Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism.
OBJECTIVE
Minocycline, a semi-synthetic tetracycline antibiotic is reported to be neuroprotective in degenerative and ischaemic models of central nervous system disease, via mechanisms involving suppression of both cytotoxic microglial activity and caspase-dependent apoptosis. We have investigated the effect of minocycline treatment on a mouse model of retinitis pigmentosa, an inherited photoreceptor neurodegenerative disorder, and contrasted this with the effect of depleting retinal microglia using liposomal clodronate.


METHODS
rds mice were treated intraperitoneally from the second postnatal day (P2) with either daily minocycline until P16, P18, P21, P24 and P27 or alternative day clodronate liposomes until P16. Immunohistochemical and immunofluorescent methods were applied for the detection of microglia (F4/80) and apoptosis (TUNEL and caspase 3 activation).


RESULTS
Photoreceptor apoptosis was delayed by minocycline treatment but not, ultimately, prevented. Markedly reduced expression of activated caspase 3 was observed in photoreceptors at the early time point, corresponding with the reduced level of apoptosis. Delayed photoreceptor apoptosis due to minocycline treatment was associated with a 50% reduction in the numbers of microglia at early timepoints. Liposomal clodronate treatment also resulted in a marked reduction in the number of microglia (63% reduction in microglia), but in contrast to minocycline treatment, this had no effect on photoreceptor apoptosis.


CONCLUSIONS
Minocycline appears to delay photoreceptor apoptosis through a microglia-independent action. Although microglial cytotoxicity has been implicated during other models of neurodegeneration, microglia are unlikely to play such a role in this model of photoreceptor dystrophy.
Hughes
Edward H
EH
University Division of Ophthalmology, Bristol Eye Hospital, University of Bristol, Lower Maudlin St., Bristol BS1 2LX, UK.
Schlichtenbrede
Frank C
FC
Murphy
Conor C
CC
Broderick
Cathryn
C
van Rooijen
Nico
N
Ali
Robin R
RR
Dick
Andrew D
AD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007381:Intermediate Filament Proteins / Q000235:genetics; D008081:Liposomes; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008911:Minocycline / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D064531:Peripherins; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D007381:Intermediate Filament Proteins; D008081:Liposomes; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D064531:Peripherins; C578996:Prph2 protein, mouse; D004002:Clodronic Acid; D008911:Minocycline