Page - 57 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 characterized.Additionally, immunechallengesintheagedCNSleadtoaprolongeddownregulationof thefractalkinereceptorthatisassociatedwithasustainedinflammatoryresponse,furthercompromising thisprotectiveneuronglia interaction[49]. Therefore, it is imperative to investigate the therapeutic potentialofFKNinthe treatmentofPDinagedanimalmodels; futurestudiesareneededtoexamine theefficacyofFKNonagedorprimedmicroglia. Figure1.Adepictionof ligand/receptorbindingforboth thesolubleandmembraneboundisoforms ofCX3CL1 (FKN) and their respective influences on the release of inflammatorymediators in the substantianigra.Asdiscussedabove, sFKNwhendeliveredviaAAVintoCX3CL1-/-mice following MPTP is associated with the suppression of cytokine production. However, when we delivered anobligatemembraneboundformofCX3CL1oravectorwithGFPtherewasnorescueofTHneurons orareduction in inflammatorymediators. 5.TherapeuticPotentialofAstaxanthin Asdiscussedabove, theSNisexposedtohigh levelsofoxidativestress relative tootherareasof thebraindueto innate featuresof theneurons thatcomprise this region[50]. Forexample, thereare lowlevelsofglutathioneandhighconcentrationof ironleadstotheproductionoffreeradicals through theFentonreaction [51]. Glutathioneactivity in this regiondeclineswithage, further reducing the capacity tomanage theaccumulationofROSin theSN.Taken together, thesecharacteristics create anenvironmentofhighoxidativestress thatcan impairneuronal function. Onenatural compoundofparticular interest isastaxanthin,anaturallyoccurringxanthophyll carotenoid. It isproducedbythemarinealgaeHeamatococcusPluvialisorsyntheticallyderivedfrom carotenoidprecursorsandusedcommercially to feedto farmedfishspecies to increasepigmentation. Astaxanthinhasmanysuggestedmechanismsofactionthatuniquelyopposepathophysiologythat underlieParkinson’sdisease includingactionsasananti-inflammatoryactionandimprovements in aspectsofmitochondrial function, indicatingadistinct andpromising therapeuticpotential in the treatmentandmanagementof symptomsinPDpatients thatare likelymore important than its role to simplyscavengefreeradicals [52–54]. Astaxanthinhaspotentanddiverseactionsasanantioxidantandis reportedtobeseveral times more effective thanother carotenoids in its class. Themolecular structureof astaxanthinallows it to reduce free radicals in a variety ofways, including absorbing them into the carbon backbone, donatingelectronsandformingadductswith thereactivespecies.Althoughxanthophyll carotenoids arestructurallysimilar, thepresenceofpolar iononeringsateitherendof theastaxanthinmolecule makesitenergeticallyfavorable. Theconfigurationallowsthemoleculetospanacrossthephospholipid bilayerofcellmembranesandprotect themembraneagainst lipidperoxidation[55]. There is substantial evidence indicating that treatmentwithastaxanthincausesa reduction in themarkersofcellularstressduetoexcessROSproduction, suchas8-isoprostane,proteincarbonyl 57