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

Acosta, Mónica L.; Shin, Yea-Seul; Ready, Sarah J.; Fletcher, Erica L.; Christie, David L.; Kalloniatis, Michael

doi:10.1152/ajpcell.00253.2009

Cited by 22 publications

(16 citation statements)

References 94 publications

(112 reference statements)

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“…Notably, the remaining photoreceptors were left in a chronically hyperoxic environment which the authors proposed could lead to accelerated photoreceptor death via oxidative stress. In the developing P23H-3 retina, photoreceptor apoptosis was accompanied by increased metabolic activity, including elevated levels of lactate dehydrogenase, ATPase activity, and ATP, representing a potential cause of photoreceptor death (Acosta et al, 2010 ). An increase in dark-adapted photoreceptor cAMP levels was also observed in the P23H rats, which was potentially toxic and capable Mapping cation entry in photoreceptors and inner retinal neurons during early degeneration in the P23H-3 rat retina of promoting cell death (Traverso et al, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Mapping cation entry in photoreceptors and inner retinal neurons during early degeneration in the P23H-3 rat retina

et al. 2013

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The proline-23-histidine line 3 (P23H-3) transgenic rat carries a human opsin gene mutation leading to progressive photoreceptor loss characteristic of human autosomal dominant retinitis pigmentosa. The aim of the present study was to evaluate neurochemical modifications in the P23H-3 retina as a function of development and degeneration. Specifically, we investigated the ion channel permeability of photoreceptors by tracking an organic cation, agmatine (1-amino-4-guanidobutane, AGB), which permeates through nonspecific cation channels. We also investigated the activity of ionotropic glutamate receptors in distinct populations of bipolar, amacrine, and ganglion cells using AGB tracking in combination with macromolecular markers. We found elevated cation channel permeation in photoreceptors as early as postnatal day 12 (P12) suggesting that AGB labeling is an early indicator of impending photoreceptor degeneration. However, bipolar, amacrine, or ganglion cells displayed normal responses secondary to ionotropic glutamate receptor activation even at P138 when about one half of the photoreceptor layer was lost and apoptosis and gliosis were observed. These results suggest that possible therapeutic windows as downstream neurons in inner retina appear to retain normal function with regard to AGB permeation when photoreceptors are significantly reduced but not lost.

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Section: Introductionmentioning

confidence: 99%

Mapping cation entry in photoreceptors and inner retinal neurons during early degeneration in the P23H-3 rat retina

et al. 2013

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“…Lactate concentration in the blood was determined using a lactate assay kit, as described previously (Acosta et al, 2010). Whole blood were homogenized in 0.9% saline and centrifuged at 2,800 g for 6 min, and the supernatant was diluted to 1:7 with saline.…”

Section: Methods Of Samples Analysismentioning

confidence: 99%

The Fluctuation Effect of Atmospheric Ammonia (Nh3) Exposure and Microclimate on Hereford Bulls Hematochemical

Mushawwir

Yong

Adriani

et al. 2010

J. Indonesian Trop. Anim. Agric.

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Ten Hereford bulls housed indoors in individual tie stalls were used to explore the relationships atmospheric ammonia exposure and microclimate on beef cattle hematochemical, and to know effect and to prediction equations the atmospheric ammonia exposure and microclimate with various hematochemical parameters. This study was conducted in Animal Station, Department of Agricultural Biotechnology, Seoul National University (SNU), Seoul, South Korea, for 40 days during summer. Results of this study indicated that there were negative correlation between ammonia with temperature and positive correlation between ammonia with humidity. There were significantly negative effect of ammonia on hematochemical, except neutrophyls and ratio of neutrophyls to lymphocytes. Simultaneous effect between ammonia, temperature and humidity, mainly effected on glucose, hexokinase, lymphocytes, neutrophyls, N:L Ratio, and lactate. Simultaneous effect between ammonia, temperature and humidity proved to be a good indicator for predicting the profile of glucose, hexokinase, lymphocytes, neutrophyls, N:L Ratio in the blood.

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“…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).…”

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

confidence: 94%

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

Cited by 22 publications

References 94 publications

Mapping cation entry in photoreceptors and inner retinal neurons during early degeneration in the P23H-3 rat retina

Mapping cation entry in photoreceptors and inner retinal neurons during early degeneration in the P23H-3 rat retina

The Fluctuation Effect of Atmospheric Ammonia (Nh3) Exposure and Microclimate on Hereford Bulls Hematochemical

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

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