Retinal ischemia, a critical factor in vision-threatening disorders, has been increasingly understood through the lens of cellular pathology and molecular biology. This condition is central to a spectrum of retinal diseases, including central or branch retinal artery/vein occlusion, age-related macular degeneration, glaucoma, and others, which are intricately linked with cumulative oxidative stress. These pathological changes, occurring at the cellular level, have profound implications on the functionality and survival of various retinal cells.
For instance, the retinal pigment epithelium (RPE), with its limited regenerative capability, plays a pivotal role in the health of rod and cone cells. The progressive degeneration and death of RPE cells is a significant contributor to the onset of diseases like age-related macular degeneration. Patients with such conditions often experience severe visual impairment, losing the ability to recognize facial features. Furthermore, this visual decline has been correlated with psychological impacts, including depression and mental breakdowns.
A key molecular player in retinal ischemia is vascular endothelial growth factor (VEGF), which is secreted in increased amounts during such conditions. The upregulation of VEGF is closely linked to the activity of hypoxia-inducible factor 1-alpha (HIF-1α), a response to oxidative stress. Pyruvate kinase M2 (PKM2) has been identified as a co-activator of HIF-1α, suggesting a complex interplay in the activation of VEGF expression. The interaction between PKM2 and HIF-1α leads to increased VEGF secretion, contributing to the development of fragile and permeable neovascular vessels, a hallmark of retinal ischemia.
Furthermore, inflammatory processes following reperfusion significantly exacerbate retinal cell death. A critical molecule in this process is monocyte chemoattractant protein-1 (MCP-1), known for its role in inducing retinal neovascularization and orchestrating the inflammatory cascade in ischemic retinopathy. MCP-1 regulates retinal neovascularization and inflammation via increased chemotaxis of cells like macrophages. Additionally, monocytes and macrophages are implicated in reactive oxygen species (ROS) production and inflammation, leading to neovascularization, vascular permeability, and dysfunction. Importantly, the interaction between PKM2 and MCP-1 has been highlighted in recent studies, such as that by Doddapattar et al. (2022), indicating a correlation between PKM2 deficiency and reduced activity of proinflammatory molecules.
The study also investigated the role of S-allyl L-cysteine (SAC), a component found in dry aged garlic extract, known for its antioxidative and neuroprotective properties. The research aimed to explore the therapeutic potential of SAC in the context of retinal ischemia. Garlic, a common ingredient in both Asian and Caucasian cuisines, presents an interesting avenue for evaluating therapeutic effects. SAC’s properties were assessed through cell culture experiments on porcine RPEs under oxidative stress conditions and in an animal model of retinal ischemia. Antioxidants, like SAC, are increasingly recognized for their role in the treatment and prevention of ischemia-related disorders.
In-depth analysis
The Therapeutic Potential of S-allyl-L-cysteine: A Comprehensive Review on Neuroprotection and Underlying Mechanisms
Abstract: S-allyl-L-cysteine (SAC), an organosulfur compound derived from garlic, has been recognized for its potent antioxidant properties and its role in traditional medicine. This review delves into the neuroprotective effects of SAC, particularly against endoplasmic reticulum (ER) stress-related neurodegenerative conditions, and explores its potential as a therapeutic agent.
SAC, primarily sourced from Allium sativum (garlic), is created through the hydrolysis of γ-glutamyl-S-allyl-cysteine (GSAC) by γ-glutamyl transpeptidase (γGTP). Notable for its high antioxidant capacity, SAC is a common dietary supplement and has a historical footprint in traditional medicine. Beyond its antioxidant prowess, SAC has demonstrated a range of biological effects including anti-diabetic, cholesterol-lowering, anticancer, and anti-hepatotoxic properties. Found in aged garlic extract (AGE), SAC has shown promise in enhancing neuronal survival and promoting axonal branching in rat hippocampal neuron cultures. Notably, its chronic low-dose intake has shown to improve learning and memory in senescence-accelerated mouse strains. Baluchnejadmojarad et al.’s study further highlighted its role in ameliorating cognitive deficits in diabetic rat models by mitigating oxidative stress and neuroinflammation.
The Endoplasmic Reticulum and Neurodegenerative Diseases
The endoplasmic reticulum (ER) is integral to various cellular functions, including protein synthesis and folding, lipid synthesis, and calcium storage. ER stress, resulting from the accumulation of misfolded proteins, is implicated in several neurological diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. This makes pharmacological agents targeting ER stress signaling pathways potential therapeutic candidates for neurodegenerative diseases.
SAC and ER Stress
SAC has been observed to protect against neuronal death induced by ER stress. The unfolded protein response (UPR), activated by ER stress, can lead to cell survival or death, depending on the severity of the stress. SAC’s neuroprotective role is evident in its ability to attenuate the activation of caspase-12, a crucial player in ER stress-induced apoptosis. Our studies have demonstrated SAC’s efficacy in preventing neuronal death induced by amyloid β-peptide and tunicamycin, both of which are involved in Alzheimer’s disease pathology.
