Neurochemical studies on the inherited retinal degeneration of the rat

Bonavita, V.; Ponte, F.; Amore, Giuseppe

doi:10.1016/0042-6989(63)90001-4

Cited by 33 publications

(15 citation statements)

References 27 publications

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“…It appears that the P23H-3 retina is working under chronic stress (103), and we demonstrated that degeneration in the P23H-3 retina is occurring in an environment of high ATP levels and high Na ϩ -K ϩ -ATPase and Mg 2ϩ -Ca 2ϩ -ATPase activity, despite a normal high-energy phosphate transport and normal lactate levels. Inhibition of cGMP-phosphodiesterase resulted in reduced LDH activity in the P23H-3 rat, a reduction that has been shown to be indicative of photoreceptor loss in other models (3,9). We also confirm an increase in the number of TUNEL-positive photoreceptors in the P23H-3 rat retina exposed to sildenafil.…”

Section: Discussionsupporting

confidence: 75%

“…At P62, no significant differences were found in LDH activity between SD and P23H-3 retinas (P ϭ 0.23 by t-test), despite the loss of a considerable number of photoreceptors [ϳ30% of the ONL (69)]. This suggests that the LDH activity within the remaining photoreceptors is likely to be elevated, given that the ONL is the major contributor to overall LDH activity (3,9). Given the significant increase in the LDH activity ratio at early ages (Fig.…”

Section: Ldh Activity In Sd and P23h-3 Retinasmentioning

confidence: 95%

“…The fundamental outcome from our studies is that even a retina that is metabolically overloaded can maintain its function until a threshold level for cell death is reached. When we applied sildenafil to the P23H-3 rat model, we were able to modify retinal LDH activity, which suggests a downregulation of aerobic metabolism and/or accelerated photoreceptor death, reminiscent of that noted in other retinal dystrophy models (RCS and rd/rd retina) (3,9,87). Inhibition of phosphodiesterase affects the already compromised cellular environment of the P23H-3 retina (high oxygen tension and high ATP levels) but not that of the normal SD retina.…”

Section: C771mentioning

confidence: 98%

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Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

Acosta¹,

Shin²,

Ready³

et al. 2010

American Journal of Physiology-Cell Physiology

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-We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal SpragueDawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na ϩ -K ϩ -ATPase and Mg 2ϩ -Ca 2ϩ -ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with ␣-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry.phosphocreatine; ATP; ␣-cyano-4-hydroxycinnamic acid; sildenafil; lactate dehydrogenase; ATPase RETINITIS PIGMENTOSA is the term given to a family of retinal disorders that cause blindness due to gradual loss of photoreceptors. Although photoreceptor cell death in retinitis pigmentosa has a number of underlying causes that include rhodopsin mutations (94), altered photoreceptor oxygen environment (36,103,104), disk morphogenesis, retinal pigment epithelium dysfunction, and chronic activation of photoreceptor transduction cascade (80), the understanding of the cell death pathways is still evolving. It is generally accepted that cell death in inherited forms of retinal degeneration occurs via the process of apoptosis (16,66,82,92), an active cellular process requiring energy (25). The concept of apoptosis as the major pathway of cell death in inherited forms of retinal degeneration has recently been questioned with a proposal that nonapoptotic pathways also contribute to photoreceptor death (7,23,42,63,86,107).Increased metabolic activity is a potential cause of photoreceptor death in some models of retinal dystrophy, such as the rd/rd (rd1) model, where cyclic nucleotide channels are malfu...

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Section: Discussionsupporting

confidence: 75%

Section: Ldh Activity In Sd and P23h-3 Retinasmentioning

confidence: 95%

Section: C771mentioning

confidence: 98%

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Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

Acosta¹,

Shin²,

Ready³

et al. 2010

American Journal of Physiology-Cell Physiology

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“…LDH activity is a signature of the metabolic status of the photoreceptors, particularly after degeneration (1,4). We have previously shown that in the mouse model of retinitis pigmentosa (rd/rd or rd1 mouse), there is a significant increase in LDH activity during the early critical ages (1) followed by a decrease when many photoreceptors have degenerated: similar to what occurs in the P23H rat.…”

Section: Are Ldh Levels Significantly Elevated In the P23h Rat Retina?mentioning

confidence: 61%

Reply to “Letter to the editor: ‘Comments on retinal metabolic state in P23H and normal retinas’”

