Tenuigenin activates the IRS1/Akt/mTOR signaling by blocking PTPN1 to inhibit autophagy and improve locomotor recovery in spinal cord injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Tenuigenin (TEN) is a main pharmacologically active component of Polygala tenuifolia Willd. (Polygalaceae), which has shown neuroprotective functions in Alzheimer's disease. Moreover, TEN also demonstrated an anti-oxidative impact in an in vitro model of Parkinson's disease, reducing damage and loss of dopaminergic neurons. AIM: This work focuses on the impact of TEN on locomotor recovery following spinal cord injury (SCI) and underpinning molecules involved. METHODS: A rat model of SCI was generated, and the rats were treated with TEN, oe-PTPN1 (PTP non-receptor type 1), a protein kinase B (Akt)/mammalian target of rapamycin (mTOR) antagonist LY294002, or an autophagy inhibitor 3-methyladenine (3-MA). Subsequently, locomotor function was detected. Pathological changes and neuronal activity in the spinal cord tissues were analyzed by hematoxylin and eosin staining, Nissl staining, and TUNEL assays. Protein expression of Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3B)-II/LC3B-I, PTPN1, IRS1, mTOR, and phosphorylated Akt (p-Akt) was analyzed by western blot assays. The LC3B expression was further examined by immunofluorescence staining. RESULTS: Treatment with TEN restored the locomotor function of SCI rats, reduced the cavity area and cell apoptosis, upregulated growth-associated protein 43 and neurofilament 200, and decreased the Beclin-1 and LC3B-II/LC3B-I levels in the spinal cord. TEN suppressed PTPN1 protein level, while PTPN1 suppressed IRS1 protein to reduce the p-Akt and mTOR levels. Either PTPN1 overexpression or LY294002 treatment blocked the promoting effect of TEN on SCI recovery. However, treatment with 3-MA suppressed autophagy, which consequently rescued the locomotor function and reduced neuron loss induced by PTPN1. CONCLUSION: This study demonstrates that TEN suppresses autophagy to promote function recovery in SCI rats by blocking PTPN1 and rescuing the IRS1/Akt/mTOR signaling.

Effect of Combination Electroacupuncture and Tenuigenin on the Migration and Differentiation of Mesenchymal Stem Cells following Ischemic Stroke.

Objectives: Since stroke is a serious health issue, novel therapeutic strategies are required. In a mouse model of ischemic stroke, this study analyzed the potential of electroacupuncture (EA) and tenuigenin (TE) to improve the efficacy of human mesenchymal stem cell (hMSC) transplantation. Methods: Middle cerebral artery occlusion (MCAO) with reperfusion was used to generate ischemic stroke. Forty-eight male C57BL/6 mice were randomly divided into five groups control, MCAO-operated, MCAO-EA, MCAO-TE, or MCAO + EA + TE. Subsequently, hMSCs were transplanted into the ischemic region and EA, TE, or the combination was administered. Behavior assessments and immunohistochemistry were conducted to evaluate motor and cognitive recovery and hMSCs survival, migration, and differentiation. Results: The combined treatment of EA and TE exhibited enhanced hMSCs survival, migration and differentiation into neural cell lineages while suppressing astrocyte formation. Immunohistochemistry demonstrated increased neurogenesis through hMSCs transplantation in the ischemic brain. Immediate behavioral improvements were not significantly different between groups, but there was a gradual recovery in motor and cognitive function over time. Conclusion: These findings highlight the potential of EA and TE co-treatment as a therapeutic strategy for ischemic stroke, opening avenues for further research to optimize treatment protocols and elucidate underlying mechanisms.

[Neurobiological effects of tenuigenin and the opportunity of it's using in the therapy of Alzheimer's and Parkinson's diseases (literature review).]

The analysis of experimental and partially clinical data about researches of neurobiological effects of tenuigenin - the most important bioactive substance of Polygala tenuifolia Willd. in this review was given. The neuroprotective and neurotrophic action of given substance were described in detail. It was noted, that the capacities of the tenuigenin to decrease the secretion of beta amyloid and to protect of neurons from damage by already made beta ameloids, to inhibit the processes of the tau proteins` hyperphosphorylation and inflammations in microglia, as well as increase the main synaptic transmission can be used by the development of effective therapeutic drugs aimed to reduce the pathogenesis of Alzheimer`s disease. The effects of dopaminergic neurons and mitochondrial membrane potential protection as well as reduction of α-synuclein phosphorylation can influence the processes by Parkinson`s disease. It was concluded, that the tenuigenin deserves further study and possibly will be used as augmentation of Alzheimer`s, Parkinson`s and other neurodegenerative diseases therapy.

