Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

[1]  M. Lavail,et al.  Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. , 2000, Human molecular genetics.

[2]  E. Zrenner Will Retinal Implants Restore Vision ? , 2002 .

[3]  D. Szarowski,et al.  Brain responses to micro-machined silicon devices , 2003, Brain Research.

[4]  Gislin Dagnelie,et al.  Visual perception in a blind subject with a chronic microelectronic retinal prosthesis , 2003, Vision Research.

[5]  K Heimann,et al.  Successful long-term implantation of electrically inactive epiretinal microelectrode arrays in rabbits. , 1999, Retina.

[6]  A. Y. Chow,et al.  The artificial silicon retina microchip for the treatment of vision loss from retinitis pigmentosa. , 2004, Archives of ophthalmology.

[7]  Takashi Fujikado,et al.  Electrical stimulation enhances the survival of axotomized retinal ganglion cells in vivo , 2002, Neuroreport.

[8]  I. Constable,et al.  Transient preservation of photoreceptors on the flanks of argon laser lesions in the RCS rat. , 1993, Current eye research.

[9]  L. Frishman,et al.  Scotopic threshold response of proximal retina in cat. , 1986, Journal of neurophysiology.

[10]  M. Lavail,et al.  Development of normal and injury-induced gene expression of aFGF, bFGF, CNTF, BDNF, GFAP and IGF-I in the rat retina. , 2001, Experimental eye research.

[11]  J. Weiland,et al.  Long-term histological and electrophysiological results of an inactive epiretinal electrode array implantation in dogs. , 1999, Investigative ophthalmology & visual science.

[12]  T. Gordon,et al.  Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. , 2000, The European journal of neuroscience.

[13]  Y. Fukuda,et al.  Survival and axonal regeneration of retinal ganglion cells in adult cats , 2002, Progress in Retinal and Eye Research.

[14]  T Gordon,et al.  Brief Electrical Stimulation Promotes the Speed and Accuracy of Motor Axonal Regeneration , 2000, The Journal of Neuroscience.

[15]  M. Lavail,et al.  Injury-induced upregulation of bFGF and CNTF mRNAS in the rat retina , 1995 .

[16]  R. Carpenter,et al.  Electrical stimulation of the human eye in different adaptational states , 1972, The Journal of physiology.

[17]  M. Lavail,et al.  Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor , 1990, Nature.

[18]  Eberhart Zrenner,et al.  Studies on the feasibility of a subretinal visual prosthesis: data from Yucatan micropig and rabbit , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[19]  A. M. Potts,et al.  The electrically evoked response of the visual system (EER). , 1968, Investigative ophthalmology.

[20]  M. Lavail,et al.  Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat. , 1975, Experimental eye research.

[21]  Thomas Schanze,et al.  Implantation of retina stimulation electrodes and recording of electrical stimulation responses in the visual cortex of the cat , 2000, Graefe's Archive for Clinical and Experimental Ophthalmology.

[22]  R. J. Mullen,et al.  Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. , 1976, Science.

[23]  P. Sieving,et al.  Preservation of inner retinal responses in the aged Royal College of Surgeons rat. Evidence against glutamate excitotoxicity in photoreceptor degeneration. , 1995, Investigative ophthalmology & visual science.

[24]  J. Flannery,et al.  Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. , 2000, Investigative ophthalmology & visual science.

[25]  W W Dawson,et al.  The electrical stimulation of the retina by indwelling electrodes. , 1977, Investigative ophthalmology & visual science.

[26]  John S. Pollack,et al.  Subretinal Artificial Silicon Retina Microchip for the Treatment of Retinitis Pigmentosa: 3 1/2 Year Update , 2004 .

[27]  J. Phelan,et al.  A brief review of retinitis pigmentosa and the identified retinitis pigmentosa genes. , 2000, Molecular vision.

[28]  A. Y. Chow,et al.  Implantation of silicon chip microphotodiode arrays into the cat subretinal space , 2001, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[29]  E Zrenner,et al.  Retinal prosthesis: an encouraging first decade with major challenges ahead. , 2001, Ophthalmology.

[30]  A. Y. Chow,et al.  Neuroprotective effect of subretinal implants in the RCS rat. , 2005, Investigative ophthalmology & visual science.

[31]  A. Y. Chow,et al.  Subretinal implantation of semiconductor-based photodiodes: progress and challenges. , 1999, Journal of rehabilitation research and development.

[32]  H. Tanihara,et al.  Brain‐derived neurotrophic factor shows a protective effect and improves recovery of the ERG b‐wave response in light‐damage , 2003, Journal of neurochemistry.

[33]  D. Bok,et al.  THE ROLE OF THE PIGMENT EPITHELIUM IN THE ETIOLOGY OF INHERITED RETINAL DYSTROPHY IN THE RAT , 1971, The Journal of cell biology.

[34]  S. Jacobson,et al.  Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa , 2000, Nature Genetics.

[35]  Neal S Peachey,et al.  Subretinal implantation of semiconductor-based photodiodes: durability of novel implant designs. , 2002, Journal of rehabilitation research and development.

[36]  A. Y. Chow,et al.  Evaluation of an Artificial Retina in Rodent Models of Photoreceptor Degeneration , 2001 .

[37]  H. Sachs,et al.  Retinal replacement—the development of microelectronic retinal prostheses—experience with subretinal implants and new aspects , 2004, Graefe's Archive for Clinical and Experimental Ophthalmology.

[38]  J. Wyatt,et al.  REVIEW ■ : Prospects for a Visual Prosthesis , 1997 .

[39]  Knighton Rw An electrically evoked slow potential of the frog's retina. II. Identification with PII component of electroretinogram. , 1975 .

[40]  M. Lavail,et al.  Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina. , 1997, Experimental eye research.

[41]  H. Ropers,et al.  Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation , 2000, Nature Genetics.

[42]  G. Brindley,et al.  The sensations produced by electrical stimulation of the visual cortex , 1968, The Journal of physiology.