Treatment Of PC12 Cells Research Articles

Comprehensive evaluation of microRNA expression profiling reveals the neural signaling specific cytotoxicity of superparamagnetic iron oxide nanoparticles (SPIONs) through N-methyl-D-aspartate receptor.

Though nanomaterials are considered as drug carriers or imaging reagents targeting the central nervous system their cytotoxicity effect on neuronal cells has not been well studied. In this study, we treated PC12 cells, a model neuronal cell line, with a nanomaterial that is widely accepted for medical use, superparamagnetic iron oxide nanoparticles (SPIONs). Our results suggest that, after treated with SPIONs, the expression pattern of the cellular miRNAs changed widely in PC12 cells. As potential miRNA targets, NMDAR, one of the candidate mRNAs that were selected using GO and KEGG pathway enrichment, was significantly down regulated by SPIONs treatment. We further illustrated that SPIONs may induce cell death through NMDAR suppression. This study revealed a NMDAR neurotoxic effect of SPIONs and provides a reliable approach for assessing the neurocytotoxic effects of nanomaterials based on the comprehensive annotation of miRNA profiling.

Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease

Polypharmacology-based strategies using drug combinations with different mechanisms of action are gaining increasing attention as a novel methodology to discover potentially innovative medicines for neurodegenerative disorders. We used this approach to examine the combined neuroprotective effects of two polyphenols, protocatechuic acid (PCA) and chrysin, identified from the fruits of Alpinia oxyphylla. Our results demonstrated synergistic neuroprotective effects, with chrysin enhancing the protective effects of PCA, resulting in greater cell viability and decreased lactate dehydrogenase release from 6-hydroxydopamine-treated PC12 cells. Their combination also significantly attenuated chemically induced dopaminergic neuron loss in both zebrafish and mice. We examined the molecular mechanisms underlying these collective cytoprotective effects through proteomic analysis of treated PC12 cells, resulting in the identification of 12 regulated proteins. Two were further characterized, leading to the determination that pretreatment with PCA and chrysin resulted in (i) increased nuclear factor-erythroid 2-related factor 2 protein expression and transcriptional activity; (ii) modulation of cellular redox status with the upregulated expression of hallmark antioxidant enzymes, including heme oxygenase-1, superoxide dismutase, and catalase; and (iii) decreased levels of malondialdehyde, a known lipid peroxidation product. Treatment with PCA and chrysin also inhibited activation of nuclear factor-κB and expression of inducible nitric oxide synthase. Our findings suggest that natural products, when used in combination, can be effective potential therapeutic agents for treating diseases such as Parkinson disease. A therapy involving both PCA and chrysin exhibits its enhanced neuroprotective effects through a combination of cellular mechanisms: antioxidant cytoprotection and anti-inflammation.

2,5-Hexanedione induces apoptosis via a mitochondria-mediated pathway in PC12 cells

2,5-Hexanedione (HD) is the main active metabolite of n-hexane and mediates the neurotoxicity of the parent compound. Studies suggested that apoptosis involved in HD neurotoxicity. However, the mechanism of HD-induced neuronal apoptosis remains unknown. To explore its underlying mechanism, we treated PC12 cells with 5, 10 and 20 mM HD for 24 h, respectively. We found that HD induced apoptotic death in PC12 cells in a dose-dependent manner. Moreover, HD down-regulated Bcl-2 expression, up-regulated Bax expression and Bax/Bcl-2 ratio, promoted the disruption of mitochondrial transmembrane potential, induced the release of cytochrome c from mitochondria, and increased the activity of caspase-3 in PC12 cells, which were all the key regulators of intrinsic apoptotic pathway. These results indicate that HD induces apoptosis via a mitochondria- mediated pathway in PC12 cells.

Prolonged oral administration of Gastrodia elata extract improves spatial learning and memory of scopolamine-treated rats.