Polygala tenuifolia: a source for anti-Alzheimer's disease drugs.

Context: Alzheimer's disease (AD) is a chronic neurodegenerative disease that originates from central nervous system lesions or recessions. Current estimates suggest that this disease affects over 35 million people worldwide. However, lacking effective drugs is the biggest handicap in treating AD. In traditional Chinese medicine (TCM), Polygala tenuifolia Willd. (Polygalaceae) is generally used to treat insomnia, memory dysfunction and neurasthenia.Objective: This review article explores the role of P. tenuifolia and its active components in anti-Alzheimer's disease.Methods: Literature for the last ten years was obtained through a search on PubMed, SciFinder, CNKI, Google Scholar, Web of Science, Science Direct and China Knowledge Resource Integrated with the following keywords: Polygala tenuifolia, polygalasaponin XXXII (PGS 32), tenuifolin, polygalacic acid, senegenin, tenuigenin, Alzheimer's disease.Results: Polygala tenuifolia and its active components have multiplex neuroprotective potential associated with AD, such as anti-Aß aggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing central cholinergic system and promote neuronal proliferation.Conclusions: Polygala tenuifolia and its active components exhibit multiple neuroprotective effects. Hence, P. tenuifolia is a potential drug against Alzheimer's disease, especially in terms of prevention.

Neuroprotective effects of tenuigenin on neurobehavior, oxidative stress, and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats.

BACKGROUND: Tenuigenin (TEN), a major active component of the Chinese herb Polygala tenuifolia root, has been used to improve memory and cognitive function in Traditional Chinese Medicine for centuries. PURPOSE: The present study was designed to explore the possible neuroprotective effect of TEN on the streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). METHODS: STZ was injected twice intracerebroventrically (3 mg/kg, ICV) on alternate days (day 1 and day 3) in Rats. Daily treatment with TEN (2, 4, and 8 mg/kg) starting from the first dose of STZ for 28 days. Memory-related behaviors were evaluated using the Morris water maze test. Hyperphosphorylation of tau proteins in hippocampus were measured by western blot assay. Superoxide dismutase activities, malondialdehyde, glutathione peroxidase and 4-hydroxy-2-nonenal adducts contents were also measured in the hippocampus. RESULTS: Treatment with TEN significantly improved STZ-induced cognitive damage, markedly reduced changes in malondialdehyde and 4-hydroxy-2-nonenal adducts, and significantly inhibited STZ-induced reduction in superoxide dismutase and glutathione peroxidase activities in the hippocampus. In addition, TEN decreased hyperphosphorylation of tau resulting from intracerebroventricular STZ (ICV-STZ) injection, and Nissl staining results showed that TEN has protective effects on hippocampal neurons. CONCLUSION: These results provide experimental evidence demonstrating preventive effect of TEN on cognitive dysfunction, oxidative stress, and hyperphosphorylation of tau in ICV-STZ rats. This study indicates that TEN may have beneficial effects in the treatment of neurodegenerative disorders such as AD.

Combined application of tenuigenin and ß-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of ß-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. PATIENTS AND METHODS: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received ß-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5-20 mg/d. Patients in the control group only received memantine 5-20 mg/d. The Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Activities of Daily Living (ADL) were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks. RESULTS: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001), lower average ADL score (p=0.00002), and lower average CDR score (p=0.030). Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60-74-years-old male patients with moderate AD. CONCLUSION: These results demonstrated that the combined application of ß-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored.

Tenuigenin protects dopaminergic neurons from inflammation via suppressing NLRP3 inflammasome activation in microglia.

