alpha-synuclein and acetovanillone

Parkinson's disease (PD), is an age-related, progressive neurodegenerative disorder that affects movement and is characterized by the loss of dopaminergic neurons in the nigrostriatal region. Although the clinical and pathological features of PD are complex, recent studies have indicated that microglial NADPH oxidase play a key role in its pathology. A little information is available regarding the role of apocyanin, an NADPH oxidase inhibitor, in ameliorating α-synuclein aggregation and neurobehavioral consequences of PD. Therefore, the present study evaluated its therapeutic potentials for the treatment of neurobehavioral consequences in lipolysaccharide (LPS) induced PD model. For the establishment of PD model LPS (5 μg/5 μl PBS) was injected into the Substantia nigra (SN) of rats. Apocyanin (10mg/kgb.wt) was injected intraperitoneal. Statistical analysis revealed that apocynin significantly ameliorated LPS induced inflammatory response characterized by NFkB, TNF-α and IL-1β upregulation as assessed by ELISA. It also prevented dopaminergic neurons from toxic insult of LPS as indicated by inhibition of apoptotic markers i.e., caspase 3 and caspase 9 as depicted from RT-PCR and ELISA studies. This was further supported by TUNEL assay for DNA fragmentation. Effectiveness of apocyanin in protecting dopaminergic neuronal degeneration was further confirmed by assessment of α-synuclein deposition as depicted by IHC analysis. Consequently, an improvement in the behavioral outcome was observed following apocyanin treatment as depicted from various behavioral tests performed. Hence the data suggests that specific NADPH oxidase inhibitors, such as apocynin, may provide a new therapeutic approach to the control of neurological disabilities induced by LPS induced PD.

Topics: Acetophenones; alpha-Synuclein; Animals; Behavior, Animal; Cytokines; Disease Models, Animal; Dopaminergic Neurons; Enzyme Inhibitors; Lipopolysaccharides; Male; NADPH Oxidases; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley

The accumulation of amyloid fibrils is a feature of amyloid diseases, where cell toxicity is due to soluble oligomeric species that precede fibril formation or are formed by fibril fragmentation, but the mechanism(s) of fragmentation is still unclear. Neutrophil-derived elastase and histones were found in amyloid deposits from patients with different systemic amyloidoses. Neutrophil extracellular traps (NETs) are key players in a death mechanism in which neutrophils release DNA traps decorated with proteins such as elastase and histones to entangle pathogens. Here, we asked whether NETs are triggered by amyloid fibrils, reasoning that because proteases are present in NETs, protease digestion of amyloid may generate soluble, cytotoxic species. We show that amyloid fibrils from three different sources (α-synuclein, Sup35, and transthyretin) induced NADPH oxidase-dependent NETs in vitro from human neutrophils. Surprisingly, NET-associated elastase digested amyloid fibrils into short species that were cytotoxic for BHK-21 and HepG2 cells. In tissue sections from patients with primary amyloidosis, we also observed the co-localization of NETs with amyloid deposits as well as with oligomers, which are probably derived from elastase-induced fibril degradation (amyloidolysis). These data reveal that release of NETs, so far described to be elicited by pathogens, can also be triggered by amyloid fibrils. Moreover, the involvement of NETs in amyloidoses might be crucial for the production of toxic species derived from fibril fragmentation.

Topics: Acetophenones; alpha-Synuclein; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Animals; Biomarkers; Cell Nucleus; Cell Survival; Chromatin; Cricetinae; Extracellular Space; Hep G2 Cells; Humans; Immunoglobulin Light-chain Amyloidosis; Lung; Mutation, Missense; NADPH Oxidases; Neutrophils; Onium Compounds; Pancreatic Elastase; Peptide Fragments; Prealbumin; Protein Structure, Quaternary; Proteolysis; Reactive Oxygen Species; Skin