(2S)-1-(4-Amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-
2-propanol dimethanesulfonate (
SUN N8075) is a novel
antioxidant with neuroprotective properties. We examined whether
SUN N8075 inhibited the neuronal damage resulting from permanent focal
cerebral ischemia, and examined its neuroprotective properties in vivo and in vitro mechanism. Focal
cerebral ischemia was induced by permanent
middle cerebral artery occlusion in mice, and the resulting
infarction, brain swelling, and neurological deficits were evaluated after 24 h or 72 h. Brain damage was assessed histochemically using
terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and antibody recognizing
4-hydroxynonenal histidine adduct (4-HNE). In the in vitro study, we examined the effects of
SUN N8075 on 1) lipid peroxidation in mouse brain homogenates and 2) cell viability and
caspase-3 protease activity under a hypoxic insult or FeSO(4) in rat cultured cerebrocortical neurons.
SUN N8075 administered either 10 min before or at 1 h after the occlusion reduced both
infarction size and neurological deficits.
SUN N8075 reduced
brain swelling when administered 10 min before, 1 h, or 3 h after occlusion. Furthermore, only pretreatment (administered 10 min before) decreased
infarct volume and
brain swelling at 72 h after
middle cerebral artery occlusion.
SUN N8075 reduced the number of TUNEL-positive cells and decreased the level of oxidative damage, as assessed by immunopositive staining to 4-HNE.
SUN N8075 inhibited lipid peroxidation, leakage of
lactate dehydrogenase,
caspase-3 activation induced by in vitro
hypoxia, and the neuronal damage induced by in vitro FeSO(4) exposure. These findings indicate that
SUN N8075 has
neuroprotective effects against acute ischemic neuronal damage in mice and may prove promising as a therapeutic
drug for
stroke.