Gastrodia elata (GE) is traditionally used for treatment of various disorders including neurodegenerative diseases such as Alzheimer's disease. To investigate the neuroprotective effect of GE, amyloid-β peptide (Aβ)-treated PC12 cells were cultured with GE aqueous extract. In vitro assay demonstrated that 50 µM of pre-aggregated Aβ was lethal to about a half portion of PC12 cells and that Aβ aggregate-induced cell death was significantly decreased with GE treatment at ≤10 mg/mL in a dose-dependent manner. To further examine in vivo cognitive-improving effects, an artificial amnesic animal model, scopolamine-injected Sprague-Dawley rats, were orally administered the extract for 6 weeks followed by behavioral tests (the passive avoidance test and Morris water maze test). The results showed that an acute treatment with scopolamine (1 mg/kg of body weight) effectively induced memory impairment in normal rats and that the learning and memory capability of scopolamine-treated rats improved after prolonged administration of GE extract (50, 250 and 500 mg/kg of body weight for 6 weeks). These findings suggest that a GE regimen may potentially ameliorate learning and memory deficits and/or cognitive impairments caused by neuronal cell death.

Protective effects of apigenin against 1-methyl-4-phenylpyridinium ion‑induced neurotoxicity in PC12 cells.

Parkinson's disease is recognized as the second most common neurodegenerative disorder after Alzheimer's disease, characterized by the loss of dopominergic neurons in the substantia nigra pars compacta and can be experimentally mimicked by the use of the neurotoxin, 1‑methyl‑4‑phenylpyridinium ion (MPP(+)), in in vitro models. In this study, we investigated the potential protective effects of apigenin (AP), galangin and genkwanin, naturally occurring plant flavonoids, on the MPP(+)‑induced cytotoxicity in cultured rat adrenal pheochromocytoma cells (PC12 cells). The PC12 cells were pre-treated with various concentrations of the test compounds for 4 h, followed by the challenge with 1,000 µM MPP(+) for 48 h. We found that only pre-treatment with AP (3, 6 and 12 µM) before injury significantly increased cell viability, decreased the release of lactate dehydrogenase, reduced the level of intracellular reactive oxygen species and elevated mitochondrial membrane potential in the MPP(+)‑treated PC12 cells. In addition, AP markedly suppressed the increased rate of apoptosis and the reduced Bcl‑2/Bax ratio induced by MPP(+) in the PC12 cells. Taken together, the findings of this study demonstrate that AP exerts neuroprotective effects against MPP(+)‑induced neurotoxicity in PC12 cells, at least in part, through the inhibition of oxidative damage and the suppression of apoptosis through the mitochondrial pathway.

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells.

Hyperglycemia plays an important role in the development of diabetic neuropathy. In this study, we investigated the protective effects of alpha lipoic acid (ALA) against high glucose-induced neurotoxicity in PC12 cells as a suitable in vitro model for studying neuronal functions. PC12 cells were treated with high glucose (25mg/ml for 24h) in the absence and presence of ALA (100μM for 24h). The viability of PC12 cells was estimated by using MTT assay. The expression of pro- apoptotic Bax, anti- apoptotic Bcl-2 and caspase 3 protein were evaluated by western blotting. The reactive oxygen species (ROS) levels were determined with 2,7-dichlorodihydro- fluorescein diacetate (H2DCFDA). Biochemical markers of oxidative stress were assessed by using the total antioxidant power (TAP), lipid peroxidation (LPO), ADP/ATP ratio, activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Pretreatment of PC12 cells with ALA, significantly improved high glucose-induced toxicity by increasing activity of antioxidant enzymes CAT and SOD in the PC12 cell. It also increased the concentrations of TAP. An elevated level of cell death and ROS in high glucose conditions, diminished with ALA treatment. Over expression of Bax and caspase 3 protein, elevation of ADP/ATP ratio and LPO level in high glucose- treated PC12 cells, were significantly reduced by ALA. It was concluded that ALA attenuates neurotoxicity induced by high glucose in PC12 cells.