The Role of Calpain in SAC’s Mechanism of Action
Calpain, a cytoplasmic cysteine protease, is believed to be a significant target of SAC. It is involved in caspase-12 activation during ER stress, primarily through calcium release from the ER. Our research indicates that SAC can directly inhibit calpain activity, suggesting a novel mechanism of action for SAC beyond its antioxidant properties. This inhibition of calpain, and consequently the reduced activation of caspase-12, underlines SAC’s neuroprotective potential against ER stress.
Analogues of SAC and Their Neuroprotective Effects
Exploring beyond SAC, various sulfur-substituted compounds like S-methyl-L-cysteine (SMC), S-ethyl-L-cysteine (SEC), and S-propyl-L-cysteine (SPC) have shown promise. Our experiments with SAC derivatives demonstrated that certain modifications can enhance neuroprotective effects against ER stress. Interestingly, SEC and SPC did not inhibit calpain activity, suggesting a different mechanism of action compared to SAC.
Conclusion
SAC presents a multifaceted approach to neuroprotection, primarily through its effects on ER stress and calpain activity. Its role in traditional medicine and dietary supplements is well-established, but its potential in therapeutic applications for neurodegenerative diseases warrants further exploration. The findings from various studies, including those on its analogues, open new avenues for research into SAC’s mechanisms and its potential as a prototype for drugs targeting neurodegenerative diseases associated with ER stress.
reference : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966174/
Discussion
Retinal ischemia is a significant contributor to a range of serious ocular disorders, including diabetic retinopathy, neovascular age-related macular degeneration (AMD), and various forms of retinal artery and vein occlusion. Over the past two decades, treatments involving anti-VEGF antibody agents and steroids have emerged as crucial interventions. However, these treatments are not universally effective, with some patients experiencing poor visual outcomes despite controlled ocular hemorrhage and macular edema.
The medical community is actively exploring new treatments to address these shortcomings. One promising area of research is the use of upstream inhibitors, like PKM2, which further inhibit the downstream VEGF biomarker, and anti-inflammatory agents that target inflammatory biomarkers such as MCP-1. These new approaches are particularly vital for cases where traditional anti-VEGF or steroid treatments fall short.
A key focus of recent research has been the potential antioxidative effect of S-allyl L-cysteine (SAC) on H2O2-induced oxidative stress cells, like retinal pigment epithelium (RPE) cells. Oxidative stress is a critical component of the ischemic cascade, and the antioxidative properties of SAC could provide an alternative approach in the prevention and treatment of ischemic-related ocular diseases. SAC has demonstrated potent antioxidative effects, including scavenging reactive oxygen species (ROS) like superoxides, hydrogen peroxide, and hydroxyl radicals. This property of SAC is particularly significant in its ability to protect against retinal ischemia, a common cause of visual impairment, by inhibiting the upregulation of VEGF, MMP-9, and HIF-1α.
The novel protective mechanisms of SAC in inhibiting biomarkers such as PKM2 and MCP-1 are crucial. These biomarkers are involved in ischemia-related neovascularization and the recruitment of macrophages that upregulate TNF-alpha along with VEGF. The research indicates that SAC can be effective in preventing the development and progression of retinal-ischemic related disorders, such as central and branch retinal vein occlusion, central and branch retinal artery occlusion, diabetic retinopathy, normal-tension glaucoma, and neovascular AMD.
The current research involving pig RPEs demonstrates that SAC can significantly attenuate cellular death induced by oxidative stress, suggesting its role as an antioxidant in preventing ischemic disorders. This is further supported by Western blot and ELISA studies, which show SAC’s protective effects against oxidative stress through the downregulation of ischemia-related factors like PKM2 and inflammatory biomarkers like MCP-1.
Moreover, recent studies have shown that pre-administered SAC can attenuate reductions in ERG b-wave ratios caused by retinal ischemia or excitotoxicity. This study extends these findings, showing that post-administration of SAC can counteract the ischemia-linked decrease in the ERG b-wave and reduce the number of RGCs in a retinal ischemic model.
While this research offers promising insights into the treatment of retinal ischemia, it is important to consider its limitations. The study’s reliance on an acute ischemia animal model may not fully replicate the chronic conditions of retinal ischemia in humans. Nonetheless, the model remains a valuable tool for understanding the pathology of retinal ischemia and testing potential treatments.
In conclusion, the research on SAC presents a significant advance in the understanding and treatment of retinal ischemia. The ability of SAC to downregulate critical biomarkers like MCP-1 and PKM2, combined with its antioxidative properties, positions it as a potential alternative and complementary treatment for ischemic-related disorders. This is particularly relevant when traditional treatments like anti-VEGF and steroids are ineffective, highlighting the importance of continued research and development in this field.
reference link : https://www.mdpi.com/1422-0067/25/2/1349
