Cornel Iridoid Glycoside and Its Effective Component Regulate ATPase Vps4A/JNK to Alleviate Autophagy Deficit with Autophagosome Accumulation.

Improving autophagy-lysosome fusion has been considered a key method in the treatment of Alzheimer's disease (AD). Cornel iridoid glycoside (CIG) is extracted from Cornus officinalis and has been shown to promote the clearance of tau oligomers via the autophagy pathway. However, the mechanisms of CIG on autophagy deficits are not understood. Here, we found autophagy deficit and tau aggregation in the brains of P301S tau transgenic mice and MAPT cells edited using CRISPR-Cas9 technology. CIG decreased tau aggregation and alleviated autophagic markers involving the JNK/Beclin-1 signaling pathway which demonstrated CIG that might enhance lysosome formation by upregulating ATPase Vps4A expression. Knocking down VPS4A increased autophagosome accumulation and attenuated the effect of CIG on p62. In addition, CIG had no effect on tau oligomers but still inhibited the level of tau monomer in VPS4A knockout cells. The effective component (Sweroside, SWE) of CIG attenuated tau oligomers accumulation and increased Vps4A level but not CHMP2B. SWE could not change the level of tau oligomers in VPS4A knockout cells. In conclusion, CIG suppressed autophagosome accumulation by regulating the ATPase Vps4A/JNK. SWE is a core of active factors of CIG in Vps4A regulation. These findings suggest CIG may be a potential drug in AD treatment.

Shenqi Xingnao Granules ameliorates cognitive impairments and Alzheimer's disease-like pathologies in APP/PS1 mouse model.

Objective: Alzheimer's disease (AD) is along with cognitive decline due to amyloid-ß (Aß) plaques, tau hyperphosphorylation, and neuron loss. Shenqi Xingnao Granules (SQXN), a traditional Chinese medicine, significantly ameliorated the cognitive function and daily living abilities of patients with AD. However, till date, no study has investigated the mechanism of action of SQXN on AD. The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice. Methods: Four-month-old APP/PS1 transgenic (Tg) mice were randomly divided into a model group and SQXN-treated (3.5, 7, 14 g/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition test. All mice were sacrificed and the brain samples were collected after 75 d. The soluble Aß contents were detected by Elisa kit; The levels of expression of NeuN, APP, phosphorylated tau and related protein were measured by Western blotting; The inflammation factors were detected by the proinflammatory panel kit. Results: Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months. Using the Morris water maze tests and Novel object recognition, we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls. SQXN also inhibited neuronal loss (NeuN marker). SQXN treatment decreased soluble Aß42 through inhibiting the expression of sAPPß and BACE-1 without regulating full-length amyloid precursor protein (FL APP). Insulin degrading enzyme (IDE), the Aß degrading enzyme, were increased by SQXN. In addition, SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3ß in the brain of APP/PS1 mice. Compared with APP/PS1 transgenic negative mice, IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-12p70, KC/GRO and TNF-α were not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic (Tg) mice. However, SQXN could inhibited the expression of IL-2. Conclusion: These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice. The possible mechanisms involve its inhibition of neuronal loss, soluble Aß deposition, tau hyperphosphorylation and inflammation.

Cornel Iridoid Glycoside Improves Locomotor Impairment and Decreases Spinal Cord Damage in Rats.

Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy.

Multi-Target Strategy and Experimental Studies of Traditional Chinese Medicine for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a multifactorial complex disease. The pathogenesis of AD is very complicated, and involves the ß-amyloid (Aß) cascade, tau hyperphosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, reduced levels of neurotrophic factors, and damage and loss of synapses as well as cholinergic neurons. The multi-target characteristics of traditional Chinese medicine (TCM) may be advantageous over single-target drugs in the treatment of complex diseases. These drugs have therefore attracted more attention in the research and development of AD therapies. This review describes advances made in experimental studies of TCM for AD treatment. It discusses research, from our group and other laboratories, on TCM compound drugs (Shenwu capsule) and approximately 10 Chinese medicinal herb extracts (tetrahydroxystilbene glucoside, epimedium flavonoid, icariin, cornel iridoid glycoside, ginsenoside, puerarin, clausenamide, huperzine A, and timosaponins).

Cornel iridoid glycoside reduces infarct size measured by magnetic resonance imaging and improves neurological function after focal cerebral ischemia in rats.

OBJECTIVE: To investigate the effect of cornel iridoid glycoside (CIG), an ingredient extracted from traditional Chinese herb Cornus offificinalis, on neurological function and infarct size in rats as measured by magnetic resonance imaging (MRI) after ischemic stroke. METHODS: Sprague-Dawley rats were divided into three group: control (n=11), model (n=20) and CIG (n=16) groups. Rats in the model and CIG groups underwent 90-min middle cerebral artery occlusion (MCAO) followed by reperfusion. Their neurological defect was measured by using a modified neurological severity score (mNSS). T2-weighted MRI (T2-MRI) of the brain was performed in vivo from 2 to 28 days after MCAO. The infarct volume in the brain was also measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining 28 days after stroke. RESULTS: CIG, 60 mg/(kg day), administered by oral gavage starting from 6 h after the onset of MCAO improved neurological function at 7, 14, 21, and 28 days post occlusion (P<0.05 orP<0.01) and decreased mortality. The infarct volumes computed from the T2-MR images were reduced in the CIG-treated group compared with the model group at 7, 14 and 28 days after MCAO (P<0.05); and the rate at which the infarct volume decreased from 2 to 28 days was higher in the CIG-treated group than that in the model group (P<0.05). The infarct volumes measured by TTC staining were also decreased 28 days after stroke (P<0.05). CONCLUSION: CIG treatment, starting from 6 h after MCAO, reduced infarct size in the brain as measured by MRI and improved neurological function 2-28 days after focal cerebral ischemia in rats, suggesting that CIG could be a clinical application in improving stroke treatment.

Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation.

Aim. The aim of the present study was to investigate the effect of cornel iridoid glycoside (CIG) on tau hyperphosphorylation induced by wortmannin (WT) and GF-109203X (GFX) and the underlying mechanisms. Methods. Human neuroblastoma SK-N-SH cells were preincubated with CIG (50, 100, and 200 µg/ml, resp.) for 24 h and then exposed to 10 µM WT and 10 µM GFX for 3 h after washing out CIG. Immunohistochemistry was used to observe the microtubular cytoskeleton of the cultured cells. Western blotting was used to measure the phosphorylation level of tau protein, glycogen synthase kinase 3 ß (GSK-3 ß ), and protein phosphatase 2A (PP2A). The activity of PP2A was detected by a biochemical assay. Results. Preincubation of CIG significantly attenuated the WT/GFX-induced tau hyperphosphorylation at the sites of Thr205, Thr212, Ser214, Thr217, Ser396, and PHF-1 and improved the damage of morphology and microtubular cytoskeleton of the cells. CIG did not prevent the decrease in p-AKT-ser473 and p-GSK-3 ß -ser9 induced by WT/GFX. However, CIG significantly elevated the activity of PP2A by reducing the demethylation of PP2A catalytic subunit (PP2Ac) at Leu309 and the ratio of PME-1/LCMT in the WT/GFX-treated cells. The results suggest that CIG may be beneficial to the treatment of AD.