Akt-activated GSK3ß inhibitory peptide effectively blocks tau hyperphosphorylation.

Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Glycogen synthase kinase 3ß (GSK3ß) overexpression has been implicated in tau hyperphosphorylation, and many GSK3ß inhibitors have been developed as potential therapeutic candidates for AD. However, the potent GSK3ß inhibitors produced are prone to side effects because they can interfere with the basic functions of GSK3ß. We previously found that when the phosphorylated PPPSPxS motifs in Wnt coreceptor LRP6 can directly inhibit GSK3ß, and thus, we produced a novel GSK3ß inhibitory peptide (GIP), specifically activated by Akt, by combining the PPPSPxS motif of LRP6 and the Akt targeted sequence (RxRxxS) of GSK3ß. GIP effectively blocked GSK3ß-induced tau phosphorylation in hippocampal homogenates and, when fused with a cell-permeable sequence, attenuated Aß-induced tau phosphorylation in human neuroblastoma cells and inhibited cell death. An in vivo study using a 3 × Tg-AD mouse model revealed that intravenous GIP significantly reduced tau phosphorylation in the hippocampus without affecting Aß plaque levels or neuroinflammation and ameliorated memory defects. The study provides a novel neuroprotective drug development strategy targeting tau hyperphosphorylation in AD.

Spontaneous type II cell-derived bronchioloalveolar adenoma in a young ICR mouse.

Although pulmonary adenomas have been reported in ICR mice, spontaneous adenomas have not been reported in mice aged ≤10 weeks. Here, we report a well-circumscribed nodule (1 mm × 1 mm) in the peripheral lesion of the left lateral lobe of a 10-week-old male ICR mouse. Histopathologic evaluation revealed a well-demarcated nodule compressing the surrounding tissue. The neoplastic cells were polygonal with indistinct cellular borders, round/oval nuclei and abundant cytoplasm. These characteristics led to the diagnosis of type II cell-derived bronchioloalveolar adenoma. Given that they are generally observed in aged laboratory animals, this case represents a rare manifestation of a spontaneous tumor in young laboratory mice before puberty.

Low-dose curcumin enhances hippocampal neurogenesis and memory retention in young mice.

Adult neurogenesis generates new functional neurons from adult neural stem cells in various regions, including the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of hippocampal dentate gyrus (DG). Available evidence shows hippocampal neurogenesis can be negatively or positively regulated by dietary components. In a previous study, we reported that curcumin (diferuloylmethane; a polyphenolic found in curry spice) stimulates the proliferation of embryonic neural stem cells (NSCs) by activating adaptive cellular stress responses. Here, we investigated whether subchronic administration of curcumin (once daily at 0.4, 2, or 10 mg/kg for 14 days) promotes hippocampal neurogenesis and neurocognitive function in young (5-week-old) mice. Oral administration of low-dose curcumin (0.4 mg/kg) increased the proliferation and survival of newly generated cells in hippocampus, but surprisingly, high-dose curcumin (10 mg/kg) did not effectively upregulate the proliferation or survival of newborn cells. Furthermore, hippocampal BDNF levels and phosphorylated CREB activity were elevated in only low-dose curcumin-treated mice. Passive avoidance testing revealed that low-dose curcumin increased cross-over latency times, indicating enhanced memory retention, and an in vitro study showed that low-concentration curcumin increased the proliferative activity of neural progenitor cells (NPCs) by upregulating NF1X levels. Collectively, our findings suggest that low-dose curcumin has neurogenic effects and that it may prevent age and neurodegenerative disease-related cognitive deficits.

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1.

Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 µM and 410 ± 60% at 5 µM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.

Mesenchymal Stem Cell Therapy and Alzheimer's Disease: Current Status and Future Perspectives.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease worldwide, but its cause remains unclear. Although a few drugs can provide temporary and partial relief of symptoms in some patients, no curative treatment is available. Therefore, attention has been focused on research using stem cells to treat AD. Among stem cells, mesenchymal stem cells (MSCs) have been used to treat the related pathologies in animal models of AD, and other neurodegenerative disease. This review describes latest research trends on the use of MSC-based therapies in AD and its action of mechanism. MSCs have several beneficial effects. They would be specified as the reduction of neuroinflammation, the elimination of amyloid-ß, neurofibrillary tangles, and abnormal protein degradation, the promotion of autophagy-associated and blood-brain barrier recoveries, the upregulation of acetylcholine levels, improved cognition, and the recovery of mitochondrial transport. Therefore, this review describes the latest research trends in MSC-based therapy for AD by demonstrating the importance of MSC-based therapy and understanding of its mechanisms in AD and discusses the limitations and perspectives of stem cell therapy in AD.

