Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract–induced Retinal Degeneration in F344/N Rats

Abstract

There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.

Responses of Transgenic Melatonin-Enriched Goats on LPS Stimulation and the Proteogenomic Profiles of Their PBMCs

“…In CCs, high levels of MT modify the intracellular organelles, intracellular membrane structure, and thus their lysosome functions, which directly affects their phagocytosis and autophagy [ 63 ]. These observations are supported by previous reports of MT effects on phagocytosis, autophagy, and mitophagy [ 64 , 65 , 66 ]. MF analysis indicated that MT mainly affected protein and enzyme bindings and their functions.…”

Effects of Different Spectrum of LEDs on Retinal Degeneration Through Regulating Endoplasmic Reticulum Stress

“…Reduction of the photoreceptor layer has been previously described in rat models of LIRD, such as F344/N rats and albino Sprague Dawley rats. 39 , 40 In our study, as expected, at high illuminance (i.e., 3000 lux), a significant reduction of photoreceptor layer thickness was found in two experimental groups, especially in the CL-3000 group, which had a lower thickness and the appearance of disordered and sparse photoreceptor segments all over the retina. At standard writing illuminance (i.e., 300 lux), retinal damage was observed in the CL-300 group, which induced a statistical reduction in the thickness of the photoreceptor layer.…”

Retinal Toxicity Induced by Chemical Agents

“…In a subsequent study, the group demonstrated that F344N rats dosed with KKE 1.0 g/kg for 90 days did not show signs of retinal degeneration. However, the RPE, only from the superior retina, had a reduced number of phagosomes [ 60 ]. The authors speculated that this result could indicate an impairment in photoreceptor outer segment phagocytosis by RPE cells, which could affect the health of the retina after the 2-year exposure observed in the previous study.…”