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

Haruhiro Yamashita, Mark J. Hoenerhoff, Keith R. Shockley, Shyamal D. Peddada, Kevin E. Gerrish, Deloris Sutton, Connie A. Cummings, Yu Wang, Julie F. Foley, Mamta Behl, Suramya Waidyanatha, Robert C. Sills, and Arun R. Pandiri.
Toxicologic Pathology (2018) DOI: PMID: 29806545



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.


Figure 1. Mean pupil size for each group over the 12 weeks of experimentation (n=15 for each group).

(A) The pupil size was expressed as a ratio of the diameter of the pupil/limbus corneae.
(B) There were no statistically significant differences in pupil size between the KKE 1.0 g/kg group and the control group (Student’s t-test).
KKE = kava kava extract.

Figure 2. Quantitative analysis of photoreceptor outer segment phagocytosis.

(A) Representative photomicrographs of transverse sections of the retina in the control group and KKE 1.0 g/kg group taken under oil immersion at 1000×. Reduced number of phagosomes (discrete dark-blue bodies) in the RPE in the superior retina from KKE 1.0 g/kg treated rat.
(B) Mean number of phagosomes ≥.75 µm diameter in four 110 µm lengths of the RPE from superior and inferior retinas (mean ± SD, n = 8 for each group). The number of phagosomes in the superior retina was significantly decreased in KKE 1.0 g/kg group compared to the control group (*p < .05, Student’s t-test).
(C) Representative TEM image of phagosomes (arrowhead) of photoreceptor outer segments in the RPE soma and the processes from a control rat.
CH = choroid, KKE = kava kava extract, PSL = photoreceptor segment layer, RPE = retinal pigment epithelium, SD = standard deviation, TEM = transmission electron microscopy.

Figure 3. The mean thickness (µm) of layers in the retina (mean ± SD, n = 4–12 for each group).

There were no changes in the KKE 1.0 g/kg group compared with the control group at any layer (Student’s t-test). No retinal degeneration lesions as seen at the 2-year time point were observed in the 90-day study.
INL = inner nuclear layer, IPL = inner plexiform layer, ONL = outer nuclear layer, OPL = outer plexiform layer, PSL = photoreceptor segment layer, R = retina.

Figure 4. Gene expression analysis.

(A) Principal component analysis (PCA) of global gene expression profiles on the retinas from control (red) and KKE 1.0 g/kg (blue) samples demonstrated a nearly distinct clustering.
(B) Heat map of differentially expressed 10 transcripts between KKE 1.0 g/kg and control groups using a false discovery rate of 5%. Red, high expression; blue, low expression; KKE = kava kava extract, CTL = control.


Table 1. Frequency of Retinal Degeneration in Male and Female F344/N Rats Treated with Kava Kava Extract by Gavage for Two Years.

Table 2. Differentially Expressed Genes in KKE 1.0 g/kg Group Compared to Control Group.