sirolimus and Parkinsonian-Disorders

The oxidative-stress-induced impairment of autophagy plays a critical role in the pathogenesis of Parkinson's disease (PD). In this study, we investigated whether the alteration of Nrf2 in astrocytes protected against 6-OHDA (6-hydroxydopamine)- and rotenone-induced PD-like phenotypes, using 6-OHDA-induced rat PD and rotenone-induced Drosophila PD models. In the PD rat model, we found that Nrf2 expression was significantly higher in astrocytes than in neurons. CDDO-Me (CDDO methyl ester, an Nrf2 inducer) administration attenuated PD-like neurodegeneration mainly through Nrf2 activation in astrocytes by activating the antioxidant signaling pathway and enhancing autophagy in the substantia nigra and striatum. In the PD Drosophila model, the overexpression of Nrf2 in glial cells displayed more protective effects than such overexpression in neurons. Increased Nrf2 expression in glial cells significantly reduced oxidative stress and enhanced autophagy in the brain tissue. The administration of the Nrf2 inhibitor ML385 reduced the neuroprotective effect of Nrf2 through the inhibition of the antioxidant signaling pathway and autophagy pathway. The autophagy inhibitor 3-MA partially reduced the neuroprotective effect of Nrf2 through the inhibition of the autophagy pathway, but not the antioxidant signaling pathway. Moreover, Nrf2 knockdown caused neurodegeneration in flies. Treatment with CDDO-Me attenuated the Nrf2-knockdown-induced degeneration in the flies through the activation of the antioxidant signaling pathway and increased autophagy. An autophagy inducer, rapamycin, partially rescued the neurodegeneration in Nrf2-knockdown Drosophila by enhancing autophagy. Our results indicate that the activation of the Nrf2-linked signaling pathways in glial cells plays an important neuroprotective role in PD models. Our findings not only provide a novel insight into the mechanisms of Nrf2-antioxidant-autophagy signaling, but also provide potential targets for PD interventions.

Topics: Adenine; Animals; Animals, Genetically Modified; Antioxidants; Antiparkinson Agents; Astrocytes; Autophagy; Behavior, Animal; Dihydroxyphenylalanine; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Male; Motor Activity; Nerve Degeneration; NF-E2-Related Factor 2; Oleanolic Acid; Parkinsonian Disorders; Phenotype; Rats, Sprague-Dawley; Repressor Proteins; Rotenone; Signal Transduction; Sirolimus

We report that rapamycin, an allosteric inhibitor of certain but not all actions of the key cellular kinase mammalian target of rapamycin (mTOR), protects neurons from death in both cellular and animal toxin models of Parkinson's disease (PD). This protective action appears to be attributable to blocked translation of RTP801/REDD1/Ddit4, a protein that is induced in cell and animal models of PD and in affected neurons of PD patients and that causes neuron death by leading to dephosphorylation of the survival kinase Akt. In support of this mechanism, in PD models, rapamycin spares phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity. The capacity of rapamycin to provide neuroprotection in PD models appears to arise from its selective suppression of some but not all actions of mTOR, as indicated by the contrasting finding that Torin1, a full catalytic mTOR inhibitor, is not protective and induces Akt dephosphorylation and neuron death.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Animals; Cell Death; Cycloheximide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factor; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; PC12 Cells; Protein Serine-Threonine Kinases; Rats; Serine; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transcription Factors; Transfection; Tyrosine 3-Monooxygenase