N-Methyl-N-Nitrosourea–Induced Acute Alteration of Retinal Function and Morphology in Monkeys

Abstract

PURPOSE. The purpose of this study was to investigate both functional and morphologic alteration of the retina acutely induced by N-methyl-N-nitrosourea (MNU) in monkeys.METHODS. The MNU was administered intravenously at a single dose of 40 mg/kg to six cynomolgus monkeys, and standard full-field electroretinograms (ERGs) were recorded 1, 3, and 7 days after dosing. In addition, the rod and cone a-waves in response to high-intensity flashes were analyzed by the a-wave fitting model (a-wave analysis). The photopic negative response (PhNR) was also recorded at the same time points. Furthermore, the retinas of two animals each were examined histopathologically 1, 3, or 7 days after dosing. RESULTS.The MNU attenuated all the standard full-field ERGs including the rod-driven and cone-driven responses; in the combined rod-cone response, the b-wave was more affected than the a-wave. In the a-wave analysis, the sensitivity parameters (S) of the rod and cone awaves had decreased on the day after dosing and remained unchanged thereafter. The maximum response parameter (R max ) of the rod a-wave gradually decreased. On the other hand, the R max in the cone a-wave transiently increased on the day after dosing and decreased thereafter; the PhNR amplitude showed a similar time course change. Histopathologically, the retinal lesion on the day after dosing mainly consisted of pyknosis and karyorrhexis in the photoreceptor nucleus. Depletion of some photoreceptor nuclei, and shortening and disorientation of the photoreceptor segments became prominent at 3 and 7 days after dosing. Localization of degenerated photoreceptors was consistent with that of rhodopsin-positive photoreceptors, resulting in a well-preserved central fovea. CONCLUSIONS.Our results indicated that MNU acutely induced rod-dominant photoreceptor degeneration in monkey retinas, but the photoreceptor function was impaired in both the rods and cones. Functional involvement of the postreceptoral components was also indicated.

Bilateral cataract surgery in a Japanese macaque (Macaca fuscata): A case report

“…Due to the lack of dark adaptation, it was difficult to make a direct comparison with the ERG results in another reported non‐human primate study 9 . However, no obvious findings were suggesting retinal degeneration 10 . The amplitude of the a‐wave of the Single flash ERG was 250 μV OD and 122 μV OS.…”

“…9 However, no obvious findings were suggesting retinal degeneration. 10 The amplitude of the awave of the Single flash ERG was 250 μV OD and 122 μV OS. The amplitude of the b-wave of the single flash ERG was 173 μV OD and 109 μV OS.…”

Intranasal administration of erythropoietin rescues the photoreceptors in degenerative retina: a noninvasive method to deliver drugs to the eye

“…Hitherto, the effects of INas delivered EPO on the retina remain to be explored. The present study is designed to deliver the EPO into the N-methyl-N-nitrosourea (MNU) administered mice via INas route (Tao et al., 2015; Kinoshita et al., 2015). The N-methyl-N-nitrosourea (MNU) administered mice serves as a pharmacologically induced RP model with rapid progress rate.…”

N‐methyl‐N‐nitrosourea induces retinal degeneration in the rat via the inhibition of NF‐κB activation

“…An alkylating agent N ‐methyl‐ N ‐nitrosourea (MNU) selectively damages photoreceptor cells and induces photoreceptor degeneration . After a single intraperitoneal injection, MNU‐treated retinas underwent both morphological and electrophysiological alterations similar to hereditary RP . MNU can induce photoreceptor degeneration in a variety of animal species .…”

“…After a single intraperitoneal injection, MNU‐treated retinas underwent both morphological and electrophysiological alterations similar to hereditary RP . MNU can induce photoreceptor degeneration in a variety of animal species . Therefore, MNU‐induced RP animal models have been extensively utilized to investigate the pathogenesis of RP …”