Etiology, pathogenesis, and experimental treatment of retinitis pigmentosa

The paper provides an interdisciplinary evaluation of the etiology, pathoge nesis, and experimental treatments of retinitis pigmentosa (RP). It address es a 10-year controversy concerning the rate of progression of RP. One labo ratory has estimated remaining visual field to be lost at a rate of 4.6% pe r year, whereas another laboratory estimates loss at 16-18%. This large dis crepancy and lack of consensus needs resolution, since they pose serious st atistical and operational problems for evaluating experimental treatment ap proaches to RP. The resolution of the controversy offered in the paper is b ased on a model of RP in which the initial rate of loss of visual field (th e induction phase) is much slower than the subsequent logarithmic first-ord er rate of loss. The rationale for this kinetic model is that loss of mitoc hondrial function, possibly due to RP-genetically-related radical processes , has to reach a critical threshold value before the mitochondrial trigger of programmed cell death or apoptosis (i.e., the release of mitochondrial c ytochrome c by the opening of the permeability transition pore, PTP) can be activated by an encounter with a second, but kinetically constant causativ e stress factor - most likely a light-stress-related factor. In its essenti al (two-causal) aspects, this kinetic model for RP is identical to the kine tic theories that have been proposed for the Gombertz human mortality plot. The described kinetic model for RP provides a solution to the visual field -loss controversy, since the first study was performed with a population co ntaining a greater number of patients in the slow stage of RP than the seco nd. Another objective of the investigation was to identify possible mechanisms of how the numerous genetic mutations in the rods of RP patients could give rise to damaging free-radical reactions capable of triggering apoptosis th rough their adverse effects on mitochondrial function. Another reason for f ocusing on radical reactions In RP was to provide a rationale for the propo sed use of an extensive array of antioxidants and nutritional supplements f or stemming progression of RP. In particular, the investigation focuses on saving cone-dependent central vision, i.e. on saving cells not affected by the genetic problems of the rods, but cells which can become lethally damag ed by a spill-over of radicals and related harmful chemical reactions occur ring in the rods. The third objective deals with the development of a rationale for a new str ategy for retarding RP. This involves the use of desmethyldeprenyl, a metab olite of the anti-Parkinson's drug, deprenyl. The rationale is, in part, ba sed on an observation that desmethyldeprenyl exerts antiapoptotic activitie s in a variety of neurodegenerative disorders. The protective mechanism inv olves the overexpression of the anti-apoptotic bcl-2 gene, leading to highe r concentrations of bcl-2 proteins, which by binding to mitochondria inhibi ts the trigger mechanism of apoptosis - the opening of PTP and release of c ytochrome C. At the same time, desmethyldeprenyl causes the underexpression of the pro-apoptotic bar gene, which via bar proteins facilitates the open ing of the PTP. Both the anti-apoptotic and proapoptotic mechanisms appear to be mediated by the binding of desmethyldeprenyl to glyceraldehyde-3-phos phate dehydrogenase. Antiapoptotic effects can also be generated by the par ent compound, deprenyl, when this is used daily in low concentrations of 1- 2 mg/100 kg body weight. Under these conditions, it appears that the anti-a poptotic metabolite, desmethyldeprenyl, predominates over the pro-apoptotic metabolites of deprenyl, I-methamphetamine and I-amphetamine. Methamphetam ine is not formed if desmethyldeprenyl is administered directly and thus co uld give desmethyldeprenyl a pharmacokinetic advantage over deprenyl. Howev er, desmethyldeprenyl is still an FDA-unapproved substance and the possibil ity that deprenyl may on its own have unique anti-apoptotic effects, becaus e of its structural similarity to desmethyldeprenyl, cannot be excluded at the present time. The relevance of these observations to RP is suggested by the findings of a recent study, that the progression of RP in transgenic mice can be retarde d by genetic overexpression of the bcl-2 gene. The possibility of achieving beneficial synergistic effects by simultaneuously causing the underexpress ion of the bar gene was not investigated. Apoptotic mechanisms have also be en implicated in other ocular diseases: glaucoma, optic neuropathies, ische mia (e.g. retinal detachment), cataract, diabetic retinopathy and macular d egeneration. Consequently, studies of possible beneficial effects of depren yl or desmethyldeprenyl are also warranted in these disorders. The paper concludes with a critical evaluation of several experimental ther apeutic regimens in current use for RP: the Russian Encad program, hyperbar ic oxygen, ozone, and traditional Chinese medicine. This evaluation focuses on potential dangers of these treatments and on the use of inappropriate o utcome measures. (C) 2000 Harcourt Publishers Ltd.