Shenzao jiannao oral liquid, an herbal formula, ameliorates cognitive impairments by rescuing neuronal death and triggering endogenous neurogenesis in AD-like mice induced by a combination of Aβ42 and scopolamine.
According to the theory of traditional Chinese medicine (TCM), Alzheimer's disease (AD) is identified as "forgetfulness" or "dementia", and is mainly caused by "kidney essence deficiency" which ultimately induces "encephala reduction". Therefore, herbal formulas possessing the efficacy of nourishing kidney essence or replenishing brain marrow are commonly served as effective strategies for AD treatment. Shenzao jiannao oral liquid (SZJN), a traditional Chinese preparation approved by the China Food and Drug Administration (CFDA), is used for the treatment of insomnia and mind fatigue at present for its efficacy of nourishing kidneys. In present study, we found that SZJN could improve cognitive function of AD-like mice.
This study aims to investigate the effects of SJZN on ameliorating cognitive deficits of AD-like mouse model, and to illuminate the underlying mechanisms from the perspective of neuroprotection and neurogenesis.
Kunming mice (28 ± 2 g) were randomly allocated into seven groups: control, sham, model, donepezil and SZJN groups (low, middle and high). The AD mouse model was established by Aβ42 combined with scopolamine. SZJN were intragastrically administrated at doses of 0.3, 1.5 and 7.5 g/kg for 28 days. Morris water maze (MWM) test was applied to determine the cognitive function. Hematoxylin eosin (HE) and Nissl staining were carried out to evaluate pathological damages in the cortex and hippocampal tissues. To explore the protective effects of SZJN on multiple pathogenic factors of AD, protein levels of Aβ42, glial fibrillary acidic protein (GFAP), Bax, Bcl-2, Caspase-3, synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), and neurogenesis related proteins were assessed using Immunofluorescence (IF) and western blot analysis. In vitro, the AD cell model was established by transduction of APP695swe genes into Neural stem cells (NSCs) isolated from the hippocampal tissues of neonatal C57BL/6 mice. Cell viability assay and neurosphere formation assay were carried out to verify the efficacy of SZJN on proliferation of NSCs.
Our results demonstrated that SZJN (1.5 g/kg and 7.5 g/kg) treatment significantly ameliorated cognitive deficits of AD-like mice. SZJN (7.5 g/kg) treatment significantly retarded the pathological damages including neuronal degeneration, neuronal apoptosis, Aβ peptides aggregation and reaction of astrocytes in AD-like mice. In addition, SZJN (7.5 g/kg) increased the expression of BDNF and SYP, and restored the abnormal level of MDA and SOD in the brain of AD-like mice. Furthermore, SZJN treatment for 28 days remarkably increased the proliferation of NSCs evidenced by more Nestin+ and BrdU+ cells in the hippocampal DG regions, and increased the amount of mature neurons marked by NeuN both in the cortex and hippocampal DG regions. In vitro, SZJN treatement (16, 32, 64 mg/ml) promoted the proliferation of NSCs evidenced by the increased amount and enlarged size of the neurospheres (p < 0.05).
Our findings indicated that SZJN could ameliorate cognitive deficits by protecting neurons from death and triggering endogenous neurogenesis. Therefore, SZJN may be considered as a promising agent to restore neuronal loss and deter the deterioration in AD patients.
Xiao H
，Li H
，Song H
，Kong L
，Yan X
，Li Y
，Deng Y
，Tai H
，Wu Y
，Ni Y
，Li W
，Chen J
，Yang J
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β-asarone improves learning and memory and reduces Acetyl Cholinesterase and Beta-amyloid 42 levels in APP/PS1 transgenic mice by regulating Beclin-1-dependent autophagy.
