The effect of
ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in
ischemia/reperfusion injury in CD1 and C57BL/6 mice.
ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after
ischemia. Forty-eight hours after
ischemia,
ST1942 (25 mg/kg) reduced the
infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after
ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by
ST1942. Also examined was the effect of
ST1942 on general and focal neurological deficits for 4 days after
ischemia. Mice receiving the
drug twice daily showed constantly reduced deficits. We then investigated the cortical
mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after
ischemia ST1942 treatment significantly counteracted
ischemia-induced activation of IL-1beta,
TNFalpha, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving
ST1942. In neuron-microglia cocultures,
ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of
ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this
5-HT receptor subtype may represent a novel target for
neuroprotective drugs in ischemic injury.