Wen-Wei Li

Summary: Background: Parkinson's disease (PD) is a common neurodegenerative disease, characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. Recent investigations have shown that mitochondrial fragmentation, an early event during apoptosis, is implicated in the degeneration of DA neurons in PD, and more importantly, preventing mitochondrial fragmentation could rescue cell death in several PD models. Therefore, mitochondrial dynamics may be a therapeutic target for early intervention in PD. However, much remains unknown about the mechanism underlying mitochondrial fragmentation in PD.Methods: The alterations in mitochondrial morphology, cell apoptosis, and mitochondrial shaping protein levels were detected after SH‐SY5Y cells were treated with various doses of MPP+ or rotenone.Results: Mitochondrial fragmentation is an early event during apoptosis caused by MPP+ but not rotenone, and Trichostatin A (TSA), a commonly used histone deacetylase (HDAC) inhibitor, selectively rescues mitochondrial fragmentation and cell death induced by lower doses of MPP+. Mitochondrial fragmentation triggered by lower doses of MPP+ may be a result of Mfn2 down‐regulation, which could be completely reversed by TSA. Further investigation suggests that TSA prevents MPP+‐induced Mfn2 down‐regulation via inhibiting histone deacetylation over Mfn2 promoter and alleviating its transcriptional dysfunction.Conclusions: Histone deacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection in PD cell model induced by MPP+. Hence, HDAC inhibitors may be a potential early treatment for PD.

Viscera-bowels theory is one of the key parts of the theoretical system of traditional Chinese medicine (TCM). The concept of viscera-bowels in TCM at the turn of the Ming-Qing Dynasties must have anatomical significance in western medical context. By then, western medicine began its dissemination into China with the conflict between it and TCM, which gradually increased, and eventually triggering the major debate between them in early 20th century. Under this background, Yun Tie-qiao definitely pointed out that TCM viscera-bowels was different from western anatomical visceral organs; rather, it was a theoretical model characterized by seasonal qi transformation. Thus, it became the beginning of the nature of five viscera - six bowels interpreted by TCM functional unit and pushing the development of modern TCM theoretical system. Hence, the correct handling of history of its evolutionary process from the TCM recognition on viscera-bowels to the western visceral idea is helpful to the orientation and its total implication in TCM viscera-bowels and its research.

Neurotrophins exert their physiological functions mainly through Trk receptors, and the neurotrophic signaling network is critical to the survival of neurons. However, therapeutic use of neurotrophins in treating neurodegenerative diseases is hampered by a number of pharmacological challenges, and the most significant challenge is their delivery into the central nervous system. Here, we reported that echinacoside, a small natural compound, elicits neuroprotection by activating Trk receptors and their downstream signal pathways. Echinacoside is the major active component of Cistanches Herba, a widely used Chinese herb with neuroprotective effects. We showed in this study that transient exposure to echinacoside is sufficient to protect neuronal cells and non‐neuronal cells over‐expressed with TrkA or TrkB against rotenone injury. Additional investigations on the mechanisms underlying suggested that transient treatment with echinacoside inhibits cytochrome c release and caspase‐3 activation caused by ensuing rotenone exposure via activating Trk‐extracellular signal‐regulated kinase (ERK) pathway in neuronal cells. As echinacoside is able to cross the blood–brain barrier freely, it may have a promising potential in neurodegenerative diseases treatment.

α-Synuclein is highly associated with some neurodegeneration and malignancies. Overexpressing wild-type or mutant α-synuclein promotes neuronal death by mitochondrial dysfunction, the underlying mechanisms of which remain poorly defined. It was recently reported that α-synuclein expression could directly lead to mitochondrial fragmentation in vitro and in vivo, which may be due to α-synuclein localization on mitochondria. Here, we applied a double staining method to demonstrate mitochondrial morphogenetic changes in cells overexpressed with α-synuclein. We show that mitochondrial localization of α-synuclein was increased following its overexpression in three distinct cell lines, including HeLa, SH-SY5Y, and PC12 cells, but no alteration in mitochondrial morphology was detected. However, α-synuclein knockdown prevents MPP⁺-induced mitochondrial fragmentation in SH-SY5Y and PC12 cells. These data suggest that α-synuclein protein levels hardly affect mitochondrial morphology in normal cell lines, but may have some influence on that under certain environmental conditions.