Beta-asarone attenuates amyloid beta-induced autophagy via Akt/mTOR pathway in PC12 cells

Alzheimer′s disease (AD) is an age related and progressive neurodegenerative disease. Autophagy is a self-degradative process and plays a critical role in removing long-lived proteins and damaged organelles. Recent evidence suggests that autophagy might be involved in the pathogenesis of AD. β-asarone have various neuroprotective effects. However, the effect of β-asarone on autophagy in amyloid β-peptide (Aβ) induced cell injury is unclear, and little is known about the signaling pathway of β-asarone in autophagy regulation. The aim of the present study was to determine whether β-asarone protects cells from Aβ1–42 induced cytotoxicity via regulation of Beclin-1 dependent autophagy and its regulating signaling pathway. We examined effects of β-asarone on cell morphology, cell viability, neuron specific enolase (NSE) levels, autophagosomes and regulating Beclin-1, p-Akt and p-mTOR expressions in Aβ1–42 treated PC12 cells. We found that β-asarone could maintain the original morphology of cells and increase cell viability and decrease NSE levels significantly. Meanwhile, β-asarone decreased Beclin-1 expression significantly. In addition, β-asarone can increase levels of p-Akt and p-mTOR. These results showed that β-asarone protected cells from Aβ1–42 induced cytotoxicity and attenuated autophagy via activation of Akt-mTOR signaling pathway, which could be involved in neuroprotection of β-asarone against Aβ toxicity. Our findings suggest that β-asarone might be a potential preventive drug for AD.

Nano-topology guided neurite outgrowth in PC12 cells is mediated by miRNAs

MicroRNAs (miRNAs) are master regulators of gene expression at post-transcriptional level. The present study investigated the involvement of miRNAs in topological guidance of neurite outgrowth in an NGF treated PC12 cell model cultured on nano-patterned polyethylene terephthalate (PET) substrates fabricated with interference lithography. The expressions of 38 neuronal miRNAs were measured and 3 were found to be differentially regulated during topological guidance of neurite outgrowth. Altering the intracellular levels of these miRNAs disrupted the orderly growth of neurite along nano-patterned substrate. Our results showed miRNAs to be versatile regulators and their involvement should be thoroughly investigated for better understanding of biological processes. From the Clinical EditorIn this basic science study, strong evidence was found that topological guidance is only one factor, and miRNA-s regulate axonal outgrowth from neurites. Nano-patterned polyethylene terephthalate substrates were used for the study, fabricated using interference lithography. Further studies of this biologically relevant process may pave the way to clinically useful axonal regrowth and axonal guidance methods.

Edaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating heme oxygenase-1 expression

Oxidative stress is involved in the pathogenesis of Parkinson's disease (PD). Edaravone has been shown to have a neuroprotective effect. In the present work, we investigated the effect of edaravone on 1-methyl-4-phenylpyridinium (MPP(+))-treated PC12 cells. Edaravone inhibited the decrease of cell viability and apoptosis induced by MPP(+) in PC12 cells. In addition, edaravone alleviated intracellular reactive oxygen species (ROS) production. MPP(+) induced heme oxygenase-1 (HO-1) expression, which was further enhanced by edaravone. The inhibitor of HO-1 zinc protoporphyrin-IX attenuated the neuroprotection of edaravone. So edaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating HO-1 expression. The data showed that edaravone was neuroprotective and could be potentially therapeutics for PD in future.

Beneficial effect of astragalosides on stroke condition using PC12 cells under oxygen glucose deprivation and reperfusion.

Astragalosides (AST) are reported to be neuroprotective in focal cerebral ischemic models in vivo. In this study, the direct effect of AST against oxygen and glucose deprivation (OGD) including neuronal injury and the underlying mechanisms in vitro were investigated. 5 h OGD followed by 24 h of reperfusion [adding back oxygen and glucose (OGD-R)] was used to induce in vitro ischemia reperfusion injury in differentiated rat pheochromocytoma PC12 cells. AST (1, 100, and 200 µg/mL) were added to the culture after 5 h of the OGD ischemic insult and was present during the reoxygenation phases. A key finding was that OGD-R decreased cell viability, increased lactate dehydrogenase, increased reactive oxygen species, apoptosis, autophagy, functional impairment of mitochondria, and endoplasmic reticulum stress in PC12 cells, all of which AST treatment significantly reduced. In addition, AST attenuated OGD-R-induced cell loss through P38 MAPK activation a neuroprotective effect blunted by SB203580, a specific inhibitor of P38 MAPK. Our data suggest that both apoptosis and autophagy are important characteristics of OGD-R-induced PC12 death and that treating PC12 cells with AST blocked OGD-R-induced apoptosis and autophagy by suppressing intracellular oxidative stress, functional impairment of mitochondria, and endoplasmic reticulum stress. Our data provide identification of AST that can concomitantly inhibit multiple cells death pathways following OGD injuries in neural cells.

