Seite - 58 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 moieties and 8OHdG [56]. Additionally, astaxanthin has been shown to increase the efficacy of endogenous antioxidant mechanisms invivo including increasing the expression or activity of glutathione, catalase, thioredoxin reductase and superoxide dismutase (SOD) [57,58]. It has also beenshowntoupregulateheme-oxygenease1 (HO-1) throughincrease inNRF[59,60]. Thesefindings suggest thatastaxanthin treatmentmayhelpalleviatesomeof theongoingoxidativestress thatoccurs duringtheprogressionofPDas it contributes tocellulardysfunction. However, in addition tooxidativedamage, there are anumberof physiological changes that occurwithage that exacerbate the cellular stress in theSN.Mitochondrialdynamics, proteosomal efficiency [61] and levels of synuclein [62] are all alteredwith age, likely rendering theDA cells morevulnerable toneurodegeneration. Agingalso leads tomicroglial primingandmay facilitate PDdiseaseprogression. Chronicmicroglial activation results inprolonged exposure to cytotoxic, pro-inflammatorycytokines, increasingcellularstressandultimatelyleadingtoneurodegeneration[33]. Age_inducedprimedmicrogliaarehyperactiveuponsubsequentstimulationandreleaseexaggerated amountsofcytokines. Theyareresistant toreversionbacktoastateof tissuerepairandmaintenance of homeostasis, as they are less responsive to regulatorymechanisms [20,63,64]. As stated above, synucleinaggregationmayalsodirectly facilitate thereleaseof these inflammatorymediators. It is thoughtthatthis inflammatoryresponsetoabnormalα-synwillperpetuateneuraldysfunctionthrough thereleaseofcytotoxiccompoundsthatoverwhelmtheDAcells, inevitably leadingtocelldeath. Given the range of pathological mechanisms involved in neurodegeneration seen in PD, astaxanthinseemstohaveauniquepotential for thetreatmentof thisdisorder.Manydiversebiological activitieshavebeendescribedintheliteraturethatareparticularrelevanttothatpathophysiologyofPD, aswellasnormalaging. Basedonthisknowledge, theinteractionofagingandparkinsoniansymptoms shouldberesponsivetotreatmentwithastaxanthin. Forexample,astaxanthinhasalsobeenimplicated inmodulatingmicroglial activity. Experimentsusingastaxanthin to treata transformedmicroglial cell line can reduce the expression of IL-6 and iNOS/NO invitro when exposed to an immune stimulussuchasLPS[65]. Theseresultswerecorroboratedbyotherstudiesusingagedanimalswhere astaxanthinreducedthereleaseofnitricoxide [56]. Thesemoleculesarereleased inhighamountsby activatedmicrogliaandareassociatedwithneuronaldamage;attenuating theoutputof inflammatory mediatorswithastaxanthinmayoffersomeneuroprotectionfromtheinflammatorycascadesoccurring in theSN. Someauthorshavereportedalterations inmitochondrial functionafterastaxanthin treatment. Althoughmostof these studieswereconducted invitro, this isofgreat interest to the treatmentof PD.Mitochondrialdysfunctionhasbeen implicated in theetiologyof thedisorderevidencedbythe commontoxins that induceParkinsonism.BothMPTPandrotenoneareusedtoproduceParkinson’s modelsbyselectively targetingmitochondria leading to thedeathofSNneurons.Multiplegenetic mutationsofproteinsinvolvedinmitochondrialdynamicshavebeenclearlylinkedtothedevelopment of familialParkinson’s. Furthermore, someof thesemitochondrialproteinsareassociatedwitha loss of functionwithage,andmaycontribute to the increased incidenceofdiagnosisover the lifespan. Furthermore, it has beendemonstrated recently thatmitochondria are a significant source of oxidativestressnotonly in theseDAneurons,butalso inadditionalnucleiknowntodegenerate in PD.For example, both the locus coeruleusandSNexpressL-type calciumchannels that allow for an extraneous calcium influx that taxes themitochondria [66,67]. Thepresence of these channels and their associated calcium burden has been proposed to be a common physiological feature that contributes to the cellular vulnerability for the brain regions affected inPD.Attenuating this mitochondrialderivedoxidativestress that results fromcalciumoverloadhas led to theuseofcalcium channel antagonists for the treatment of PD [68]. These dihydropyrdines, specifically israpidine, havebeenshowntobe tolerableandsafeamongPDpatientsarenowinPhase III clinical trial [69]. The success of these drugs lends support for the therapeutic use of AXT as well. There is substantialevidence tosuggest thatastaxanthinworksat the levelof themitochondria.Accordingto HPLCanalysisofcellular fractions,astaxanthinwill accumulate inmitochondria,andhas thecapacity 58