squamosamide and Parkinsonian-Disorders

FLZ is a synthetic new derivative of squamosamide. Pharmacological study found that FLZ given orally improved the abnormal behavior caused by the functional disturbance of dopaminergic and cholinergic neurons in mice. FLZ significantly increased the content of dopamine and its metabolites in striatum in MPTP model mice. FLZ also remarkably protected dopaminergic PC-12 cells against dopamine and MPP+ induced injury and apoptosis in vitro. The compound inhibited the formation of dopamine-melanin and protein polymers. Additionally, FLZ inhibited cytochrome-c release from mitochondria and caspase-3 activation by dopamine in PC-12 cells. The above results suggest that compound FLZ possesses anti-PD activity through neuroprotection.

Topics: Animals; Antiparkinson Agents; Benzeneacetamides; Disease Models, Animal; Humans; Parkinsonian Disorders; Phenols

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by motor impairments and loss of dopaminergic neurons in the substantia nigra. FLZ (formulated as: N-2-(4-hydroxy-phenyl)-ethyl]-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic derivative of squamosamide from a Chinese herb and has been proven to protect dopaminergic neurons in subacute PD models. However, whether FLZ has a neuroprotective effect on chronic PD model is still unknown. The present study was designed to verify the neuroprotection of FLZ on chronic PD mouse model induced by MPTP combined with probenecid (MPTP/p). The results showed that treatment of mice with FLZ for 9 weeks significantly improved motor behavior and dopaminergic neuronal function of mice injected with MPTP/p. The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level, and tyrosine hydroxylase (TH) activity, as well as decrease of α-synuclein (α-Syn) expression, α-Syn phosphorylation, nitration, and aggregation. Moreover, FLZ decreased the interaction between α-Syn and TH, which eventually improved dopaminergic neuronal function. Mechanistic study demonstrated that FLZ increased Akt and mTOR phosphorylation, suggesting that FLZ activated Akt/mTOR signaling pathway and this might be involved in the neuroprotection of FLZ. The present results provided more elaborate in vivo evidences to support the neuroprotective effect of FLZ on dopaminergic neurons of chronic PD mouse model and the potential of FLZ to be developed as new drug to treat PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzeneacetamides; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Male; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Parkinsonian Disorders; Phenols; Probenecid; Rotarod Performance Test; Tyrosine 3-Monooxygenase

Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases.. For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS)- and 1-methyl-4-phenylpyridinium-(MPP+)-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP-) induced PD mouse model was used.. FLZ showed potent efficacy in protecting dopaminergic (DA) neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH) immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX), the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1) FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2) FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47PHOX to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal-glial cultures was further substantiated by an in vivo study, which showed that FLZ significantly protected against MPTP-induced DA neuronal loss, microglial activation and behavioral changes.. Taken together, our results clearly demonstrate that FLZ is effective in protecting against LPS- and MPTP-induced neurotoxicity, and the mechanism of this protection appears to be due, at least in part, to inhibition of PHOX activity and to prevention of microglial activation.

Topics: Animals; Antiparkinson Agents; Benzeneacetamides; Cells, Cultured; Dinoprostone; Dopamine; Female; Lipopolysaccharides; Male; Membrane Glycoproteins; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NADPH Oxidase 2; NADPH Oxidases; Nerve Degeneration; Neurons; Neuroprotective Agents; Parkinsonian Disorders; Phenols; Pregnancy; Protein Transport; Rats; Rats, Inbred F344; Reactive Oxygen Species; Tumor Necrosis Factor-alpha