Hydroxychloroquine Alters the ERG in an Animal Model of ADRP (the Pigmented P23H Rat)

Abstract

Abstract: : Purpose: High doses of the anti–inflammatory drug hydroxychloroquine (HCQ) are associated with an irreversible degenerative retinopathy, but lower doses are deemed safe. This work tested the hypothesis that moderate doses of HCQ exacerbate functional loss in an animal model of autosomal dominant retinitis pigmentosa (ADRP), the pigmented P23H rat. Methods: Rats received 6.5 mg (kg body wt)^–1 (recommended safe dose in humans) or 65 mg (kg body wt)^–1 daily doses of HCQ (oral, aqueous solution absorbed in a Cheerio^TM) beginning at 21 days. The corneal electroretinogram (ERG) was recorded at 5 and 16 weeks, and compared to age–matched controls (n = 4 in each group). Normalized amplitude–intensity series for the a–waves were fit with the function A/A_m = 1 – exp(–k I), where I is the flash strength (scotopic cd s m^–2), and A_m is the maximum amplitude obtained with a super–saturating stimulus. Results: At 5 weeks of age, after receiving HCQ for only 14 days, maximum b–wave amplitudes and a–wave sensitivity (k), were significantly reduced in the low–dose group compared to controls (p < 0.05). Maximum a–wave amplitudes in low–dose animals were somewhat lower than controls at this age (p = 0.11). All measures (maximum a– and b–wave amplitudes, and a–wave sensitivity) were significantly lower in the high–dose group compared to the low–dose group at 5 weeks of age. The dose–dependent difference in maximum a–wave amplitudes was no longer significant at 16 wks. Conclusions: The pigmented P23H rat exhibits an early rapid phase of functional loss (4–16 weeks) followed by a prolonged slower phase (16–28 wks, unpublished data). HCQ accelerates the early phase of functional loss in a dose–dependant manner in the P23H rat. An HQC dose considered safe in humans is sufficient to accelerate functional loss during this early phase. A predisposition of P23H animals to HQC–related retinopathy, or an additive stress on the photoreceptors due to the presence of the mutation and HQC, are suggested by these data.

Keywords: electroretinography: non-clinical • pharmacology • photoreceptors