CellDeathPathways:aNovelTherapeuticApproachforNeuroscientistsG.Morris1,2&A.J.Walker2&M.Berk3,4,5,6&M.Maes2,7&B.K.Puri8Received:16August2017/Accepted:26September2017/Publishedonline:19October2017#TheAuthor(s)2017.ThisarticleisanopenaccesspublicationAbstractInthefirstpart,thefollowingmechanismsinvolvedindifferentformsofcelldeathareconsidered,withaviewtoidentifyingpotentialtherapeutictargets:tumournecrosisfac-torreceptors(TNFRs)andtheirengagementbytumournecro-sisfactor-alpha(TNF-α);poly[ADP-ribose]polymerase(PARP)-1cleavage;theapoptosissignallingkinase(ASK)-c-JunN-terminalkinase(JNK)axis;lysosomalpermeability;activationofprogrammednecroticcelldeath;oxidativestress,caspase-3inhibitionandparthanatos;activationofinflammasomesbyreactiveoxygenspeciesandthedevelop-mentofpyroptosis;oxidativestress,calciumdyshomeostasisandironinthedevelopmentoflysosomal-mediatednecrosisandlysosomalmembranepermeability;andoxidativestress,lipidperoxidation,irondyshomeostasisandferroptosis.Inthesecondpart,thereisaconsiderationoftheroleoflethalandsub-lethalactivationofthesepathwaysinthepathogenesisandpathophysiologyofneurodegenerativeandneuroprogressivedisorders,withparticularreferencetotheTNF-α-TNFRsignal-lingaxis;dysregulationofASK-1-JNKsignalling;prolongedorchronicPARP-1activation;theroleofpyroptosisandchron-icinflammasomeactivation;andtherolesoflysosomalpermeabilisation,necroptosisandferroptosis.Finally,itissug-gestedthat,inadditiontotargetingoxidativestressandinflam-matoryprocessesgenerally,neuropsychiatricdisordersmayre-spondtotherapeutictargetingofTNF-α,PARP-1,theNod-likereceptorNLRP3inflammasomeandthenecrosomalmolecularswitchreceptor-interactingproteinkinase-3,sincetheirwide-spreadactivationcandriveand/orexacerbateperipheralinflam-mationandneuroinflammationevenintheabsenceofcelldeath.Tothisend,theuseisproposedofacombinationofthetetracyclinederivativeminocyclineandN-acetylcysteineasadjunctivetreatmentforarangeofneuropsychiatricdisorders.KeywordsApoptosis.Necroptosis.Ferroptosis.N-acet...