BACKGROUND: Emerging evidence indicates that nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of PD. Tenuigenin, a major active component of Polygala tenuifolia, has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. METHODS: In the present study, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was established to explore the effect of tenuigenin on dopaminergic neurons in substantia nigra. We next activated NLRP3 inflammasome in both BV2 microglia cells and adult mice to investigate the mechanisms for the neuroprotective effect of tenuigenin. RESULTS: We demonstrated that treatment with tenuigenin increased striatal dopaminergic levels and improved motor impairment induced by MPTP. Also, tenuigenin significantly ameliorated the degeneration of dopaminergic neurons and inhibited NLRP3 inflammasome activation in substantia nigra of MPTP mouse model. We further found that tenuigenin reduced intracellular reactive oxygen species (ROS) production and suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1ß secretion in BV2 microglia cells. These data indicate that tenuigenin inhibits the activation of NLRP3 inflammasome via downregulating ROS. Correspondingly, in vivo data showed that tenuigenin attenuates microglia activation induced by lipopolysaccharide (LPS) in substantia nigra via suppressing NLRP3 inflammasome. CONCLUSIONS: Our findings reveal that tenuigenin protects dopaminergic neurons from inflammation partly through inhibition of NLRP3 inflammasome activation in microglia, and suggest the promising clinical use of tenuigenin for PD therapy.

Protective effects of tenuigenin on lipopolysaccharide and d-galactosamine-induced acute liver injury.

Tenuigenin (TEN), a major active component of polygala tenuifolia root, has been reported to have a number of biological properties, such as anti-oxidative and anti-inflammatory activities. However, the protective effect of TEN on acute liver injury has not yet been reported. This research aims to detect the protective effect of TEN on lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced acute liver injury in mice and to investigate the molecular mechanisms. TEN was administered intraperitoneally 1 h before LPS/D-GalN treatment. The levels of TNF-α, IL-1ß, ALT, and AST were measured. The expression of NF-κB, ASK1, MAPKs, Nrf2, and HO-1 were detected by western blot analysis. The results showed that TEN significantly inhibited LPS/D-GalN-induced serum ALT and AST levels. TEN also inhibited LPS/D-GalN-induced TNF-α and IL-1ß production. Furthermore, LPS/D-GalN-induced hepatic MDA and MPO activities were also inhibited by TEN. In addition, TEN was found to inhibit LPS/D-GalN-induced ASK1 expression, NF-κB and MAPKs activation and up-regulate the expression of Nrf2 and HO-1. In conclusion, TEN protected against LPS/GalN-induced acute liver injury by suppressing inflammatory and oxidative responses.

Protective effects of tenuigenin on Staphylococcus aureus-induced pneumonia in mice.

Pneumonia is the leading cause of death in infants and young children. Staphylococcus aureus (S.aureus) is one of the most important bacteria that leads to pneumonia. Tenuigenin (TGN), a major active component isolated from the root of the Chinese herb Polygala tenuifolia, has been known to have anti-inflammatory effect. In this study, we aimed to investigate the protective effects of TGN on S.aureus-induced pneumonia in mice. The results showed that TGN significantly attenuated S.aureus-induced lung histopathological changes. TGN also inhibited lung wet/dry (W/D) ratio, and inflammatory cytokines TNF-α and IL-1ß production. Furthermore, S.aureus-induced NF-κB activation was significantly inhibited by the treatment of TGN. In conclusion, the results of this study showed that TGN protected against S.aureus-induced pneumonia by inhibiting NF-κB activation. TGN might be a potential agent in the treatment of pneumonia induced by S.aureus.

Tenuigenin inhibits LPS-induced inflammatory responses in microglia via activating the Nrf2-mediated HO-1 signaling pathway.

Tenuigenin (TGN), a major active component of polygala tenuifolia root, has been reported to have anti-inflammatory effect. In this study, we investigated the anti-neuroinflammatory effects of TGN on LPS-induced inflammation both in vitro and in vivo. The levels of tumor necrosis factor -α (TNF-α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), and prostaglandin E2 (PGE2) were measured by ELISA. The expression of Nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were detected by western blot analysis. The results showed that TGN strongly inhibited LPS-induced TNF-α, IL-1ß, IL-6, and PGE2 production. The expression of Nrf2 and HO-1 were up-regulated by TGN in a dose-dependent manner. Furthermore, the anti-inflammatory effects of TGN were significantly inhibited by transfection with Nrf2 siRNA or protoporphyrin (SnPP), an HO-1 activity inhibitor. In vivo, TGN attenuated LPS-induced memory deficit in the Morris water maze and passive avoidance tasks. Also, TGN inhibited LPS-induced TNF-α and IL-1ß expression in brain tissues. In conclusion, the results of this study indicated that TGN inhibited LPS-induced inflammatory responses in microglia via activating the Nrf2-mediated HO-1 signaling pathway.

Tenuigenin down-regulates the release of nitric oxide, matrix metalloproteinase-9 and cytokines from lipopolysaccharide-stimulated microglia.

Tenuigenin (TEN), an active component of Polygala tenuifolia root extracts, has been shown to provide neuroprotection in neurodegenerative disorders. To date, most of these studies have focused on the effect that TEN has on neurons. Because activated microglia can release neurotoxic factors that cause neuronal damage, the present study was designed to investigate the effects of TEN on activated microglia. The results showed that TEN can significantly decrease the release of nitric oxide (NO) from lipopolysaccharide (LPS)-activated rat microglia in a dose-dependent manner. The western blotting results showed that TEN did not inhibit iNOS expression at protein level. However, the electron paramagnetic resonance (EPR) technique revealed that TEN directly scavenged the NO radical. Additionally, TEN can significantly decrease the secretion and mRNA levels of matrix metalloproteinase-9 (MMP-9) and pro-inflammatory cytokines (TNF-α/IL-1ß) in activated microglia. At a high dose (10-4M), TEN can significantly inhibit the secretion of another gelatinolytic MMP, MMP-2, but it had no effect on the mRNA level of MMP-2. In conclusion, these results suggest that TEN exerts an anti-inflammatory effect by down-regulating the release of NO, MMP-9 and cytokines.

Tenuigenin promotes the osteogenic differentiation of bone mesenchymal stem cells in vitro and in vivo.

Osteoporosis, which is a systemic skeletal disease characterized by low bone mineral density and microarchitectural deterioration of bone quality, is a global and increasing public health problem. Recent studies have suggested that Tenuigenin (TEN), a class of native compounds with numerous biological activities such as anti-resorptive properties, exerts protective effects against postmenopausal bone loss. The present study aims to investigate the osteogenic effects of TEN on bone mesenchymal stem cells (BMSCs) in vitro and in vivo. Alkaline phosphatase (ALP) activity/staining, Alizarin red staining and the expression of osteogenic markers, including runt-related transcription factor 2, osterix, osteocalcin, collagen Iα1, ß-catenin and glycogen synthase kinase-3ß were investigated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of TEN. An ovariectomized (OVX) mouse model was used to investigate the effect of TEN treatment for 3 months in vivo. We found that ALP activity, mineralized nodules and the expression of osteogenic markers were increased and WNT/ß-catenin signaling was enhanced in vitro and in vivo. Bone parameters, including trabecular thickness, trabecular number and bone mineral density were higher in the OVX+TEN group than in control OVX mice. Our results suggest the therapeutic potential of TEN for the treatment of patients with postmenopausal osteoporosis.

Tenuigenin exhibits protective effects against LPS-induced acute kidney injury via inhibiting TLR4/NF-κB signaling pathway.

Tenuigenin (TNG) has been reported to have various pharmacological activities, such as anti-oxidative and anti-inflammatory activities. However, the protective effects of TNG on lipopolysaccharides (LPS)-induced acute kidney injury (AKI) are still not clear. The aim of this study was to investigate the protective effects and mechanism of TGN on LPS-induced AKI in mice. The kidney histological change, levels of blood urea nitrogen (BUN), and creatinine were measured to assess the protective effects of TNG on LPS-induced AKI. The levels of TNF-α, IL-1ß, and IL-6 in serum and kidney tissues were detected by ELISA. The extent of nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot analysis. The results showed that TNG markedly attenuated the histological alterations, BUN and creatinine levels in kidney. TNG also suppressed LPS-induced TNF-α, IL-1ß, and IL-6 production. Furthermore, the expression of TLR4 and NF-κB activation induced by LPS were markedly inhibited by TNG. In conclusion, this study demonstrated that TNG protected against LPS-induced AKI by inhibiting TLR4/NF-κB signaling pathway.

