Effect of steroidal and non-steroidal drugs on the microglia activation pattern and the course of degeneration in the retinal degeneration slow mouse.
BACKGROUND
In hereditary retinal degeneration, microglia cells become activated, migrate through the outer nuclear layer (ONL) and accumulate in the subretinal space. Although this inflammatory process is not likely to be responsible for the onset of photoreceptor apoptosis, cytotoxic substances secreted by activated microglia could potentially accelerate and perpetuate the degenerative process. Anti-inflammatory drugs have been shown to modulate the microglia response in neurodegenerative disorders and potentially ameliorate the disease progression in various animal model systems. In this study we wanted to test the impact of the most commonly used anti-inflammatory drugs (acetylsalicylate and prednisolone) on the microglia activation pattern, the rate of caspase-3-dependent photoreceptor apoptosis and the course of the degeneration in the retinal degeneration slow (rds) mouse retina.


METHODS
169 pigmented rds mice and 30 CBA wild-type mice were used for this study. The treatment groups were injected daily with either acetylsalicylate (200 mg/kg) or prednisolone (2 mg/kg) i.p. from day 0 up to 3 months. Animals were sacrificed at days 10, 14, 16, 18, 20, 30, 40, 60 and 90. Cryoprotected frozen sections were immunostained with F4/80 and cleaved caspase-3 antibodies. The main outcome measures were the total microglia count in the subretinal space, the total cleaved caspase-3-positive cells in the ONL and the averaged number of photoreceptor rows in the midperipheral retina.


RESULTS
Neither acetylsalicylate nor prednisolone reduced subretinal microglia accumulation in the rds mouse degeneration model. Moreover, they aggravated migration and accumulation in the early time course. The apoptotic cascade started earlier and was more pronounced in both treatment groups compared to the control group. The pace of retinal degeneration was not reduced in the treatment groups compared to the untreated control. In contrast, acetylsalicylate did significantly accelerate the photoreceptor cell degeneration in comparison to the prednisolone (p < 0.001) and to the control group (p < 0.001).


CONCLUSIONS
Acetylsalicylate and prednisolone do not decrease the microglia response in the rds mouse and are not neuroprotective. More research is needed to clarify the molecular mechanisms which lead to photoreceptor cell death and to elucidate the complex role of microglia in inherited retinal degeneration.
Sarra
G M
GM
University Eye Clinic, Inselspital, CH-3010 Bern, Switzerland. gian-marco.sarra@insel.ch
Sarra
F G
FG
Schlichtenbrede
F C
FC
Trittibach
P
P
Estermann
S
S
Tsiroukis
E
E
Ali
R R
RR
Luthert
P J
PJ
Reichel
M B
MB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D018613:Microscopy, Confocal; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000943:Antigens, Differentiation; D005938:Glucocorticoids; C036763:monocyte-macrophage differentiation antigen; D011239:Prednisolone; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001241:Aspirin