TY - JOUR
T1 - Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control
AU - van der Merwe, Yolandi
AU - Murphy, Matthew C.
AU - Sims, Jeffrey R.
AU - Faiq, Muneeb A.
AU - Yang, Xiao Ling
AU - Ho, Leon C.
AU - Conner, Ian P.
AU - Yu, Yu
AU - Leung, Christopher K.
AU - Wollstein, Gadi
AU - Schuman, Joel S.
AU - Chan, Kevin C.
N1 - Funding Information:
This work was supported in part by the National Institutes of Health R01-EY028125 (Bethesda, Maryland); BrightFocus Foundation G2019103 (Clarksburg, MD, USA); Liesegang Fellowship (New York, New York); Research to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Award (New York, New York); and an Unrestricted Grant from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology. The funders above did not have any involvement in the study design, data collection, data analysis, interpretation, or manuscript writing.
Publisher Copyright:
© 2021, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2021/4
Y1 - 2021/4
N2 - Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.
AB - Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.
KW - Citicoline
KW - Glaucoma
KW - Intraocular pressure
KW - Magnetic resonance imaging
KW - Optokinetics
KW - Visual system
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U2 - 10.1007/s13311-021-01033-6
DO - 10.1007/s13311-021-01033-6
M3 - Article
C2 - 33846961
AN - SCOPUS:85104404100
SN - 1933-7213
VL - 18
SP - 1339
EP - 1359
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 2
ER -