Human Norovirus Replication in Temperature-Optimized MDCK Cells by Forkhead Box O1 Inhibition.

Human noroviruses (HuNoVs) are a leading cause of gastroenteritis outbreaks worldwide. However, the paucity of appropriate cell culture model for HuNoV replication has prevented developing effective anti-HuNoV therapy. In this study, first, the replication of the virus at various temperatures in different cells was compared, which showed that lowering the culture temperature from 37°C significantly increased virus replication in Madin-Darby canine kidney (MDCK) cells. Second, the expression levels of autophagy-, immune-, and apoptosis-related genes at 30°C and 37°C were compared to explore factors affecting HuNoV replication. HuNoV cultured at 37°C showed significantly increased autophagy- (ATG5 and ATG7) and immune- (IFNA, IFNB, ISG15, and NFKB) related genes compared to mock. However, the virus cultured at 30°C showed significantly decreased expression of autophagy- (ATG5 and ATG7) and not significantly different in major immune- (IFNA, ISG15, and NFKB) related genes compared to mock. Importantly, expression of the transcription factor FOXO1, which controls autophagy- and immune-related gene expression, was significantly lower at 30°C. Moreover, FOXO1 inhibition in temperature-optimized MDCK cells enhanced HuNoV replication, highlighting FOXO1 inhibition as an approach for successful virus replication. In the temperature-optimized cells, various HuNoV genotypes were successfully replicated, with GI.8 showing the highest replication levels followed by GII.1, GII.3, and GII.4. Furthermore, ultrastructural analysis of the infected cells revealed functional HuNoV replication at low temperature, with increased cellular apoptosis and decreased autophagic vacuoles. In conclusion, temperature-optimized MDCK cells can be used as a convenient culture model for HuNoV replication by inhibiting FOXO1, providing adaptability to different genotypes.

Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1.

Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of small-molecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound 5 (SU0383) with IC50(NUDT1) = 0.034 µM and IC50(OGG1) = 0.49 µM. The compound SU0383 displayed low toxicity in two human cell lines at 10 µM. Experiments confirm the ability of SU0383 to increase sensitivity of tumor cells to oxidative stress. Dual inhibitors of these two enzymes are expected to be useful in testing multiple hypotheses regarding the roles of 8-oxo-dG in multiple disease states.

Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways.

Neuroinflammation is a specific or nonspecific immunological reaction in the central nervous system that is induced by microglia activation. Appropriate regulation of activated microglial cells is therefore important for inhibiting neuroinflammation. Hesperetin is a natural flavanone and an aglycone of hesperidin that is found in citrus fruits. Hesperetin reportedly possesses anti-inflammatory, anti-cancer, and antioxidant effects. However, the anti-neuroinflammatory effects of hesperetin on microglia are still unknown. Here, we investigated the anti-neuroinflammatory effects of hesperetin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We found that hesperetin strongly inhibited nitric oxide production and expression of inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. Hesperetin also significantly reduced secretion of inflammatory cytokines including interleukin (IL)-1ß and IL-6. Furthermore, hesperetin down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase, exerting anti-inflammatory effects. Hesperetin suppressed astrocyte and microglia activation in the LPS-challenged mouse brain. Collectively, our findings indicate that hesperetin inhibits microglia-mediated neuroinflammation and could be a prophylactic treatment for neurodegenerative diseases.

Neuroprotective effects of MHY908, a PPAR α/γ dual agonist, in a MPTP-induced Parkinson's disease model.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation.

DICAM Attenuates Experimental Colitis via Stabilizing Junctional Complex in Mucosal Barrier.

BACKGROUND: Adhesion molecules maintain the intestinal barrier function that is crucial to prevent intestinal inflammation. Dual immunoglobulin domain-containing adhesion molecule (DICAM) has been recently identified and known for the involvement in cell-cell adhesion through homophilic interaction and heterophilic interaction with integrin αVß3. We tested whether the change of DICAM expression affects the severity of colonic inflammation. METHODS: Colitis was induced with oral administration of 2.5% dextran sulfate sodium (DSS) in 8-week-old male mice for 5 days. The function of DICAM under inflammatory condition was investigated using loss-of-function and gain-of-function models such as DICAM-deficient mice and adenoviral transduction of DICAM into Caco-2 colonic epithelial cells. RESULTS: DICAM increased in parallel with the degree of inflammation after 5-day administration of DSS and decreased with the resolution of inflammation. DICAM was expressed in the epithelial junctional complex and colocalized with ZO-1. Treatment with TNF-α or IFN-γ in Caco-2 cells significantly increased DICAM in protein and RNA level. The DICAM knockout mice showed more severe DSS-induced colitis compared with WT littermates. Adenoviral transduction of DICAM into Caco-2 cells significantly attenuated the inflammation-mediated decrease of adhesion molecules, including ZO-1 and occludin. Furthermore, Caco-2 cells with DICAM overexpression maintained intestinal barrier function under IFN-γ treatment as estimated by transepithelial electrical resistance. CONCLUSION: Our study demonstrates that DICAM which is increased in an inflammatory condition has a protective role in experimental colitis by stabilizing the integrity of junctional complex in the intestinal mucosal barrier.

Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression.

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson's disease and Alzheimer's disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.

Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis.

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer with poor prognosis. In the present study, we demonstrated that Src, a non-receptor tyrosine kinase, might provide an effective therapeutic strategy to overcome TNBC invasion and metastasis, which are mediated via the synergistic action of the lysosomal enzyme cathepsin S (CTSS) and gelatinase MMP-9. Knock-down of MMP-9 and CTSS using siRNAs resulted in a synergistic suppression of MDA-MB-231 cell invasion, which was similarly observed with pharmacological inhibitors. During the screening of new drug candidates that suppress both CTSS and MMP-9, BJ-2302, a novel 7-azaindolin-2-one derivative, was discovered. Src, an upstream activator of both pathways (PI3K/Akt and Ras/Raf/ERK) responsible for the expression of CTSS and MMP-9, was identified as a high-affinity target of BJ-2302 (IC90: 3.23 µM) through a Src kinase assay and a drug affinity responsive target stability (DARTS) assay. BJ-2302 effectively suppressed MDA-MB-231 cell invasion (Matrigel invasion assay) and metastasis (chorioallantoic membrane assay xenografted with MDA-MB-231-luc2-tdTomato cancer cells). Unlike Z-FL-COCHO (potent CTSS inhibitor), BJ-2302 did not induce any cytotoxicity in MCF-10A normal breast epithelial cells. Additionally, BJ-2302 (1 mg/kg) strongly suppressed TNBC cell proliferation in vitro and tumor growth in a xenograft mouse tumor model. The anti-metastatic and anti-tumor effects of BJ-2302 were superior to those of Z-FL-COCHO (1 mg/kg) or batimastat (30 mg/kg), a pan-MMP inhibitor. In summary, inhibition of Src kinase suppressed TNBC tumor growth and metastasis, and Src inhibitors such as BJ-2302 may constitute a novel therapeutic tool to treat breast cancer that expresses high levels of CTSS and MMP-9.

ATP-Linked Chimeric Nucleotide as a Specific Luminescence Reporter of Deoxyuridine Triphosphatase.

Nucleotide surveillance enzymes play important roles in human health, by monitoring damaged monomers in the nucleotide pool and deactivating them before they are incorporated into chromosomal DNA or disrupt nucleotide metabolism. In particular, deamination of cytosine, leading to uracil in DNA and in the nucleotide pool, can be deleterious, causing DNA damage. The enzyme deoxyuridine triphosphatase (dUTPase) is currently under study as a therapeutic and prognostic target for cancer. Measuring the activity of this enzyme is important both in basic research and in clinical applications involving this pathway, but current methods are nonselective, detecting pyrophosphate, which is produced by many enzymes. Here we describe the design and synthesis of a dUTPase enzyme-specific chimeric dinucleotide (DUAL) that replaces the pyrophosphate leaving group of the native substrate with ATP, enabling sensitive detection via luciferase luminescence signaling. The DUAL probe functions sensitively and selectively to quantify enzyme activities in vitro and in cell lysates. We further report the first measurements of dUTPase activities in eight different cell lines, which are found to vary by a factor of 7-fold. We expect that the new probe can be of considerable utility in research involving this clinically significant enzyme.

One-step construction of a molybdenum disulfide/multi-walled carbon nanotubes/polypyrrole nanocomposite biosensor for the ex-vivo detection of dopamine in mouse brain tissue.

We developed a new strategy for construction of a biosensor for the neurotransmitter dopamine. The biosensor was constructed by one-step electrochemical deposition of a nanocomposite in aqueous solution at pH 7.0, consisting of molybdenum disulfide, multi-walled carbon nanotubes, and polypyrrole. A series of analytical methods was performed to investigate the surface characteristics and the improved electrocatalytic effect of the nanocomposite, including cyclic voltammetry, electrochemical impedance spectroscopy, field-emission scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. The constructed biosensor showed high sensitivity (1.130 µAµM-1cm-2) with a dynamic linearity range of 25-1000 nM and a detection limit of 10 nM. Additionally, the designed sensor exhibited strong anti-interference ability and satisfactory reproducibility. The practical application of the sensor was manifested for the ex vivo determination of dopamine neurotransmitters using brain tissue samples of a mouse Parkinson's disease model.

Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide.

Adherent-invasive E. coli colonization and Toll-like receptor (TLR) expression are increased in the gut of inflammatory bowel disease (IBD) patients. However, the underlying mechanism of such changes has not been determined. In the current study, it was examined whether gut serotonin (5-hydroxytryptamine, 5-HT) can induce adherent-invasive E. coli colonization and increase TLR expression. In a co-culture system, commensal E. coli strain (BW25113, BW) adhered minimally to colon epithelial cells, but this was significantly enhanced by 5-HT to the level of a pathogenic strain (EDL933). Without inducing bacterial virulence, such as, biofilm formation, 5-HT enhanced BW-induced signaling in colon epithelial cells, that is, NADPH oxidase (NOX)-dependent superoxide production, the up-regulations of IL-8, TLR2, TLR4, and ICAM-1, and the down-regulations of E-cadherin and claudin-2. In a manner commensurate with these gene modulations, BW induced an increase in NF-κB and a decrease in GATA reporter signals in colon epithelial cells. However, 5-HT-enhanced BW adhesion and colon epithelial responses were blocked by knock-down of NOX2, TLR2, or TLR4. In normal mice, 5-HT induced the invasion of BW into gut submucosa, and the observed molecular changes were similar to those observed in vitro, except for significant increases in TNFα and IL-1ß, and resulted in death. In dextran sulfate sodium-induced colitis mice (an IBD disease model), in which colonic 5-HT levels were markedly elevated, BW administration induced death in along with large amount of BW invasion into colon submucosa, and time to death was negatively related to the amount of BW injected. Taken together, our results demonstrate that 5-HT induces the invasion of commensal E. coli into gut submucosa by amplifying commensal bacteria-induced epithelial signaling (superoxide production and the inductions of NOX2 and TLR2/TLR4). The authors suggest that these changes may constitute the molecular basis for the pathogenesis of IBD.

5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells.

Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent®) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.

Silibinin suppresses astroglial activation in a mouse model of acute Parkinson's disease by modulating the ERK and JNK signaling pathways.

Parkinson's disease (PD) is the second-most common neurodegenerative disease after Alzheimer's disease, and is characterized by dopaminergic neuronal loss in midbrain. The MPTP-induced PD model has been well characterized by motor deficits and selective dopaminergic neuronal death accompanied by glial activation. Silibinin is a constituent of silymarin, an extract of milk thistle seeds, and has been proposed to have hepatoprotective, anti-cancer, anti-oxidative, and neuroprotective effects. In the present study, the authors studied the neuroprotective effects of silibinin in an acute MPTP model of PD. Silibinin was administered for 2 weeks, and then MPTP was administered to mice over 1 day (acute MPTP induced PD). Silibinin pretreatment effectively ameliorated motor dysfunction, dopaminergic neuronal loss, and glial activations caused by MPTP. In addition, an in vitro study demonstrated that silibinin suppressed astroglial activation and ERK and JNK phosphorylation in primary astrocytes in response to MPP(+) treatment. These findings show silibinin protected dopaminergic neurons in an acute MPTP-induced mouse model of PD, and suggest its neuroprotective effects might be mediated by the suppression of astrocyte activation via the inhibition of ERK and JNK phosphorylation. In conclusion, the study indicates silibinin should be viewed as a potential treatment for PD and other neurodegenerative diseases associated with neuroinflammation.

Silibinin prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease via mitochondrial stabilization.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the nigrostriatal pathway. The lipophile 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cross the blood-brain barrier and is subsequently metabolized into toxic1-methyl-4-phenylpyridine (MPP(+) ), which causes mitochondrial dysfunction and the selective cell death of dopaminergic neurons. The present article reports the neuroprotective effects of silibinin in a murine MPTP model of PD. The flavonoid silibinin is the major active constituent of silymarin, an extract of milk thistle seeds, and is known to have hepatoprotective, anticancer, antioxidative, and neuroprotective effects. In the present study, silibinin effectively attenuated motor deficit and dopaminergic neuronal loss caused by MPTP. Furthermore, in vitro study confirmed that silibinin protects primary cultured neurons against MPP(+) -induced cell death and mitochondrial membrane disruption. The findings of the present study indicate that silibinin has neuroprotective effects in MPTP-induced models of PD rather than antioxidative or anti-inflammatory effects and that the neuroprotection afforded might be mediated by the stabilization of mitochondrial membrane potential. Furthermore, these findings suggest that silibinin protects mitochondria in MPTP-induced PD models and that it offers a starting point for the development of treatments that ameliorate the symptoms of PD.