Tenuigenin Prevents IL-1ß-induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing PI3K/AKT/NF-κB Signaling Pathway.

Tenuigenin (TEN), the main active component of Polygala tenuifolia, has been reported to have anti-inflammatory effects. However, the effects of TEN on IL-1ß-stimulated osteoarthritis chondrocytes have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and mechanism of TEN on IL-1ß-stimulated human osteoarthritis chondrocytes. Human osteoarthritis chondrocytes were pretreated with or without TEN for 1 h and then stimulated with IL-1ß. The production of NO and PGE2 were detected by the Griess reagent and ELISA. The expression of NF-κB and MAPKs (p38, JNK, ERK) were measured by Western blot analysis. The production of MMP-1, MMP3, and MMP13 were measured by ELISA. The results showed that treatment of TEN significantly inhibited IL-1ß-induced NO and PGE2 production. TEN also suppressed IL-1ß-induced MMP-1, MMP3, and MMP13 expression. Furthermore, TEN was found to inhibit IL-1ß-induced NF-κB activation, PI3K, and AKT phosphorylation. In conclusion, these results suggest that TEN inhibits IL-1ß-induced inflammation in human osteoarthritis chondrocytes by inhibiting PI3K/AKT/NF-κB signaling pathway.

Tenuigenin inhibits RANKL-induced osteoclastogenesis by down-regulating NF-κB activation and suppresses bone loss in vivo.

Tenuigenin, a major active component of polygala tenuifolia root, has been used to treat patients with insomnia, dementia, and neurosis. In this study, we aimed to investigate the effects of tenuigenin on osteoclastogenesis and clarify the possible mechanism. We showed that tenuigenin inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption without cytotoxicity, which was further demonstrated by reduced osteoclast specific gene expression such as TRAP, c-Src, ATP6v0d2, etc. Moreover, the inhibitory effect of tenuigenin was associated with impaired NF-κB activity owing to delayed degradation/regeneration of IkBa and inhibition of p65 nuclear translocation. Consistent with the in vitro results, micro-ct scanning and analysis data showed that tenuigenin suppressed RANKL-induced bone loss in an animal model. Taken together, our data demonstrate that tenuigenin inhibit osteoclast formation and bone resorption both in vitro and in vivo, and comprise a potential therapeutic alternative for osteoclast-related disorders such as osteoporosis and cancer-induced bone destruction.

Tenuigenin enhances hippocampal Schaffer collateral-CA1 synaptic transmission through modulating intracellular calcium.

BACKGROUND: Tenuigenin (TEN), a natural product from the Chinese herb Polygala tenuifolia root, has been reported to improve cognitive function and exhibits neuroprotective effects in pharmacological studies of the central nervous system. Synaptic transmission is the essential process of brain physiological functions such as learning and memory formation, and TEN has been shown to facilitate the basic synaptic transmission. HYPOTHESIS/PURPOSE: Although our previous work has demonstrated that TEN is able to potentiate the basic synaptic transmission, the potential mechanism remains unclear. Here we investigated the effect of TEN on the synaptic transmission and analysed the potential mechanism. We hope that these findings will contribute to explain the role of TEN as a nootropic product or neuroprotective drug in the future. METHODS: Field excitatory postsynaptic potentials (fEPSPs), spontaneous excitatory postsynaptic currents (sEPSCs) and miniature spontaneous excitatory postsynaptic currents (mEPSCs) were recorded, by using in vitro field potential electrophysiology and whole-cell patch clamp techniques in acute hippocampal slices from rats. RESULTS: TEN perfusion significantly enhanced the slope of fEPSPs and reduced the ratio of paired-pulse facilitation. Moreover, TEN increased the frequency and amplitude of sEPSCs but only improved the frequency of mEPSCs rather than amplitude in hippocampal CA1 pyramidal neurons. With removal of extracellular calcium, TEN treatment also enhanced the mEPSCs frequency without affecting amplitude. Interestingly, the increase of mEPSCs frequency caused by TEN was blocked by chelation of intracellular calcium with BAPTA-AM. CONCLUSION: These results indicate that TEN enhances the basic synaptic transmission via stimulating presynaptic intracellular calcium.

