Abstract
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 β (Aβ) 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 Aβ peptide25–35 (Aβ25–35) 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 Aβ25–35 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-α (TNF-α) in the hippocampus and amygdala was measured 2 h after the Aβ25–35 injection. We found that silibinin significantly attenuated memory deficits caused by Aβ25–35 in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Aβ25–35. 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-α mRNA in the hippocampus and amygdala induced by Aβ25–35. These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Aβ25–35 and (ii) may be a potential candidate for an AD medication.
- AD, Alzheimer’s disease
- NO, nitric oxide
- Aβ, amyloid β peptide
- CMC, carboxymethylcellulose
- ONOO−, peroxynitrite
- iNOS, inducible nitric-oxide synthase
- LPS, lipopolysaccharide
- RT-PCR, reverse transcription-polymerase chain reaction
- silibinin, (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl]chroman-4-one
- TNF-α, tumor necrosis factor-α
Footnotes
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This work was supported in part by grants-in-aid for “Academic Frontier Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Grant-in-Aid for Scientific Research (B) from MEXT of Japan [Grant 20390073]; Grant-in-Aid for Exploratory Research from Sprout Society for the Promotion of Science [Grant 19659017]; grants-in-aid for Regional Joint Research Program for Private Universities to cover current expenses from MEXT; Research Science of Pharmaceutical and Medical Devices and Research on the Risk of Chemical Substances from the Ministry of Health, Labor and Welfare (MHLW) of Japan; Research on Regulatory Science of Pharmaceutical and Medical Devices from MHLW, International Research Project Supported by the Meijo Asian Research Center; a research grant from Japan China Medical Association, Japan; and research grants from the Takeda Science Foundation, from the Uehara Memorial Foundation, and from the Nagai Foundation Tokyo.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- Received April 15, 2009.
- Accepted July 27, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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