Selective scavenging of peroxynitrite by minocycline contributes to its neuroprotective properties

Abstract

The antibiotic minocycline has long been known for its neuroprotective properties, particularly under inflammatory conditions. According to the prevailing concept, minocycline exerts its protective effects mostly by inhibiting the induction of proinflammatory enzymes in glial cells such as nitric oxide synthase-2 or NADPH-oxidase. We herein provide evidence that the tetracycline-derivative minocycline acts as a highly selective scavenger of peroxynitrite. The antibiotic did not react with superoxide or nitric oxide (·NO) radicals at concentrations up to 100 μM, but peroxynitrite was scavenged in the submicromolar concentration range. The potency was 100 x higher than that of tetracycline or gentamicin. In a neuronal cell system treated with peroxynitrite, minocycline prevented mitochondrial DNA damage and glutathione depletion. Maintenance of neuronal viability under peroxynitrite stress was shown to be solely dependent on direct chemical scavenging by minocycline. The Parkinsonian pathology-associated protein asynuclein (ASYN) was chosen in order to study the impact of minocycline on peroxynitrite- mediated nitrations. Submicromolar concentrations of minocycline prevented ASYN tyrosine nitration by PON. Nitrations were prevented more effectively than methionine oxidation and ASYN-dimerization, following peroxynitrite-treatment. Based on these observations, we suggest the direct peroxynitrite-scavenging capacity as an additional mechanism to explain minocycline´s well-known neuroprotective properties under inflammatory conditions.