Silibinin attenuates amyloid beta(25-35) peptide-induced memory impairments: implication of inducible nitric-oxide synthase and tumor necrosis factor-alpha in mice.
In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (Abeta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of Abeta peptide(25-35) (Abeta(25-35)) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the Abeta(25-35) injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 h after the Abeta(25-35) injection. We found that silibinin significantly attenuated memory deficits caused by Abeta(25-35) in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Abeta(25-35). Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by Abeta(25-35). These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Abeta(25-35) and (ii) may be a potential candidate for an AD medication.
Lu
P
P
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Mamiya
T
T
Lu
L L
LL
Mouri
A
A
Niwa
M
M
Hiramatsu
M
M
Zou
L B
LB
Nagai
T
T
Ikejima
T
T
Nabeshima
T
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D018836:Inflammation Mediators / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010446:Peptide Fragments / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018836:Inflammation Mediators; D010446:Peptide Fragments; D012333:RNA, Messenger; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); C002744:3-nitrotyrosine; D014443:Tyrosine; D000077385:Silybin; D052247:Nitric Oxide Synthase Type II