Investigation of Chemical Composition of Lippia Citriodora: Essential Oil of Lippia Citriodora Promote Survival of PC12 Cells Following Treatment With H2O2

Introduction: Lemon herbena (Lippia citriodora) is a member of Verbenaceae family. This plant is endemic to South America and can growth in other areas, such as Iran. The aim of this study was to investigate and compare the chemical composition of the two production plants in the greenhouse and field of a lemon. Materials and Methods: Plants were cultivated in a Sarayan Ferdowsi area (south of Khorasan). Fourth kg of leaves was collected. Then, essential oil was extracted from fresh leaves using water and steam distillation. Finally, we treated PC12 cells with the essential oil that obtained from Lippia citriodora. The cell viability was evaluated by the MTT (3-[4, 5-dimethylthiazol2-yl]-2, 5-diphenyl tetrazolium bromide) assay. Results: Our results from GCMS (Gas chromatography–mass spectrometry) method showed that greenhouse and field samples contained 0.68% and 0.62% (w/w), respectively. In addition, the data showed that the essential oil decreased oxidative stress-induced PC12 cell death. Conclusion: The results suggest that Lippia citriodora could be a potential candidate for treatment of neurodegenerative diseases.

Cellular Antioxidant Activity and Pharmacokinetic Study of Polymethoxylated Flavonoids in Extract of Citrus reticulata ‘Chachi’ Peel

A rat pheochromocytoma (PC12) cell line was used to study the effects of several polymethoxylated flavonoids (PMFs) and extract of Citrus reticulata ‘chachi’ peel (ECRP) on hydrogen peroxide (H2O2)-induced apoptosis. In PC12 cells, H2O2-induced apoptosis was accompanied by rising malondialdehyde (MDA) level, as well as reducing activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). However, treating PC12 cells with PMFs and ECRP blocked H2O2-induced apoptosis by decreasing the MDA level and augmenting the activities of SOD and GSH-Px. Moreover, liquid chromatography coupled with UV detection was developed to simultaneously determine nobiletin and tangeretin in rat plasma after oral administration of ECRP, using quercetin as the internal standard. Plasma samples extracted by liquid-liquid extraction were separated on a Phenomenex Luna C18 column and detected by a UV detector. The calibration curves were linear over the range of 5.5 – 2757 ng mL-1 for nobiletin (r2 >0.999) and 6.3 - 2847 ng mL-1 for tangeretin (r2 > 0.999), respectively. The lower limits of quantification were 0.2 ng mL-1 for nobiletin and tangeretin. The intra- and inter-day precisions were less than 15% and the accuracies ranged from 3.4% to 12.2%. The recoveries of nobiletin and tangeretin were 91.1% – 95.4% and 93.7 – 96.2% respectively. Nobiletin and tangeretin remained stable at low temperatures (-20°C and 4°C) and after freeze-thaw cycles. The validated method was successfully applied to investigate the pharmacokinetics of the main PMFs of ECRP extract after oral administration to rat.

Capsaicin induces apoptosis in PC12 cells through ER stress

Capsaicin, the pungent agent in chili peppers, has been shown to act as a tumor-suppressor in cancer. In our previous study, capsaicin was shown to induce apoptosis in the rat pheochromocytoma cell line (PC12 cells). Thus, the aim of the present study was to determine the potential mechanism by which capsaicin induces apoptosis. We treated PC12 cells with 50, 100 and 500 μM capsaicin and measured the reticular calcium content and expression of the reticular calcium transport systems. These results were correlated with endoplasmic reticulum (ER) stress markers CHOP, ATF4 and X-box binding protein 1 (XBP1), as well as with apoptosis induction. We observed that capsaicin decreased reticular calcium in a concentration-dependent manner. Simultaneously, expression levels of the sarco/endoplasmic reticulum pump and ryanodin receptor of type 2 were modified. These changes were accompanied by increased ER stress, as documented by increased stress markers. Thus, from these results we propose that in PC12 cells capsaicin induces apoptosis through increased ER stress.