Acosta¹,

Shin²,

Ready³

et al. 2010

American Journal of Physiology-Cell Physiology

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REPLY: B. Winkler questions the validity of some of our conclusions in relation to a mutant model of retinitis pigmentosa (Proline-23-Histidine rat) published in a recent issue (1). He bases his objections on three issues: 1) Lactate dehydrogenase activity in the P23H does not appear to be elevated during the early critical stages "of the 8 days that were sampled between P1 and P21, there were only small (Ͻ5%), statistically insignificant differences in LDH activity between SD and mutant retinas". 2) Calculating the total ATP content appears to be greatly elevated. 3) ATP location within the vertebrate retina suggests altered ATP levels may be irrelevant.We have addressed the three issues below. There is no change in our conclusions that LDH activity and ATP content are both elevated early in development of the P23H rat retina, as is Na ϩ -K ϩ -ATPase activity. Are LDH Levels Significantly Elevated in the P23H Rat Retina?LDH activity is a signature of the metabolic status of the photoreceptors, particularly after degeneration (1, 4). We have previously shown that in the mouse model of retinitis pigmentosa (rd/rd or rd1 mouse), there is a significant increase in LDH activity during the early critical ages (1) followed by a decrease when many photoreceptors have degenerated: similar to what occurs in the P23H rat. It is not clear how Winkler concluded that there are "statistically insignificant differences in LDH activity between SD and mutant retina", when no statistical tests were cited for such a statement.ANOVA is a parametric test that analyzes the mean across groups reducing the chances of committing a type I error. The averaged percentage change across ages is small but significant (P1 ϭ 8%, P4 ϭ Ϫ3%, P6 ϭ 2%, P10 ϭ 18%, P12 ϭ 3%, P15 ϭ 4%, P17 ϭ 13%, P21 ϭ 22%). Statistical analysis using two-way ANOVA showed that LDH activity between P1 and P21 was significantly higher in the P23H-3 than in SD retinas (P Ͻ 0.01) (2).We have now also applied a nonparametric binomial test. The binomial test does not take into account the strength of the changes but calculate the probability that the increase-decrease is due to chance (probability 0.5). Across P1-P21 ages we observed that in 38 of 49 trials, LDH levels were increased in the P23H retina when compared with the SD retina. The two-tail P value is 0.0001. We reject the null hypothesis that LDH levels are equal in the two populations. Total Retinal ATP Content Appears to be Greatly ElevatedIn referring to the concentration of ATP in the retina, Winkler applies the correct analysis but assumes that our data can be directly transformed. We express our values in millimoles per gram protein secondary to perchloric acid extraction Address for reprint requests and other correspondence: M. Kalloniatis, ). Fig. 1. Total ATP and phosphocreatine (PCr) content in the developing SD and P23H retina expressed in mM per retina.

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“…Since the accumulation of pigmented cell debris is characteristic for retinal degeneration in RCS rats, it has been proposed that nutritional or metabolic factors are a possible cause for the degeneration of photoreceptors. Dowling [1964] discussed the possibility of vitamin A deficiency as a cause for the disease; Reading [1964] found changes in the activity of the hexose monophosphate shunt in RCS retinae and Bonavita et al [1963] reported changes in the lactate dehydrogenase activity in the retina starting at the age of 15 days.…”

Section: Retinal Dystrophy In Rcs Ratsmentioning

confidence: 99%

The Royal College of Surgeons Rat: An Animal Model for Inherited Retinal Degeneration with a Still Unknown Genetic Defect

Strauß

Stumpff²,

Mergler³

et al. 1998

Cells Tissues Organs

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The Royal College of Surgeons (RCS) rat is the first known animal with inherited retinal degeneration. Despite the fact that the genetic defect is not known, the RCS rat is widely used for research in hereditary retinal dystrophies. This review tries to summarize observations which have been made in the RCS rat and to make an attempt to formulate candidate genes which may the cause for the retinal degeneration in this rat strain. The genetic defect in RCS rats causes the inability of the retinal pigment epithelium (RPE) to phagocytose shed photoreceptor outer segments. In normal rats or humans, this circadian process is regulated by both the cyclic adenosine monophosphate (cAMP) and the calcium/ inositol phosphate systems. The calcium/inositol phosphate system seems to be linked to the phagocytosis receptors which recognize photoreceptor outer membranes to initialize phagocytosis. The cAMP system appeared as modulator of the regulation of phagocytosis. An increase in the intracellular cAMP concentration is an ‘off’ signal for phagocytosis. In RPE cells from RCS rats many observations have been made which indicate a changed second messenger metabolism concerning both the cAMP and the calcium/inositol phosphate systems. The genetic defect seems to concern a protein which is involved in the initialization of a second messenger pathway. We conclude that the genes coding for the phagocytosis receptor or for proteins which are linked to receptors (for example G proteins) are good candidates for defective genes in RCS rats.

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Neurochemical studies on the inherited retinal degeneration of the rat

Cited by 33 publications

References 27 publications

Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

Reply to “Letter to the editor: ‘Comments on retinal metabolic state in P23H and normal retinas’”

The Royal College of Surgeons Rat: An Animal Model for Inherited Retinal Degeneration with a Still Unknown Genetic Defect

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