Prevention of in vitro and in vivo acute ischemic neuronal damage by (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate (SUN N8075), a novel neuroprotective agent with antioxidant properties.
(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.
Kotani
Y
Y
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Morimoto
N
N
Oida
Y
Y
Tamura
Y
Y
Tamura
S
S
Inoue
T
T
Shimazawa
M
M
Yoshimura
S
S
Iwama
T
T
Hara
H
H
D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D013997:Time Factors
D000447:Aldehydes; D000814:Aniline Compounds; D018696:Neuroprotective Agents; D010879:Piperazines; C413884:SUN N8075; D007501:Iron; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal