A similar neuroprotective effect of minocycline has been observed in various animal models of neuronal degeneration such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease
18 19 and global and focal cerebral ischemia.
16 17 In most of these studies, suppression of microglial/macrophagic responses was similar to this report. For example, in the MPTP-mouse model of Parkinson’s disease, minocycline was shown to protect nigral cells by inhibiting microglial activation
18 resulting in a reduction in interleukin (IL)-1β and the inducible form of nitric oxide synthase (iNOS) levels.
19 Similarly, Yrjanheikki et al.
16 17 showed that minocycline reduced inflammation, protected neurons within a wide time window, and inhibited IL-1β converting enzyme (ICE) and cyclooxygenase (COX)-2. Other studies, showing potent protective effects of minocycline in models of CNS degenerative diseases including multiple sclerosis
27 and amyotrophic lateral sclerosis (ALS),
28 also pointed to a mechanism of inhibiting microglial cell activation. In a mixed spinal cord culture,
29 minocycline prevented proliferation and activation of microglial cells before neuronal death and diminished the increased release of IL-1β and nitric oxide (NO). It also inhibited the
N-methyl-
d-aspartate (NMDA)–induced activation of p38 MAPK in microglial cells. Tetracycline, an analogue of minocycline, has also been shown to inhibit iNOS mRNA expression in murine macrophages.
30 Our present results are consistent with findings in these earlier studies and extend our understanding to retinal photoreceptors. In contrast, recent studies have also demonstrated that minocycline prevents neuronal loss by direct inhibition of cytochrome
c release
31 and by inhibiting caspase-dependent/independent cell death pathways.
32 Therefore, it is possible that neuroprotection of photoreceptors by minocycline in this study is a combination of diminished microglial/macrophagic activation and a direct action on cell death pathways. Further studies are needed to delineate its mechanism(s) of action.