Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats

Yuanyuan Deng, Long Long, Keke Wang, Jiayin Zhou, Lingrong Zeng, Lianzi He, Qihai Gong, Yuanyuan Deng, Long Long, Keke Wang, Jiayin Zhou, Lingrong Zeng, Lianzi He, Qihai Gong

Abstract

Beta-amyloid (Aβ) deposition, associated neuronal apoptosis and neuroinflammation are considered as the important factors which lead to cognitive deficits in Alzheimer's disease (AD). Icariside II (ICS II), an active flavonoid compound derived from Epimedium brevicornum Maxim, has been extensively used to treat erectile dysfunction, osteoporosis and dementia in traditional Chinese medicine. Recently, ICS II attracts great interest due to its broad-spectrum anti-cancer property. ICS II shows an anti-inflammatory potential both in cancer treatment and cerebral ischemia-reperfusion. It is not yet clear whether the anti-inflammatory effect of ICS II could delay progression of AD. Therefore, the current study aimed to investigate the effects of ICS II on the behavioral deficits, Aβ levels, neuroinflammatory responses and apoptosis in Aβ25-35-treated rats. We found that bilateral hippocampal injection of Aβ25-35 induced cognitive impairment, neuronal damage, along with increase of Aβ, inflammation and apoptosis in hippocampus of rats. However, treatment with ICS II 20 mg/kg could improve the cognitive deficits, ameliorate neuronal death, and reduce the levels of Aβ in the hippocampus. Furthermore, ICS II could suppress microglial and astrocytic activation, inhibit expression of IL-1β, TNF-α, COX-2, and iNOS mRNA and protein, and attenuate the Aβ induced Bax/Bcl-2 ratio elevation and caspase-3 activation. In conclusion, these results showed that ICS II could reverse Aβ-induced cognitive deficits, possibly via the inhibition of neuroinflammation and apoptosis, which suggested a potential protective effect of ICS II on AD.

Keywords: Alzheimer’s disease; ICS II; apoptosis; beta-amyloid; neuroinflammation.

Figures

FIGURE 1
FIGURE 1
Icariside II ameliorated Aβ25-35-induced learning and memory impairments. Rats were slowly injected Aβ25-35 or vehicle bilaterally into each lateral ventricle and then given 20 mg/kg ICS II for 15 days. Morris water maze was performed for 5 consecutive days from day 11 after surgery. (A) The escape latency of the rats to reach the hidden platform from days 1 to 4. (B) The time spent in the target quadrant and the frequency crossing the target quadrant. (C) The percentage of the time spent in target quadrant on the 5th day. (D) The average swimming speed. Data were expressed as mean ± SEM (n = 10∼12). ∗P < 0.05, ∗∗P < 0.01 vs. sham; #P < 0.05 vs. Aβ alone.
FIGURE 2
FIGURE 2
Icariside II attenuated Aβ25-35-induced morphological alterations in the hippocampus. (A–D) The sections of hippocampus CA1 region were obtained and stained with HE (magnification 400×, scale bar = 20 μm).
FIGURE 3
FIGURE 3
Icariside II protected against Aβ25-35-induced neuronal death in the hippocampus. (A–D) Nissl staining of hippocampus CA1 region sections (magnification 400×, scale bar 50 μm). (E) Quantitative analysis of Nissl bodies in the hippocampus CA1 region. Data were expressed as mean ± SEM, n = 4. ∗∗P < 0.01 vs. sham; #P < 0.05 vs. Aβ alone.
FIGURE 4
FIGURE 4
Icariside II improved Aβ25-35-induced neuronal apoptosis in the hippocampus. (A–D) TUNEL staining of hippocampus CA1 region sections (magnification 400×, scale bar 50 μm) and (E) quantitative analysis of apoptotic cells in the hippocampus CA1 region. Data were expressed as mean ± SEM, n = 4. ∗∗P < 0.01 vs. sham; ##P < 0.01 vs. Aβ alone.
FIGURE 5
FIGURE 5
Icariside II inhibited Aβ1-40 levels in the hippocampus of Aβ25-35-induced rats. Aβ1-40 levels were examined by Western blot. (A) The antibody-reactive band of the Aβ1-40.(B) Quantitative analysis of Aβ1-40 levels. Data were expressed as mean ± SEM (n = 3). ∗∗P < 0.01 vs. sham; ##P < 0.01 vs. Aβ alone.
FIGURE 6
FIGURE 6
Icariside II attenuated astrocytes and microglia response after Aβ injection. (A) GFAP immunoreactivity of hippocampus CA1 and DG region. (B) and (C) GFAP OD and number of astrocytes. (D) IBA-1 immunoreactivity of hippocampus CA1 and DG region. (E) and (F) IBA-1 OD and number of microglia. Magnification 400×, scale bar = 50 μm. Data were expressed as mean ± SEM, n = 4. ∗P < 0.05, ∗∗P < 0.01 vs. sham; #P < 0.05, ##P < 0.01 vs. Aβ alone.
FIGURE 7
FIGURE 7
Icariside II decreased the mRNA expression of TNF-α, IL-1β, COX-2, and iNOS after Aβ injection. The expression of TNF-α, IL-1β, COX-2, and iNOS mRNA was examined by real time RT-PCR. (A) TNF-α mRNA; (B) IL-1β mRNA; (C) COX-2 mRNA; (D) iNOS mRNA. Data were expressed as mean ± SEM (n = 6). ∗P < 0.05, ∗∗P < 0.01 vs. sham; ##P < 0.01 vs. Aβ alone.
FIGURE 8
FIGURE 8
Icariside II prevented the protein expression of TNF-α, IL-1β, COX-2, and iNOS after Aβ injection. The expressions of TNF-α, IL-1β, COX-2, and iNOS protein were detected by Western blot analysis. (A) The antibody-reactive band of the TNF-α, IL-1β, COX-2, and iNOS, respectively. (B) Quantitative analysis of TNF-α protein; (C) Quantitative analysis of IL-1β protein; (D) Quantitative analysis of COX-2 protein; (E) Quantitative analysis of iNOS protein. The relative OD was normalized to β-actin. Data presented as mean ± SEM, n = 3. ∗P < 0.05, ∗∗P < 0.01 vs. sham; #P < 0.05, ##P < 0.01 vs. Aβ alone.
FIGURE 9
FIGURE 9
Icariside II reduced the Bax/Bcl-2 ratio in the hippocampus of Aβ25-35-induced rats. (A) Representative bands of Bax and Bcl-2 of different groups. (B) Bax/Bcl-2 ratio. The relative OD was normalized to β-actin. Data were expressed as mean ± SEM (n = 3). ∗∗P < 0.01 vs. sham; ##P < 0.01 vs Aβ alone.
FIGURE 10
FIGURE 10
Icariside II repressed the Aβ-induced activation of caspase-3. (A) The antibody-reactive band of pro and active-caspase-3. (B) Quantitative analysis of pro-caspase-3. (C) Quantitative analysis of active-caspase-3. The relative OD was normalized to β-actin. Data were expressed as mean ± SEM (n = 3). ∗P < 0.05, ∗∗P < 0.01 vs. sham; ##P < 0.01 vs. Aβ alone.

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