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Updated: Dec 11, 2025
Retinal Pathophysiological Evaluation in a Rat Model
Published on: May 6, 2022
Effects of a monocarboxylate transport 1 inhibitor, AZD3965, on retinal and visual function in the rat
Annette E Allen1, Elizabeth A Martin2, Katherine Greenwood2,3
1Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Background And Purpose:
Inhibition of monocarboxylate transport 1 (MCT1) is of interest in targeting highly glycolytic tumours. However, MCT1 is expressed in retina, and so inhibition of MCT1 could affect retinal function.
Experimental Approach:
AZD3965, an MCT1 inhibitor selected for clinical development, and two additional MCT1 inhibitors were evaluated for effects on visual acuity in albino (Han Wistar) rats. The effects of AZD3965 on visual acuity and electroretinography (ERG) were further investigated in pigmented (Long-Evans) rats, with dosing for up to 7 days.
Key Results:
All three MCT1 inhibitors reduced visual acuity within 2 h of dosing, suggesting a class effect. The deficit caused by AZD3965 (1,000 mg·kg-1 p.o. per day for 4 days) in Long Evans rats recovered to pre-dose levels 7 days after cessation of dosing. AZD3965 (50 to 1,000 mg·kg-1 p.o.) reduced the amplitude of scotopic a- and b-waves, and photopic b-wave of the ERG in a dose-related fashion, within 2 h of dosing. The effects on the scotopic ERG had diminished by Day 7 of dosing, demonstrating partial restoration of function despite continued treatment. Seven days after cessation of dosing at the highest dose tested (1,000 mg·kg-1 ), there was recovery of both scotopic a- and b- waves and, to a lesser extent, photopic b-wave. ERG was affected at lower plasma exposures than was visual function.
Conclusions And Implications:
This study clarifies the role of the MCT1 transporter in retinal function. The monitorability of the functional effects on the retina enabled safe clinical use of AZD3965.
Insights
Monocarboxylate transport 1 (MCT1) inhibitors, including AZD3965, temporarily reduce visual acuity and retinal function in rats. However, these effects are reversible upon cessation of dosing, supporting the safe clinical use of MCT1 inhibitors.
Area of Science:
- Pharmacology
- Ophthalmology
- Oncology
Background:
- Monocarboxylate transport 1 (MCT1) inhibition is a strategy for targeting highly glycolytic tumors.
- MCT1 is present in the retina, raising concerns about potential ocular side effects.
Purpose of the Study:
- To evaluate the impact of MCT1 inhibitors, specifically AZD3965, on visual function in rats.
- To determine the reversibility of visual and retinal function changes induced by AZD3965.
Main Methods:
- Three MCT1 inhibitors, including AZD3965, were tested for effects on visual acuity in albino rats.
- AZD3965's effects on visual acuity and electroretinography (ERG) were further studied in pigmented rats over 7 days.
Main Results:
- All tested MCT1 inhibitors caused a rapid, dose-dependent decrease in visual acuity.
- AZD3965 induced dose-related reductions in scotopic and photopic ERG amplitudes.
- Visual and ERG function recovered to baseline levels within 7 days after AZD3965 treatment cessation.
Conclusions:
- This study elucidates the role of MCT1 in retinal function and confirms its impact on visual acuity.
- The observed reversibility of functional deficits supports the safe clinical application of AZD3965, with monitoring of retinal function.