Tenuigenin ameliorates acute lung injury by inhibiting NF-κB and MAPK signalling pathways.

We aimed to explore the protective effect of tenuigenin (TNG) on lipopolysaccharide (LPS)-stimulated inflammatory responses in acute lung injury (ALI). Thus, we assessed the effects of TNG on the LPS-induced production of tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß in the culture supernatants of RAW 264.7 cells. Male BALB/c mice were pretreated with commercial TNG (2, 4 and 8 mg/kg) and dexamethasone (Dex, 5mg/kg) for 1h prior to LPS (0.5 mg/kg) challenge. After 12h, airway inflammation was assessed. Our results showed that TNG dramatically decreased the production of TNF-α, IL-1ß, and IL-6 in vitro and in vivo as well as the expression of COX-2 protein in vivo. Treatment with TNG not only significantly ameliorated LPS-stimulated histopathological changes but also reduced the myeloperoxidase (MPO) activity and the wet-to-dry weight ratio of the lungs. Furthermore, TNG blocked IκBα phosphorylation and degradation and inhibited p38/ERK phosphorylation in LPS-induced ALI. These findings suggest that TNG may have a protective effect on LPS-induced ALI and may be useful for the prevention and treatment of ALI in the clinical setting.

Tenuigenin attenuates α-synuclein-induced cytotoxicity by down-regulating polo-like kinase 3.

BACKGROUND AND AIMS: Tenuigenin (Ten) is a Chinese herbal extract with antioxidative and antiinflammatory effects on toxin-induced cell models of Parkinson's disease (PD); however, its effects on α-synuclein toxicity-based PD models remain unknown. α-synuclein hyperphosphorylation is a key event in PD pathogenesis and potential target of therapeutic interventions. We tested whether Ten alleviates α-synuclein-induced cytotoxicity via reducing kinases that phosphorylate α-synuclein. METHODS: SH-SY5Y cells transiently transfected with wild-type or A53T mutant α-synuclein were used to evaluate the effect of Ten on the levels of α-synuclein phosphorylation-related kinases. Cells treated with 10 µM Ten for 24 h were measured for viability (proliferation and apoptosis assays) and cellular proteins harvested and fractioned. The levels of total and phosphorylated α-synuclein and five associated kinases (polo-like kinase [PLK] 1-3, casein kinase [CK] 1-2) were evaluated by Western blotting. RESULTS: Overexpression of either wild-type or A53T mutant α-synuclein decreased cell viability and increased α-synuclein phosphorylation. Ten treatment-protected cells from this α-synuclein-induced toxicity and dramatically reduced α-synuclein phosphorylation and PLK3 (but not other kinase) levels. CONCLUSION: In α-synuclein cell model of PD, Ten is effective in attenuating α-synuclein-induced toxicity and α-synuclein phosphorylation probably via targeting PLK3, suggesting it could be an efficient therapeutic drug to treat α-synuclein-related neurodegeneration.

Tenuigenin ameliorates learning and memory impairments induced by ovariectomy.

Estrogen deficiency is associated with cognitive impairment. Hormone replacement therapy (HRT) has proven to be effective in preventing and reversing the memory and learning deficiencies. However, conventional estrogenic treatment could increase the risks of breast cancer and venous thromboembolism. Tenuigenin (TEN) is putatively believed as the active component extracted from a Chinese herb Polygala tenuifolia root. Although TEN has been shown to enhance learning and memory in healthy mice, it remains unknown whether or not TEN could ameliorate learning and memory impairments. In the present study, mice were divided into four groups: sham-operated (sham), ovariectomized (OVX), OVX+estradiol benzoate (EB) and OVX+TEN groups. Step-through passive avoidance and Y-maze tests were used to assess learning and memory abilities, and the number of nitric oxide synthase (NOS) positive neurons and the synaptic measurement of hippocampal CA1 area were examined. The results showed that TEN was given orally to OVX mice, leading to the improvement of learning and memory in step-through passive avoidance and Y-maze tests. TEN could reduce the loss of NOS positive neurons and prevent the synaptic morphological changes induced by ovariectomy. Our results suggest that TEN may exert a potential therapeutic value for menopause cognitive dysfunction.