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, and studies have suggested that β-asarone has pharmacological effects on beta-amyloid (Aβ) injected in the rat hippocampus. However, the effect of β-asarone on autophagy in the APP/PS1 transgenic mouse is unreported. APP/PS1 transgenic mice were randomly divided into six groups (n=10/group): an untreated group, an Aricept-treated group, a 3-MA-treated group, a rapamycin-treated group, an LY294002-treated group, a β-asarone-treated group. The control group consisted of wild-type C57BL/6 mice. All treatments were administered to the mice for 30 days. Spatial learning and memory were assessed by water maze, passive avoidance, and step-down tests. AChE and Aβ42 levels in the hippocampus were determined by ELISA. p-Akt, p-mTOR, and LC3B expression were detected by flow cytometry. The expression of p-Akt, p-mTOR, Beclin-1, and p62 proteins was assessed by western blot. Changes in autophagy were viewed using a transmission electron microscope. APP and Beclin-1 mRNA levels were measured by Real-Time PCR. The learning and memory of APP/PS1 transgenic mice were improved significantly after β-asarone treatment compared with the untreated group. In addition, β-asarone treatment reduced AChE and Aβ42 levels, increased p-mTOR and p62 expression, decreased p-Akt, Beclin-1, and LC3B expression, decreased the number of autophagosomes and reduced APP mRNA and Beclin-1 mRNA levels compared with the untreated group. That is, β-asarone treatment can improve the learning and memory abilities of APP/PS1 transgenic mouse by inhibiting Beclin-1-dependent autophagy via the PI3K/Akt/mTOR pathway.
Deng M
，Huang L
，Ning B
，Wang N
，Zhang Q
，Zhu C
，Fang Y
... -
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Yishen Huazhuo Decoction Induces Autophagy to Promote the Clearance of Aβ(1-42) in SAMP8 Mice: Mechanism Research of a Traditional Chinese Formula Against Alzheimer's Disease.
Studies have found that autophagy could promote the clearance of Aβ. To promote and maintain the occurrence of autophagy in Alzheimer's Disease (AD) might be a potential way to reduce neuronal loss and improve the learning and memory of AD.
To investigate the possible mechanisms of Yishen Huazhuo Decoction (YHD) against AD model.
Forty 7-month-old male SAMP8 mice were randomly divided into model (P8) group and YHD group, 20 in each group, with 20 SAMR1 mice as control (R1) group. All mice were intragastrically administered for 4 weeks, YHD at the dosage of 6.24g/kg for YHD group, and distilled water for P8 group and R1 group. Morris Water Maze (MWM) test, Nissl's staining, TEM, TUNEL staining, immunofluorescence double staining, and western blot analysis were applied to learning and memory, structure and ultrastructure of neurons, autophagosome, apoptosis index, Aβ, LAMP1, and autophagy related proteins.
The escape latency time of YHD group was significantly shorter on the 4th and 5th day during MWM test than those in P8 group (P=0.011, 0.008<0.05), and the number of crossing platform in YHD group increased significantly (P=0.02<0.05). Nissl's staining showed that the number of neurons in YHD group increased significantly (P<0.0001). TEM showed in YHD group that the nucleus of neurons was slightly irregular, with slightly reduced organelles, partially fused and blurred cristae and membrane of mitochondria. The apoptosis index of YHD group showed a decreasing trend, without statistically significant difference (P=0.093>0.05), while Caspase3 expression in YHD group was significantly lower (P=0.044<0.05). YHD could promote the clearance of Aβ1-42 protein, improve the expression of Beclin-1 and p-Bcl2 proteins, reduce mTOR and p62 proteins.
YHD could induce autophagy initiation, increase the formation of autophagosomes and autolysosome, promote the degradation of autophagy substrates, thereby regulating autophagy, and promoting the clearance of Aβ1-42 to improve memory impairment in SAMP8 mice.
Wang K
，Sun W
，Xu J
，Qin Q
，Yu Z
，Cheng R
，Zhang L
，Liu S
，Zhou Z
，Zhang Y
，Cui Y
... -
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