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BrainSci. 2016,6, 41 to increasemitochondrialactivityas indicatedbyincreasedrespirationandmitochondrialmembrane potential (MMP) [70]. Mitochondrial dysfunction is a common pathophysiological observation in PD, and is recapitulated in the α-synuclein model. It has been shown that treating isolated mitochondriawithα-synucleinoligomers inducedmitochondrialdysfunctionby inhibitingcomplex1 and associated with reduced calcium retention time, release of ROS and induced mitochondrial swelling[7]. InspecificstudiesrelatedtoPD,astaxanthinhasbeenshowntoprotectSH-SY5Ycells from6-OHDA[53]. Inasimilarexperiment, astaxanthin treatmentmitigatedcytotoxicity inPC12cells fromMPP+inducedcytotoxicity.MPP+isa toxicmetaboliteof thedopaminergicneurotoxinMPTP used inexperimentalanimalmodelsofPD[71]. Thesecell culture resultswerecorroboratedbyan invivostudyusingastaxanthin toprevent theneurodegeneration in theSNinresponse todoseof MPTP (1 i.p. dose 30mg/kgdaily for 28days) [54]. This treatment regimeneffectivelyprotected against thelossof tyrosinehydroxylaseintheSNandstriatumafterchronicexposuretotheneurotoxin. However, it is important tounderstandthatmanydrugs thathavebeensuccessful insomepre-clinical modelsofPDhavefailed to translate topatientswithPD.Developingandtestingpre-clinicalmodels involvingdiseaserelevantproteinssuchasα-synucleinandthe impactofagingmustbeconsidered for futurestudies. 6.Conclusions Parkinson’sdisease isprimarilycharacterizedbydegenerationof thedopaminergicneuronsof thesubstantianigra. Thepathophysiologyunderlying this celldeath isnotyet clearlyunderstood, although it is evident thatmanybiological processes are impaired in this vulnerable brain region, explaining the rapid deterioration of the SN with age. Neuroinflammation is an integral factor perpetuating cellular damage during progression of the disease, and efforts to mitigate the inflammatorycascadehavebeensuccessful inexperimentalsettings,suggestingthatanti-inflammatory treatmentsareaviable therapeuticstrategytoemployinmanagingParkinson’sdisease. Fractalkine signalinghasproventobeacriticalpathwayininflammation-mediatedcelldeaththatoccurs inanimal modelsofPD.Astaxanthinhasdiversebiologicalactivities thathavebeenreported in the literature, manyofwhichseemtodirectlyoppose thepathologicalmechanisms involvedinneurodegeneration of theSN.Bothfractalkineandastaxanthinrepresent twopromisingnovel therapeuticagents for the treatmentandmanagementofPD. Acknowledgments:ThisworkwassupportedbyNIAgrantsAG04418 (PCB),AG044919 (PCB);VAIO1BX000231 (PCB), and theMichael J Fox foundation (KN/PCB). Thisworkwas supported by the federal government. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the UnitedStatesGovernment. AuthorContributions:This isa reviewpaper,butP.C.B.,K.N., andJ.M.conceivedanddesignedtheexperiments fromour lab thatarecitedwithin thedocument;B.G.andJ.M.performedthepreviousexperimentsandanalyzed thedatadiscussedwithin the text;B.G.,P.C.B., andK.N.wrote thepaper. Conflictsof Interest:Theauthorsdeclarenoconflictof interest. The foundingsponsorshadnorole in thedesign of the study; in the collection, analyses, or interpretationofdata; in thewritingof themanuscript, and in the decisiontopublish theresults. References 1. Kowal,S.L.;Dall,T.M.;Chakrabarti,R.; Storm,M.V.; Jain,A.Thecurrentandprojectedeconomicburdenof Parkinson’sdisease in theUnitedStates.Mov.Disord. 2013,28, 311–318. [CrossRef] [PubMed] 2. Braak,H.;Ghebremedhin,E.;Rüb,U.;Bratzke,H.;DelTredici,K.Stages in thedevelopmentofParkinson’s disease-relatedpathology.CellTissueRes. 2004,318, 121–134. [CrossRef] [PubMed] 3. Zhang,W.;Wang,T.;Pei,Z.;Miller,D.S.;Wu,X.;Block,M.L.;Wilson,B.;Zhang,W.;Zhou,Y.;Hong, J.-S.S.; Zhang, J. Aggregated alpha-synuclein activatesmicroglia: Aprocess leading to disease progression in Parkinson’sdisease.FASEBJ.2005,19, 533–542. [CrossRef] [PubMed] 4. Stefanis,L.α-Synuclein inParkinson’sdisease.ColdSpringHarb. Perspect.Med. 2012,2, a009399. [CrossRef] [PubMed] 59