GTP Hydrolysis of TC10 Promotes Neurite Outgrowth through Exocytic Fusion of Rab11- and L1-Containing Vesicles by Releasing Exocyst Component Exo70

The use of exocytosis for membrane expansion at nerve growth cones is critical for neurite outgrowth. TC10 is a Rho family GTPase that is essential for specific types of vesicular trafficking to the plasma membrane. Recent studies have shown that TC10 and its effector Exo70, a component of the exocyst tethering complex, contribute to neurite outgrowth. However, the molecular mechanisms of the neuritogenesis-promoting functions of TC10 remain to be established. Here, we propose that GTP hydrolysis of vesicular TC10 near the plasma membrane promotes neurite outgrowth by accelerating vesicle fusion by releasing Exo70. Using Förster resonance energy transfer (FRET)-based biosensors, we show that TC10 activity at the plasma membrane decreased at extending growth cones in hippocampal neurons and nerve growth factor (NGF)-treated PC12 cells. In neuronal cells, TC10 activity at vesicles was higher than its activity at the plasma membrane, and TC10-positive vesicles were found to fuse to the plasma membrane in NGF-treated PC12 cells. Therefore, activity of TC10 at vesicles is presumed to be inactivated near the plasma membrane during neuronal exocytosis. Our model is supported by functional evidence that constitutively active TC10 could not rescue decrease in NGF-induced neurite outgrowth induced by TC10 depletion. Furthermore, TC10 knockdown experiments and colocalization analyses confirmed the involvement of Exo70 in TC10-mediated trafficking in neuronal cells. TC10 frequently resided on vesicles containing Rab11, which is a key regulator of recycling pathways and implicated in neurite outgrowth. In growth cones, most of the vesicles containing the cell adhesion molecule L1 had TC10. Exocytosis of Rab11- and L1-positive vesicles may play a central role in TC10-mediated neurite outgrowth. The combination of this study and our previous work on the role of TC10 in EGF-induced exocytosis in HeLa cells suggests that the signaling machinery containing TC10 proposed here may be broadly used for exocytosis.

MiR-146a regulates SOD2 expression in H2O2 stimulated PC12 cells.

SOD2 (superoxide dismutase 2) is one of the endogenous antioxidant enzymes that protect against reactive oxygen species. While explorations of SOD2 expression regulation are mainly focused on transcriptional and post-translational activation, there are few reports about the post-transcriptional regulation of SOD2. MicroRNAs (miRNAs) are 21nt-25nt (nucleotide) small noncoding RNAs that have emerged as indispensable regulators of gene expression. Here we show that miR-146a, a widely expressed miRNA, is up-regulated by H2O2-induced stress. By sequence analysis we found a binding site for miR-146a in the sod2 mRNA 3′UTR, and a luciferase reporter assay confirmed that miR-146a can interact with this sod2 regulatory region. Our results further show that miR-146a could down-regulate the SOD2 protein expression, and antisense-miR-146a could reverse the decrease of both the SOD2 level and cell viability in H2O2 treated PC12 cells. In conclusion, here we have identified a novel function of miR-146a in the post-transcriptional regulation of SOD2 expression.

CoCl2 induces PC12 cells apoptosis through p53 stability and regulating UNC5B

The receptor uncoordinated 5B (UNC5B) induces apoptosis in the absence of its cognate ligand netrin-1. However, the role of UNC5B in hypoxia-induced apoptosis is not known. Here, we have demonstrated the biological functions of UNC5B in hypoxia-induced apoptosis and related regulatory pathways and examined the effects of UNC5B on p53-dependent apoptosis in PC12 cells under hypoxic conditions. First, we characterized p53-dependent PC12 cell death induced by CoCl2. Our data showed that CoCl2 increased p53 stabilization and transcriptional activity. The downregulation of p53 expression with specific small interfering RNA (p53 siRNA) in CoCl2-treated PC12 cells caused reduction in apoptosis, UNC5B expression, and p21 expression. Moreover, in PC12 cells, ectopic expression of UNC5B significantly enhanced apoptosis, while silencing of UNC5B with siRNA significantly inhibited apoptosis. In addition, netrin-1 significantly inhibited CoCl2-induced p53 stability and UNC5B expression and CoCl2-induced caspase-3 activity and cell death. Collectively, these results demonstrate a novel role for p53 in the control of CoCl2-induced apoptosis through the regulation of UNC5B.