Mitochondria are highly dynamic organelles, which undergo continuous cycles of fission and fusion. Mitochondrial dynamics (fission and fusion) plays important roles in maintaining neuronal functions, including biogenesis, mitochondrial distribution and cell injury or death. Mfnl/2 and Opal mediate mitochondrial fusion, whereas Drp1 and Fis1 regulate mitochondrial fission. Mutations of Opal cause autosomal dominant optic atrophy, and mutations of Mfn2 lead to Charcot-Marie-Tooth disease type 2A. Moreover, increasing evidences show that abnormal mitochondrial dynamics are involved in pathogenesis of late-onset neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. This paper reviews the current advances of abnormal mitochondrial dynamics relevant to neuronal loss in neurodegenerative diseases.

Cyclooxygenase (COX) is the major target of non-steroidal anti-inflammatory drugs (NSAIDs). Since its discovery in the early 1990s, COX has been identified as a major player in inflammatory reactions. "neuroinflammation" is triggered and sustained by activation of resident cells, particularly microglia. Intensive researches have been made in the last decade concerning the COX pathway and its effect on microglial activation as well as other processes involved in neurondegeneration. This article reviewed new data in this area, focusing on three major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). By highlighting current knowledge in this field, it may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.

To investigate the protective effects of cistanche total glycosides (CTG) on dopaminergic neuron in substantia nigra (SN) of model mice of Parkinson's disease (PD). Experimental mice were randomly divided into 5 groups, the normal control group, the model group, the high (400 mg/kg), moderate (200 mg/kg) and low (100 mg/kg) dose CTG groups. Mouse model of chronic PD was induced by peritoneal injection of MPTP (1-methyl-4-phenyl-1,2,3,6-ttrahydropyridine) 30 mg/kg for 5 successive days. Climbing test was used to estimate the neurobehavior of mice on the 7th and 14th day (D7 and D14) after initiating MPTP injection; meantime, quantitative immunohistochemistry was conducted to detect the number of dopaminergic neuron in SN and expression of tyrosine hydroxylase (TH) in striatum. The average time of climbing in the high dose CTG group on D7 and D14 was significantly shorter than that in the model group (P < 0.01). The mean optic density (OD) of TH in striatum was higher in the three CTG groups than that in the model group on D7 (P < 0.01); but on D14, significance only showed in the high and moderate dose CTG groups (P < 0.01). Moreover, the MPTP induced decrease of TH positive neuron could be antagonized by CTG, but significant difference only showed between the high dose CTG group and the model group at the two time points of observation (P < 0.05). CTG could improve the neurobehavior of PD model mice significantly, and inhibit the decrease of nigral dopaminergic neurons and TH expression in striatum.

The interrelationship between α-synuclein (α-syn) and mitochondria is not clearly understood. Owing to the lack of the signal peptide and its predominant localization in the cytosol, α-syn is generally considered to affect mitochondrial function through some secondary effects. Contrary to this assumption, here, we show that a portion of α-syn is present in the membrane of mitochondria in normal dopaminergic neurons. The same profile is also found in other α-syn-positive neurons. Thus, binding to the membrane of mitochondria is the physiological nature of α-syn and might also contribute to the pathological role of this protein in the mitochondrial dysfunction in Parkinson's disease.

In recent years, the term "conformational disease" has been used to describe a range of disorders which are linked to misfolding and aberrant structural change in proteins. The molecular bases underlying the pathogenesis of neurodegenerative diseases are gradually being disclosed, and almost all of the diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and prion disease are increasingly being realized to have common molecular mechanisms including the accumulation of misfolded or aggregation-prone proteins, thus, they can be termed "neurodegenerative conformational disease". There is now increased understanding of the molecular pathways involved in protein misfolding and aggregation and cellular toxicity in neurodegenerative conformational diseases. These are leading to approaches toward rational therapeutics.