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Oral human-equivalent L-DOPA/Carbidopa dosages administered during the postnatal critical period of neuroplasticity rescues retinal morphology and visual function in a mouse model of human albinism

Oral human-equivalent L-DOPA/Carbidopa dosages administered during the postnatal critical period of neuroplasticity rescues retinal morphology and visual function in a mouse model of human albinism
Oral human-equivalent L-DOPA/Carbidopa dosages administered during the postnatal critical period of neuroplasticity rescues retinal morphology and visual function in a mouse model of human albinism
Purpose : Evidence of ongoing retinal development in children with albinism has been demonstrated. L-DOPA, a key molecule for the correct development of the retina, is known to be deficient in the developing albino eye, resulting in abnormalities of retinal structure and visual impairment. Thus, we investigated if human equivalent doses of L-DOPA/Carbidopa (i.e. doses established for the treatment of infantile dystonia and amblyopia), can rescue visual function in a mouse model of human oculocutaneous albinism (OCA), if administered during the postnatal critical period of neuroplasticity.

Methods : C57BL/6J (B6; n=24) and C57BL/6J-c2J OCA (CALBs; n=10) mice were treated with a 28-day course of oral L-DOPA/Carbidopa 9.4/2.3 mg/kg, from 15 to 43 days postnatal age (PNA) and compared to untreated B6 mice (n=8) and CALBs (n=16). Retinal morphology and function were assessed at 6 weeks PNA using optical coherence tomography and electroretinography. Photopic spatial frequency thresholds (i.e. visual acuity) were assessed by optokinetic nystagmus using an OptoMotry system at 7 weeks PNA.

Results : At 6 weeks PNA, the outer nuclear layer (ONL) thickness of untreated CALBs was significantly increased (61.5±0.2 vs 66.6±0.2 μm; p=0.0004). The ONL of treated CALBs (61.9±0.2 μm) recovered the same thickness found in B6 mice (61.3±0.3μm; p=0.779). A- and B-wave amplitudes were significantly diminished in untreated CALBs (284±18 vs 176±15 μV; p=0.0033; and -136±19 vs -85±9 μV; p=0.0298). Treated CALBs recovered amplitudes similar to B6 mice (340±16 and -183±9 μV, respectively). Photopic spatial frequency thresholds, were significantly lower in untreated CALBs; clock-wise (CW) (0.458±0.059 vs 0.188±0.095 c/d; p=0.0038) and clock-counter-wise (CCW) (0.401±0.012 vs 0.107±0.001 c/d; p=0.0012). Both thresholds improved in treated CALBs, reaching comparable levels to B6 mice (CW: 0.419±0.021 vs 0.292±0.026 c/d; p=0.1009; and CCW: 0.382±0.027 vs 0.330±0.044 c/d, respectively; p=0.5778).

Conclusions : Our results demonstrate that human equivalent doses of oral L-DOPA/Carbidopa supplementation during the critical postnatal period of retinal neuroplasticity can rescue visual function and retinal morphology in a mouse model of albinism. This novel work brings an effective treatment for children with albinism one step closer.
0146-0404
1393
Sanchez-Bretano, Aida
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Scott, Jennifer
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Newall, Tutte
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Lynn, Savannah
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Griffiths, Helen
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Salman, Ahmed
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Lotery, Andrew
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Ratnayaka, J. Arjuna
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Self, James
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Lee, Helena
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Sanchez-Bretano, Aida
23183db4-2bd9-42af-9e36-a580e3a52ad1
Scott, Jennifer
bdc803de-3082-4727-a4ca-f5a1cf3fcfcc
Newall, Tutte
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Lynn, Savannah
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Griffiths, Helen
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Salman, Ahmed
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Lotery, Andrew
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Ratnayaka, J. Arjuna
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Self, James
0f6efc58-ae24-4667-b8d6-6fafa849e389
Lee, Helena
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Sanchez-Bretano, Aida, Scott, Jennifer, Newall, Tutte, Lynn, Savannah, Griffiths, Helen, Salman, Ahmed, Lotery, Andrew, Ratnayaka, J. Arjuna, Self, James and Lee, Helena (2019) Oral human-equivalent L-DOPA/Carbidopa dosages administered during the postnatal critical period of neuroplasticity rescues retinal morphology and visual function in a mouse model of human albinism. Investigative Ophthalmology & Visual Science, 60 (9), 1393.

