Intraocular CNTF reduces vision in normal rats in a dose-dependent manner.
OBJECTIVE
CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function.


METHODS
Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically.


RESULTS
In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses.


CONCLUSIONS
Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.
McGill
Trevor J
TJ
Canadian Centre for Behavioural Neuroscience, The University of Lethbridge, Lethbridge, Alberta, Canada.
Prusky
Glen T
GT
Douglas
Robert M
RM
Yasumura
Douglas
D
Matthes
Michael T
MT
Nune
George
G
Donohue-Rolfe
Kate
K
Yang
Haidong
H
Niculescu
Diana
D
Hauswirth
William W
WW
Girman
Sergej V
SV
Lund
Raymond D
RD
Duncan
Jacque L
JL
LaVail
Matthew M
MM
D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000633:toxicity*; D000229:Dependovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography / Q000187:drug effects*; D005822:Genetic Vectors; D007267:Injections; D008027:Light / Q000009:adverse effects; D017120:Nystagmus, Optokinetic / Q000187:drug effects*; D020419:Photoreceptor Cells, Vertebrate / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D020318:Rats, Long-Evans; D012684:Sensory Thresholds / Q000187:drug effects; D013477:Superior Colliculi / Q000187:drug effects; D014786:Vision Disorders / Q000139:chemically induced*; D014792:Visual Acuity / Q000187:drug effects*; D014822:Vitreous Body
D020934:Ciliary Neurotrophic Factor