minocycline and Retinitis-Pigmentosa

The etiology of retinitis pigmentosa (RP)-associated cystoid macular edema (CME) has been related to retinal neuroinflammation and microglial activation. Minocycline, a drug FDA-approved for anti-microbial indications, also inhibits microglial activation and expression of inflammatory mediators. This study investigates the safety and efficacy of oral minocycline as primary treatment for RP-associated CME.. A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with RP-associated CME. Participants had lead-in assessments prior to the initiation of oral minocycline 100 mg twice daily for 12 months. Main outcome variables included changes in best-corrected visual acuity (BCVA) and retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography relative to mean of pre-treatment measurements.. The study drug was well tolerated and not associated with any severe adverse events. No significant changes in mean BCVA from study baseline were noted in either the study eye (+ 0.7 ± 4.1 letters at 6 months, - 1.1 ± 1.7 letters at 12 months) or the qualifying fellow eye (- 0.3 ± 3.4 letters at 6 months, - 0.3 ± 4.6 letters at 12 months) (p > 0.05 for all comparisons). Mean percentage changes in CST from baseline however decreased progressively with treatment (decreases at 6 and 12 months: study eyes 3.9 and 9.8%; qualifying fellow eyes 1.4 and 7.7%). Considering all eyes (n = 10), mean percentage CST decrease at 6 and 12 months was 2.7 ± 9.5% (p = 0.39) and 8.7 ± 9.5% (p = 0.02) respectively.. Oral minocycline administration over 12 months was associated with no significant changes in mean BCVA and a small but progressive decrease in mean CST.. NCT02140164 (05/2014).

Topics: Humans; Macular Edema; Minocycline; Prospective Studies; Retina; Retinitis Pigmentosa; Tomography, Optical Coherence

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)-/-Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

Topics: Animals; Anti-Bacterial Agents; Cell Death; Disease Models, Animal; Female; Male; Mice; Minocycline; Monocytes; Neuroprotective Agents; Photoreceptor Cells, Vertebrate; Receptors, CCR2; Retina; Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.

Topics: Animals; Animals, Newborn; Apoptosis; CX3C Chemokine Receptor 1; Cyclic Nucleotide Phosphodiesterases, Type 6; Disease Models, Animal; Enzyme Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Minocycline; Mutation; Neuroprotective Agents; Pyrazoles; Receptors, Chemokine; Retina; Retinal Degeneration; Retinitis Pigmentosa

Numerous mutations in over 100 rod genes are the well-established cause of apoptotic death of these cells and development of night blindness in retinitis pigmentosa (RP). Cone death is either concomitant or follows rod death with resultant loss of critical peripheral and central day vision. As cones are generally not encumbered by genetic mutations, the causes of their death and its prevention are the central problems of RP research. Currently no FDA-approved medications are available for retarding RP progression.. It is proposed that cones, which are outnumbered 20:1 by rods, undergo apoptosis as a consequence of neurotrophic factor deficiencies and oxidative stresses accompanying massive rod death: increased retinal oxygen tension; leakage of lipid-peroxidation catalysts from disrupted membranes; reactive oxygen species from active/hyperactive microglia ingesting rod-apoptotic bodies. Accordingly we developed and tested a treatment regimen with a range of antioxidants in combination with the off-label use of deprenyl (1 mg/day), a safe antiapoptotic agent, which also upregulates eight neurotrophic factors. Since deprenyl inhibits only one of four mitochondrial apoptotic pathways, we added the antibiotic minocycline (100 mg/day) to our protocol at month 76. Minocycline complements deprenyl's therapeutic properties: it inhibits all four apoptotic pathways; inhibits apoptosis-initiating proteins; as phenol exerts powerful antioxidant properties; upregulates three antioxidant enzymes; downregulates oxidative/inflammatory microglia activities. Its safe long-term use for acne and rheumatoid arthritis received FDA approval; it passes the blood/brain and blood/retinal barriers readily; and because of its rapid and complete absorption causes no intestinal disturbances. The National Eye Institute has initiated in 2010 and 2011 clinical trials with minocycline (200 mg/day) for diabetic macular edema and retinal branch vein occlusion.. The hypothesis was tested for 140 months with one RP patient monitored by Humphrey Perimetry, which was quantitated by two parameters: (a) sum of decibel units, (b) number of detected light sources (visual field). Although no decline was observed in these parameters during the first 50 months of treatment, they declined by 10-28% during months 50-65. These declines reversed upon introduction of minocycline: over the total 140-month treatment, the right eye visual field showed 0% decline and left eye 13.3% decline. Rate constants for logarithmic decline of visual field measured prior to treatment indicate that visual fields would have decreased by 64% and 70%, respectively by month 140 in the absence of treatment.

Topics: Adult; Antioxidants; Apoptosis; Drug Repositioning; Drug Therapy, Combination; Female; Humans; Minocycline; Models, Biological; Nerve Growth Factors; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Selegiline; Time Factors; Treatment Outcome; Visual Fields

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.. 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).. 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.. 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.

Topics: Animals; Apoptosis; Clodronic Acid; In Situ Nick-End Labeling; Intermediate Filament Proteins; Liposomes; Membrane Glycoproteins; Mice; Mice, Knockout; Microglia; Minocycline; Nerve Tissue Proteins; Neuroprotective Agents; Peripherins; Photoreceptor Cells, Vertebrate; Retinitis Pigmentosa