alpha-synuclein and squamosamide

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. The pathology of PD is caused by progressive degeneration of dopaminergic neurons and is characterized by the presence of intracellular inclusions known as Lewy bodies, composed mainly of α-synuclein. Heat shock proteins (HSPs) are crucial in protein quality control in cells. HSP70 in particular prevents the aggregation of protein aggregation, such as α-synuclein, providing a degree of protection against PD. The compound FLZ has been shown to protect several PD models in previous studies and was reported as an HSP inducer to protect against MPP

Topics: alpha-Synuclein; Animals; Benzeneacetamides; Cell Line, Tumor; HSP70 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurotoxicity Syndromes; Phenols

Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats injured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of α-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed α-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment.

Topics: alpha-Synuclein; Animals; Apomorphine; Benzeneacetamides; Cell Death; Disease Models, Animal; Dopamine Agonists; Dopaminergic Neurons; Male; Motor Activity; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Phenols; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Repressor Proteins; Signal Transduction; Transcription Factors; Tyrosine 3-Monooxygenase

The pathogenesis of Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in substantia nigra (SNpc). FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental Parkinson's disease (PD) models. However, it is still unclear whether FLZ protects against PD through regulating the function of dopaminergic system. In this study, we carried out a set of in vitro and in vivo experiments to address these questions. Oral administration of FLZ significantly improved motor dysfunction of mice challenged by MPTP. The beneficial effects of FLZ on motor behavior attributed to the elevation of dopamine level in striatum, tyrosine hydroxylase (TH)-positive cells, and TH activity in the middle brain of mouse. Mechanism study showed that treatment of FLZ increased the phosphorylation of activating protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Using LY294002 to block phosphoinositide 3-kinases (PI3K)/Akt signaling pathway prevented the phosphorylation of mTOR and attenuated the neuroprotection of FLZ in MN9D cells challenged by MPP(+). In addition, FLZ reduced the expression of RTP801, an important protein in PD, in mice and cells intoxicated by MPTP/MPP(+). Taken together, these results revealed a novel role that FLZ elevated TH expression and activity in dopaminergic neuron through activation of Akt/mTOR survival pathway and inhibition of RTP801 in MPTP/MPP(+)-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising anti-PD drug.

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Animals; Benzeneacetamides; Blotting, Western; Cell Line; Chromones; Corpus Striatum; DNA-Binding Proteins; Dopamine; Dopaminergic Neurons; Flow Cytometry; Immunohistochemistry; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Morpholines; Movement Disorders; MPTP Poisoning; Neuroprotective Agents; Oncogene Protein v-akt; Phenols; Postural Balance; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors; Tyrosine 3-Monooxygenase

Compound FLZ (cFLZ) is a synthetic novel derivative of natural squamosamide. Previous pharmacological study found that cFLZ improved the abnormal behavior and the decrease of dopamine content in striatum in 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) model mice. 1-Methyl 4-phenylpyridinium (MPP+) is the active metabolite of MPTP to cause Parkinsonism in experimental animals. The purpose of this paper was to further study the protective action of cFLZ against MPP+-induced apoptosis and alternations of related signaling transduction. The results indicated that cFLZ at concentrations of 0.1 microM and 1 microM prevented 100 microM MPP+-induced apoptosis of SH-SY5Y cells, and inhibited the release of cytochrome C and apoptosis-inducing factor (AIF), and the activation of caspase 3 and NF-kappaB as well as alpha-synuclein gene and protein expressions. The results suggest that cFLZ possesses potent neuroprotective activity and may be a potential anti-Parkinson's disease drug worthy for further study.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Analysis of Variance; Apoptosis; Benzeneacetamides; Caspase 3; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation; Humans; Neuroblastoma; Neurotoxins; Phenols; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction