dorsomorphin and Neuroblastoma

Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP(+)) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP(+)-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; ARNTL Transcription Factors; Body Temperature; Catalytic Domain; Cell Line, Tumor; Chronobiology Disorders; Cryptochromes; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Motor Activity; MPTP Poisoning; Neostriatum; Neuroblastoma; Nuclear Receptor Subfamily 1, Group D, Member 1; Phosphorylation; Protein Processing, Post-Translational; Pyrazoles; Pyrimidines

Resveratrol (RSV), a polyphenolic phytoestrogen, has been shown to activate the serine/threonine kinase 5'-adenosine monophosphate-activated protein kinase (AMPK) and to stimulate insulin signaling and glucose uptake in skeletal muscle cells. A direct effect of RSV on neuronal insulin signaling, however, has not been demonstrated. Here, we report that RSV stimulates glucose uptake and potentiates insulin signaling in Neuro-2A (N2A) cells, which is characterized by the increased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β). Furthermore, RSV activates AMPK in N2A cells, which can be prevented using a specific pharmacological inhibitor, Compound C. Compound C abrogates RSV-induced Akt and GSK-3β phosphorylation and glucose uptake. Thus, we demonstrate that RSV potentiates insulin signaling and glucose uptake via AMPK activation in neuronal cells.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cell Line, Tumor; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Insulin; Mice; Neuroblastoma; Neurons; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Resveratrol; Signal Transduction; Stilbenes