Record type: Meeting abstract

Abstract

Purpose : Evidence of ongoing retinal development in children with albinism has been demonstrated. L-DOPA, a key molecule for the correct development of the retina, is known to be deficient in the developing albino eye, resulting in abnormalities of retinal structure and visual impairment. Thus, we investigated if human equivalent doses of L-DOPA/Carbidopa (i.e. doses established for the treatment of infantile dystonia and amblyopia), can rescue visual function in a mouse model of human oculocutaneous albinism (OCA), if administered during the postnatal critical period of neuroplasticity.

Methods : C57BL/6J (B6; n=24) and C57BL/6J-c2J OCA (CALBs; n=10) mice were treated with a 28-day course of oral L-DOPA/Carbidopa 9.4/2.3 mg/kg, from 15 to 43 days postnatal age (PNA) and compared to untreated B6 mice (n=8) and CALBs (n=16). Retinal morphology and function were assessed at 6 weeks PNA using optical coherence tomography and electroretinography. Photopic spatial frequency thresholds (i.e. visual acuity) were assessed by optokinetic nystagmus using an OptoMotry system at 7 weeks PNA.

Results : At 6 weeks PNA, the outer nuclear layer (ONL) thickness of untreated CALBs was significantly increased (61.5±0.2 vs 66.6±0.2 μm; p=0.0004). The ONL of treated CALBs (61.9±0.2 μm) recovered the same thickness found in B6 mice (61.3±0.3μm; p=0.779). A- and B-wave amplitudes were significantly diminished in untreated CALBs (284±18 vs 176±15 μV; p=0.0033; and -136±19 vs -85±9 μV; p=0.0298). Treated CALBs recovered amplitudes similar to B6 mice (340±16 and -183±9 μV, respectively). Photopic spatial frequency thresholds, were significantly lower in untreated CALBs; clock-wise (CW) (0.458±0.059 vs 0.188±0.095 c/d; p=0.0038) and clock-counter-wise (CCW) (0.401±0.012 vs 0.107±0.001 c/d; p=0.0012). Both thresholds improved in treated CALBs, reaching comparable levels to B6 mice (CW: 0.419±0.021 vs 0.292±0.026 c/d; p=0.1009; and CCW: 0.382±0.027 vs 0.330±0.044 c/d, respectively; p=0.5778).

Conclusions : Our results demonstrate that human equivalent doses of oral L-DOPA/Carbidopa supplementation during the critical postnatal period of retinal neuroplasticity can rescue visual function and retinal morphology in a mouse model of albinism. This novel work brings an effective treatment for children with albinism one step closer.

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More information

Accepted/In Press date: 1 April 2016
Published date: 22 July 2019
Additional Information: This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019
Venue - Dates: The Association for Research in Vision and Ophthalmology: (ARVO 2019), , Vancouver, Canada, 2019-04-28 - 2019-05-02

Identifiers

Local EPrints ID: 433975
URI: http://eprints.soton.ac.uk/id/eprint/433975
ISSN: 0146-0404
PURE UUID: a23d978e-62cf-4861-a7a3-e392f6dd8397
ORCID for Savannah Lynn: ORCID iD orcid.org/0000-0003-2513-3144
ORCID for Ahmed Salman: ORCID iD orcid.org/0000-0003-4300-2033
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for James Self: ORCID iD orcid.org/0000-0002-1030-9963
ORCID for Helena Lee: ORCID iD orcid.org/0000-0002-2573-9536

Catalogue record

Date deposited: 09 Sep 2019 16:30
Last modified: 10 Nov 2021 03:54

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Contributors

Author: Aida Sanchez-Bretano
Author: Jennifer Scott
Author: Tutte Newall
Author: Savannah Lynn ORCID iD
Author: Helen Griffiths
Author: Ahmed Salman ORCID iD
Author: Andrew Lotery ORCID iD
Author: James Self ORCID iD
Author: Helena Lee ORCID iD

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