1,12-Substituted tetracyclines as antioxidant agents

Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups

“…TUDCA, PMIN, and MNC pretreatment reduced lipid peroxidation during sulfa-induced bilirubin encephalopathy to basal levels observed in nonjaundiced N/j controls consistent with their reported antioxidant activities (8,9,12). However, only MNC was neuroprotective against BIND.…”

“…This is not surprising as a previous study reported that PMIN is a more potent antioxidant than MNC at least as indexed by three commonly used assays, 2,2-diphenyl-1-picrylhydrazyl, 2,2′′-azinobis(3-ethylbenzothiazoline-6-sulfonate), and superoxide scavenging in vitro (8). The higher antioxidant activity of PMIN relative to MNC in vitro is attributed to the presence of an extra heterocyclic ring and supplementary >NH and -OH functions (8). PMIN, however, despite its effective inhibition of lipid peroxidation, did not provide neuroprotection against BIND.…”

“…This strongly suggests that some nonantioxidant property of the parent compound MNC is lost in the chemical modification producing PMIN. In fact, PMIN as contrasted with MNC is nonchelating, failing to bind Mg 2+ (8), Zn 2+ (8), or Ca 2+ (14), and as a result differs from MNC in being HNe expression was significantly different across study groups (ANoVA F = 5.93; P < 0.001); post hoc analysis showed that HNe levels in j/j saline, j/j sulfa + tuDCA, j/j sulfa + PMIN, and j/j sulfa + MNC were each significantly lower than those of j/j sulfa animals (*P < 0.05) but not significantly different from N/j controls. each bar represents the mean ± sD.…”

“…Neuroprotection against BIND both nonbactericidal and devoid of matrix metalloproteinase inhibitory activity (8,14). The former would not be expected to impact BIND risk whereas the latter might (13) and therefore merits further study.…”

“…We hypothesized that antioxidants inhibit oxidative stress and block BIND in the Gunn rat model of kernicterus. Three different antioxidants were administered in a prophylactic mode: TUDCA, 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), a novel derivative of minocycline with potent antioxidant activity (8), and minocycline (MNC), a second-generation tetracycline with antioxidant properties (9) previously shown to prevent BIND in Gunn rat pups (10,11).…”