The Investigation of Fungal Stat-Regulating Compounds on Retinal Müller and Microglial Functions and Their Therapeutic Profiles in Glaucomatous Neurodegeneration

Neuroinflammation has been implicated in retinal degeneration, exacerbating retinal damage.
It can cause damage or even death of retinal cells and contribute to the progression and mortality
of glaucoma and age-related macular degeneration. Glaucoma is a type of retinal neurodegenerative
disease characterized by the loss of retinal ganglion cells and is associated with the excessive
activation of microglia and neuroinflammation. The over-activated microglia could release large
amounts of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and
interleukin-1β (IL-1β), which directly damage neurons, leading to the death of retinal nerve cells.
First, we found the fungal compound gentisyl alcohol isolated from Aspergillus giganteus. It
significantly reduces the production of nitric oxide (NO), TNF-α levels, intracellular ROS levels,
and the expression of iNOS and COX-2 proteins in LPS-stimulated BV-2 cells. According to cell
signaling findings, gentisyl alcohol significantly inhibits the phosphorylation of STAT3 and NFκB induced by LPS in BV-2 cells. In vivo experiments demonstrated that administration of gentisyl
alcohol improved retinal function impairment caused by intravitreal injection of LPS in mice.
Electroretinography (ERG) results, including A, B, and PhNR waves, showed that gentisyl alcohol
were able to maintain partial ERG function after LPS or high IOP insults. In conclusion, gentisyl
alcohol exhibits its anti-neuroinflammatory and antioxidant effects by inhibiting microglial
activation and, in in vivo experiments, demonstrates a protective role in retinal function under
different types of glaucoma. The second issue, we investigated the retinoprotective effects of
isorhamnetin (ISO), an active component of Cuscuta chinesis, using both in vitro and in vivo
macular degeneration-like models. Especially, the retinal OCT, ERG and PLR systems in vivo were
improved by ISO. Our results found that ISO with STAT inhibition exerts protective effects on the
retina in an AMD-like mouse model, primarily through its anti-inflammatory properties, inhibiting
glial-mediated inflammation and regulating immune cell activity. In summary, our results
demonstrate that these two natural compounds exerted the inhibitory activities on microglia and
retinal cells through STAT-dependent and other signalings. Both compounds have different
therapeutic potential for retinal disease such as glaucoma and macular degeneration. Also, these
findings could suggest the new mode of action to treat retinal degenerative diseases.