Silibinin Attenuates Amyloid β_25–35Peptide-Induced Memory Impairments: Implication of Inducible Nitric-Oxide Synthase and Tumor Necrosis Factor-α in Mice

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 ␤ (A␤) 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 A␤ peptide [25][26][27][28][29][30][31][32][33][34][35] (A␤ [25][26][27][28][29][30][31][32][33][34][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 A␤ 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-␣ (TNF-␣) in the hippocampus and amygdala was measured 2 h after the A␤ 25-35 injection. We found that silibinin significantly attenuated memory deficits caused by A␤ [25][26][27][28][29][30][31][32][33][34][35] in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by A␤ [25][26][27][28][29][30][31][32][33][34][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-␣ mRNA in the hippocampus and amygdala induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] . These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] and (ii) may be a potential candidate for an AD medication.

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

“…In this view, silibinin should not interfere with the anticancer property of oxaliplatin. 41 The present data highlight the anti-neuropathic properties of silibinin which, together with its protective effects in hepatic diseases 15,30,31,44 as well as in neurodegenerative disorders, 31 suggest its clinical applicability as an adjuvant in cancer patients to prevent or reduce chemotherapy-induced toxicity. The protective effects and the anticancer activity confer to silibinin a ubiquitous profile that differentiates this molecule from other antioxidant drugs clinically used to treat oxaliplatin-induced neuropathic pain.…”

Silymarin Attenuated the Amyloid β Plaque Burden and Improved Behavioral Abnormalities in an Alzheimer’s Disease Mouse Model

“…Nabeshima et al recently reported that silibinin, a component of silymarin, prevents acute and subchronic memory loss induced by the intraventricular injection of A25-35 into mice, due to its strong free radical- scavenging activity 57) and its inhibition of nitric-oxide synthase and tumor necrosis factor-. 58) However, no data on AD pathology due to silibinin were given in these reports. The differences in the protective effects of silibinin and silymarin on memory task might be explained by distinct protocols of material (a component of silymarin or crude extract), duration (11 d or 6 months), and in vivo model (acute model by exogenous A injection or chronic model by APP transgene), respectively.…”

Imipramine, in Part through Tumor Necrosis Factor α Inhibition, Prevents Cognitive Decline and β-Amyloid Accumulation in a Mouse Model of Alzheimer's Disease

“…In the same mice model, Alkam et al (2008) showed an increase of mnesic performances in novel object recognition task after thalidomide treatment, a degrader of TNF-␣ mRNA, or intracerebroventricular injection of an anti-TNF-␣ antibody. Recently, Lu et al (2009a) demonstrated that silibinin, a flavonoid, attenuates memory impairment in cued and contextual fear-conditioning test, through amelioration of oxidative stress and inflammatory response induced by an intracerebroventricular injection of A␤25-35. In a clinical open-label pilot study, perispinal use of a TNF-␣ inhibitor, etanercept, in AD patients claimed detectable improvement of cognitive performance (Tobinick et al, 2006).…”