinal ischemia–reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells. Methods Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R). Results DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of − 6.6 kcal/mol, suggesting highly stable binding. Conclusion Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia–Reperfusion in the Eyes of Sprague Dawley Rats

“…A similar protective effect is a hallmark of other anti-ischemic agents as well [ 31 , 32 , 49 ]. It is well documented that a common consequence of ischemia–reperfusion injury is edema [ 46 , 50 ], and then necro-apopto-autophagy, i.e., initiation of different cell-death mechanisms, resulting in thinning of retinal layers [ 47 , 51 , 52 ]. Edema, however, may be transient, which implies a reversible injury as well [ 46 , 53 ].…”

Immunological Landscape of Retinal Ischemia-Reperfusion Injury: Insights into Resident and Peripheral Immune Cell Responses

“…Lastly, the integration of multi-omics approaches (genomics, proteomics, metabolomics) in RIRI research will enable a more comprehensive understanding of the disease at the molecular level [30,196,[205][206][207]. This approach is anticipated to uncover novel biomarkers and therapeutic targets, paving the way for personalized medicine in RIRI management.…”