Oral 8-Aminoguanine Protects Aging Eyes and Preserves Vision in Preclinical Study

Oral 8-Aminoguanine Protects Aging Eyes and Preserves Vision in Preclinical Study

A groundbreaking study shows that a daily oral dose of 8-aminoguanine can protect retinal health and slow loss with aging, opening new avenues for the treatment of degenerative eye diseases.

In a recent study published in the journalCommunication biologyused aged Fischer 344 rats to investigate the potential of orally administered 8-aminoguanine (8-Ag) in protecting against age-related retinal degeneration. The main experiment lasted 8 weeks, with a small subcohort of animals followed for 17 weeks due to high mortality in old age. The intervention involved providing 22-month-old rats with a low dose of 8-Ag-in drinking water.

The study results highlight the protective effects of 8-Ag against retinal atrophy, with significant preservation of retinal structure and function being observed after only 8 weeks of intervention. These observations, specifically increased retinal thickness, improved electroretinogram responses, and enhanced photoreceptor integrity, were further confirmed in the small, long-term (17-week) cohort. However, the limited sample size reduces statistical certainty. Notably, 8-Ag significantly improved rod (scotopic) function, while cone (photopic) function was not rescued by 8-Ag, although histological analysis revealed preservation of cone structure, particularly in the lower retina. These results highlight the potential of 8-ags in future clinical interventions in age-related retinal diseases.

background

Older adults are naturally susceptible to several structural and functional retinal changes, including neural retinal thinning and decrease in electroretinogram (ERG) responses, as well as photoreceptor loss. Degenerative diseases such as age-related macular degeneration (AMD) collectively influence “age-related retinal degeneration,” which greatly impact daily functions and quality of life (QOL) in this vulnerable yet growing population.

Previous studies using mouse model systems suggest that the interaction of multiple environmental and genetic factors influences the development of age-related macular degeneration (AMD). In particular, age has been highlighted as a primary non-modifiable risk factor in AMD incidence and progression, with studies estimating a fourfold increase in AMD incidence every decade after 55 years.

Unfortunately, current treatment options for AMD are limited, and although some risk factors (e.g. smoking) have been identified, the mechanisms underlying AMD pathology are poorly understood. Elucidating the oxidative, inflammatory, and microglial changes associated with aging may facilitate the development of future therapeutic interventions to slow the progression of AMD.

About the study

Previous research has suggested the potential of purine nucleoside phosphorylases (PNPases) in combating age-related conditions, particularly oxidative stress and inflammation, across various organ systems. PNPases are enzymes that modulate inosine-guanosine and hypoxanthine-xanthine ratios, thereby contributing to reduced oxidative stress and inflammatory responses. Mouse models have shown that 8-aminoguanine (8-AG), a PNPase inhibitor, can protect against strokes, extend lifespan, and improve cardiovascular health, suggesting that age reversal occurs from 8-Ag.

The present study aims to assess whether the anti-aging therapeutic potential of 8-Ag extends to AMD and other age-related retinal diseases. It used female 22-month-old Fisher 344 (F344) rats, equally divided into cases (8-Ag-FED) and controls (water-fed). Cases were administered 5 mg/kg body weight (BW) of 8-Ag-Ag-Ag-Ag weight dissolved in water. The first study lasted 8 weeks, but a subcohort of survivors (1 control and 2 cases) was reassessed at the end of 17 weeks to assess the long-term effects of 8-Ag.

Experimental assays included spectral domain-optical coherence tomography (SD-OCT), immunohistochemistry (IHC), and electroretinogram (ERG) for retinal morphological assessments, RNA-seq-based transcriptome analysis for immune (inflammatory) and stress response analysis, purine metabolome analyses, and real-time polymerase chain reaction (RT-PCR) for quantification of gene and cytokine expression.

Study results

After 8 weeks of interventions, comparisons between 8-Ag and water-fed F344 rats showed that the former cohort demonstrated significantly better preservation of retinal structure and function than the latter cohort. SD-OCT assessments revealed improved photoreceptor integrity and increased retinal thickness in cases compared to controls. ERG data analyzes confirmed these results and showed that the retinal responses of the cases were significantly improved compared to control rats.

IHC and Histological assays found significant reductions in oxidative damage markers in the cases' retinas. The number of apoptotic cells in these cases was similarly reduced compared to that of the control group. In particular, cases showed attenuated immune responses at the gene and protein levels, highlighting the tissue protective effects of 8-Ag. Specific proinflammatory cytokines such as IL-33 and IL-1α were also reduced in the retinas of treated animals.

Mechanistic assessments showed that oxidative stress (lipid and DNA) and inflammatory responses (microglial activity) were significantly attenuated in 8-Ag-fed rats compared to their water-fed counterparts. Importantly, only rod (scotopic) function was significantly improved with 8-Ag treatment, while cone (photopic) function showed no significant change by ERG, although regional preservation of cone structure was observed histologically.

These results were even more striking in the extended (17-week) study. While the high F344 mortality at 24 weeks allowed evaluation of only two cases and one control, the cases demonstrated retained retinal structure and function, while the control had almost complete loss of vision. However, the very limited number of animals in this long-term group makes these results very preliminary and should be interpreted with caution.

Conclusions

The present study expanded the anti-aging benefits of 8-Ag, previously described as alleviating age-related cardiovascular and multiorgan conditions. It shows that even low doses (5 mg/kg/day) of the orally administered PNPase inhibitor can significantly alleviate age-related retinal degeneration in rats by suppressing oxidative stress, reducing inflammation, and supporting retinal morphology and functions in retinal morphology and supporting further investigations in AMD-specific models.

While some effects were maintained in the small number of long-term survivors, the data on duration of benefit remain high quality. Future studies should examine the safety and effectiveness of the compound in human models under controlled clinical conditions.

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