Activation of xanthine oxidase mediates intermittent hypoxia‐induced HIF‐2 degradation

We previously showed that IH leads to increased degradation of HIF‐2α via [Ca2+]i activated calpains, which contributes to IH‐induced oxidative stress via insufficient transcription of antioxidant enzymes (J. Nanduri et al. PNAS, 2009). In this study, we examined the mechanisms associated with activation of calpains by IH in PC12 cell cultures. In IH treated PC12 cells, ROS levels as well as calpain activity increased and anti‐oxidant treatment prevented these effects suggesting the involvement of ROS signaling. Pharmacological or genetic blockade of NADPH oxidase 2 (Nox2) had no effect on IH‐evoked calpain activation and HIF‐2α degradation. However, IH markedly increased xanthine oxidase (XO) activity. Allopurinol, a XO inhibitor or silencing of XO by siRNA prevented IH induced HIF‐2α degradation, increased intracellular calcium levels and calpain activity. Systemic adminsitration of allopurinol to rats during the IH exposure prevented the oxidative stress, rescued HIF‐2α degradation in the adrenal medulla and prevented hypertension. These results demonstrate that ROS generated by XO activation mediates IH‐induced HIF‐2α down regulation and suggest that ROS‐induced ROS as a potential mechanism contributing to IH‐induced cardiovascular morbidity.

Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide (25-35).

In this study, we treated PC12 cells with 0–20 μM amyloid-β peptide (25–35) for 24 hours to induce cytotoxicity, and found that 5–20 μM amyloid-β peptide (25–35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease in PC12 cell viability induced by amyloid-β peptide (25–35). Diazoxide protected PC12 cells against amyloid-β peptide (25–35)-induced increases in mitochondrial membrane potential and intracellular reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from amyloid-β peptide (25–35)-induced increases in both mitochondrial membrane potential and intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could not reverse the amyloid-β peptide (25–35)-induced increase in intracellular reactive oxygen species. A 24-hour exposure to amyloid-β peptide (25–35) did not result in apoptosis or necrosis, suggesting that the increases in both mitochondrial membrane potential and reactive oxygen species levels preceded cell death. The data suggest that amyloid-β peptide (25–35) cytotoxicity is associated with adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β peptide (25–35).

Hopeahainol A attenuates memory deficits by targeting β‐amyloid in APP/PS1 transgenic mice

Increasing evidence demonstrates that amyloid beta (Aβ) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Aβ is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase-inhibitory and anti-oxidative in H(2)O(2)-treated PC12 cells. In this study, we reported that HopA might bind to Aβ(1-42) directly and inhibit the Aβ(1-42) aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Aβ(1-42) and Aβ-binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long-term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD.

Induction of Dickkopf-1 contributes to the neurotoxicity of MPP+ in PC12 cells via inhibition of the canonical Wnt signaling pathway

The secreted glycoprotein Dickkopf-1 (Dkk1), an antagonist of the Wnt/β-catenin pathway, has been implicated in many neurodegenerative diseases. However, it is unknown whether Dkk1 is involved in the pathogenesis of Parkinson's disease (PD). In this study, we discovered that Dkk1 was induced in MPP+-treated PC12 cells and the increase of Dkk1 preceded PC12 cell loss. RhDkk1 aggravated the neurotoxicity of MPP+ in PC12 cells. Furthermore, the level of Dkk1 was correlated with the number of apoptotic PC12 cells. The apoptosis could be decreased by Dkk1-siRNA in MPP+-induced PC12 cells and Dkk1-siRNA regulated the expression of β-catenin and p-Ser9-GSK-3β in MPP+-induced PC12 cells. LiCl (an inhibitor of GSK-3β) also rescued the loss of PC12 cell viability and the apoptosis induced by MPP+. These data suggest that the induction of Dkk1 contributes to the MPP+-induced neurotoxicity in PC12 cells via inhibition of the canonical Wnt pathway and Dkk1 antagonists which could rescue the Wnt pathway might be neuroprotective in PD.