Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults. Extensive evidences have documented that oxidative stress mediates a critical role in the pathogenesis of DR. Acrolein, a product of polyamines oxidation and lipid peroxidation, has been demonstrated to be involved in the pathogenesis of various human diseases. Acrolein’s harmful effects are mediated through multiple mechanisms, including DNA damage, inflammation, ROS formation, protein adduction, membrane disruption, endoplasmic reticulum stress, and mitochondrial dysfunction. Recent investigations have reported the involvement of acrolein in the pathogenesis of DR. These studies have shown a detrimental effect of acrolein on the retinal neurovascular unit under diabetic conditions. The current review summarizes the existing literature on the sources of acrolein, the impact of acrolein in the generation of oxidative damage in the diabetic retina, and the mechanisms of acrolein action in the pathogenesis of DR. The possible therapeutic interventions such as the use of polyamine oxidase inhibitors, agents with antioxidant properties, and acrolein scavengers to reduce acrolein toxicity are also discussed.

Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.

Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX), is protective against neurodegeneration and inflammation in the models of diabetic retinopathy and excitotoxicity. In the present study, utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined the impact of SMOX blockade on retinal neurodegeneration and optic nerve inflammation. The increased expression of SMOX observed in EAE retinas was associated with a significant loss of retinal ganglion cells, degeneration of synaptic contacts, and reduced visual acuity. MDL 72527-treated mice exhibited markedly reduced motor deficits, improved neuronal survival, the preservation of synapses, and improved visual acuity compared to the vehicle-treated group. The EAE-induced increase in macrophage/microglia was markedly reduced by SMOX inhibition. Upregulated acrolein conjugates in the EAE retina were decreased through MDL 72527 treatment. Mechanistically, the EAE-induced ERK-STAT3 signaling was blunted by SMOX inhibition. In conclusion, our studies demonstrate the potential benefits of targeting SMOX to treat MS-mediated neuroinflammation and vision loss.

Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.

Background: Tirzepatide (Mounjaro or Zepbound), a dual GLP-1/GIP receptor agonist, is approved for type 2 diabetes and weight management. Despite its efficacy, real-world safety data remain limited. This study analyzed post-marketing adverse events (AEs) associated with tirzepatide using the FDA Adverse Event Reporting System (FAERS) to identify emerging safety concerns. Methods: FAERS reports from 2022 to Q1 2025 were analyzed. Disproportionality analyses (proportional reporting ratio [PRR], reporting odds ratio [ROR], empirical Bayes geometric mean [EBGM], and information component [IC]) were performed to detect safety signals. Reports were stratified by year, demographics, and AE type, focusing on cases in which tirzepatide was the primary suspect. Results: Among 65,974 reports, the majority originated from the U.S. (96%), with middle-aged females (40–59 years; 67%) most frequently affected. Incorrect dose administration was the top AE, increasing 8-fold from 1248 (2022) to 9800 (2024), with strong risk signals (ROR 22.15, 95% CI (20.75–23.65), and ROR 23.43, 95% CI (22.82–24.05), respectively, and PRR 16.80, 95% CI (15.74–17.93), and PRR 17.62, 95% CI (17.16–18.09), respectively). Other common AEs included injection-site reactions (e.g., pain [5273 cases in 2024]), gastrointestinal issues (nausea [3602 in 2024]), and off-label use. Class-related AEs (e.g., decreased appetite and blood glucose fluctuations) were also reported. Conclusions: Tirzepatide is associated with significant dosing errors, injection-site reactions, and gastrointestinal AEs in real-world use. The rising trend in reports underscores the need for enhanced provider and patient education, clearer dosing guidelines, and proactive monitoring. Further research is warranted to explore causative factors and optimize risk mitigation strategies.

Diabetic retinopathy, a major cause of vision loss, is characterized by neurovascular changes in the retina. The lack of effective treatments to preserve vision in diabetic patients remains a significant challenge. A previous study from our laboratory demonstrated that 12-week treatment with MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX, a critical regulator of polyamine metabolism), reduced neurodegeneration in diabetic mice. Utilizing the streptozotocin-induced diabetic mouse model and MDL 72527, the current study investigated the effectiveness of SMOX inhibition on the measures of vision impairment and neuro-glial injury following 24 weeks of diabetes. Reductions in visual acuity, contrast sensitivity, and inner retinal function in diabetic mice were improved by MDL 72527 treatment. Diabetes-induced changes in neuronal-specific class III tubulin (Tuj-1), synaptophysin, glutamine synthetase, and vimentin were attenuated in response to SMOX inhibition. In conclusion, our findings show that SMOX inhibition improved visual acuity, contrast sensitivity, and inner retinal function and mitigated diabetes-induced neuroglial damage during long-term diabetes. Targeting SMOX signaling may provide a potential strategy for reducing retinal neuronal damage and preserving vision in diabetes.