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Adult neurogenesis and brain remodelling after brain injury: From bench to bedside?

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The concept of brain remodelling upset fundamental ideas concerning the neurologic system and opened new fields of research. Therapies currently under evaluation hold promising results and could have a real prognostic impact in future years, but the translation of these therapies from the laboratory to the clinic is still far from completion
  Review Adult   neurogenesis   and   brain   remodellingafter   brain   injury:From   bench   to   bedside? Herve´ Quintard a, *,   CatherineHeurteaux b ,CaroleIchai a,1 a Intensive   Care   Unit,   CHU    Nice,   4,   rue   Pierre-De´ voluy,   06000   Nice,   France b Institut    de   Pharmacologie   Mole´ culaire   et    Cellulaire   (CNRS),   Universite´  de   Sophia-Antipolis,   660,   route   des   Lucioles,   06560   Valbonne,   France 1.   Introduction The   incidences   of    stroke   and   brain   trauma   have   been   estimatedin   the   US   at   750,000   [1]   and   1.5   million   per   year   [2],respectively.Brain   damage   related   to   these   cerebral   pathologies   represents   amajor   cause   of    mortality,   morbidity,   cognitive   impairment   andlearning   disability.   The   loss   of    autonomy   in   public   health   isdramatic   with   a   median   disability-adjusted   life   year   (DALY)   of 781   per   100,000   habitants   [1].   A   better   understanding   of    themechanisms   involved   in   brain   damage   is   necessary   to   improvetherapy.   It   is   established   that   excitotoxicity,   apoptosis,   inflamma-tion   and   oxidative   stress   develop   after   stroke   or   brain   trauma[3].   Unfortunately,   neuro-protective   therapy   focused   on   thesedifferent   mechanisms   fails   to   improve   functional   recovery.Beyond   this   neurodegenerative   step,   a   promising   neuro-restorative   period   has   recently   been   discovered   based   on   complexbiochemical   and   micro-cellular   mechanisms   that   develop   in   viabletissue.   This   endogenous   remodelling   of    the   cerebral   nervoussystem   (CNS)   is   not   sufficient   to   restore   neurological   function,   butstimulation   of    the   pathways   involved   could   be   a   promisingapproach.   Webriefly   summarize   the   endogenous   mechanismsinvolved   in   this   process   and   review   some   different   potentialtherapies,   which   could   improve   this   restorative   mechanism. 2.    The   birth   of    a   new   concept:   adult   neurogenesis Whereas   the   dogma   of    a   fixed   number   of    neurons   in   the   brainwas   accepted   worldwide   over   one   century   ago   [4],a   revolutionaryconcept   has   been   developed   by   Allen   et   al.   [5].The   latter   authorsfirst   described   that   some   dividing   cells   persist   in   the   postnatalcerebral   nervous   system   (CNS)   in   rats.   The   adult   brain   continu-ously   supplies   new   neurons   to   the   olfactory   bulb   and   hippocam-pus.   With   the   development   of    new   methods   for   labelling   dividingcells,   Altman   et   al.   confirmed   these   data   and   described   differentcerebral   localizations   for   these   dividing   cells   [6–8]   in   animalmodels.   Adult   neurogenesis   persists   in   two   principal   regions:   thesubventricular   zone   of    the   lateral   ventricle   (SVZ)   and   thesubgranular   zone   (SGZ)   of    the   hippocampal   dentate   gyrus   (DG)[9]   (Fig.   1).Recent   data   suggest   neurogenesis   is   present   also   in   the Anaesth   Crit   Care   Pain   Med34   (2015)   239–245 A   R    T   I   C   L    E   I   N   F   O  Articlehistory: Received   13    June   2014Accepted   19   February   2015Available   online   29    July   2015 Keywords: NeurogenesisVasculogenesisBrain   injuryBrain   traumaStrokeNeuro-restorative   treatment A   B   S   T   R    A   C   T Objective:   Braintraumaandstrokecauseimportantdisabilities.Themechanismsinvolvedarenowwelldescribed,butalltherapeuticsdevelopedthusfarforneuro-protectionarecurrentlyunsuccessfulatimprovingneurologicprognosis.Therecentlystudiedneuro-restorativetimefollowingbraininjurymaypointtowardsapromisingtherapeuticapproach.Thepurposeofthispaperistoexplainthemechanismsofthisrevolutionaryconcept,giveanoverviewofrelatedknowledgeanddiscussitstransferintoclinicalpractice. Datasourcesandsynthesis: AnoverviewoftheneurogenesisconceptusingMEDLINE,EMBASEandCENTRALdatabaseswascarriedoutinMay2014.Theclinicaltrials.govregistrywasusedtosearchforongoingclinicaltrialsinthisdomain. Conclusion: Theconceptofbrainremodellingupsetfundamentalideasconcerningtheneurologicsystemandopenednewfieldsofresearch.Therapiescurrentlyunderevaluationholdpromisingresultsandcouldhavearealprognosticimpactinfutureyears,butthetranslationofthesetherapiesfromthelaboratorytotheclinicisstillfarfromcompletion.  2015Socie´te´ franc ¸ aised’anesthe´sieetdere´animation(Sfar).PublishedbyElsevierMassonSAS.Allrightsreserved. * Corresponding   author.   Tel.:   +33   4   92   03   33   00. E-mail   addresses:   quintard.h@chu-nice.fr   (H.   Quintard),   heurteaux@ipmc.cnrs.fr(C.   Heurteaux),   ichai.c@chu-nice.fr   (C.   Ichai). 1 Tel.:   +33   4   92   03   33   00.http://dx.doi.org/10.1016/j.accpm.2015.02.0082352-5568/  2015   Socie´te´ franc ¸ aise   d’anesthe´sie   et   de   re´animation   (Sfar).   Published   by   Elsevier   Masson   SAS.   All   rights   reserved.  hypothalamus   and   the   cortex   [10–13].Erikson   et   al.   [14]   were   thefirst   to   describe   this   cell   proliferation   in   the   DG   of    the   human   brain.Cells   from   the   SVZ   that   are   nestin   –   and   glial   fibrillary   acidicprotein   (GFAP)   –   immunoreactive   radial   glia-like   cells,   migratealong   the   rostral   migratory   stream   to   the   olfactive   bulb   anddifferentiate   into   granule   and   periglomerular   neurons   [15].   Adultstem   cell-generated   progeny   is   essential   for   maintaining   andreorganizing   the   olfactory   bulb   [16].   Dividing   cells   are   alsocontinuously   generated   from   the   SGZ   and   laterally   migrate   theshort   distance   into   the   granule   cell   layer   of    the   dentate   gyrus   andextend   their   axonal   projection   to   the   target   CA3   region   [17].   Thenew   synapse   connections   enhance   long-term   potentiation   andcontribute   to   learning   and   memory   functions   [18–21]. 3.   Neurogenesis   and    vascular    remodelling    in   brain   injury  During   brain   injury,   these   mechanisms   are   amplified.   Severalstudies   have   described   that   immature   cells   proliferate   significantlyin   niches   after   stroke   or   TBI   [22–24].This   occurs   within   the   DGgranular   layer,   where   the   newly   generated   cells   differentiate   intomature   DG   granule   neurons,   form   synapses   and   extend   axons   tothe   CA3   regions   10   weeks   after   injury   [25].   Depletion   of    thishippocampalneurogenesis   is   associatedwith   impairedhippo-campal-dependentlearning[26,27]after   injury.In   reality,onlya   smallpercentageof    cells   differentiate   intoneurons[22].Neuronaldifferentiationdependson   severalproteins   (Noggin,neurogenesin-1,Sox,Hes6)thatcan   modulate   the   endogenousbonemorphogenetic   protein   (BMP)signallinginvolvedindevelopment   [28–30].   Newborncells   arealso   encountereddirectly   near   the   lesion   where   they   can   persistat   least   2   monthsafterinjury.   This   represents   onlya   fraction   of    precursorsbecausemost   of    themdo   notsurvive   secondary   totheinflammatoryresponsein   themicroglia   encounteredduringmigration[22,31].   Themigrationfrom   niches   to   lesionshasbeen   describedas   developing   alongblood   vessels   [32,33],which   underlinestheextremedependence   of    thesenewborncells   on   the   vasculaturesystem[32].The   vasculature   is   activated   after   injury,   followed   by   vascularremodelling   [34,35].   The   latter   includes   angiogenesis,   develop-ment   of    new   capillaries   from   vessels   and   vasculogenesis,development   of    new   vessels   depending   on   endothelial   progenitorcells   moving   from   bone   narrow   to   the   lesions.   Angiogenesis   is   amultistep   process   involving   endothelial   cell   proliferation,   migra-tion,   tube   formation,   branching   and   anastomosis   [36]   (Fig.   2).Itbegins   earlier   than   neurogenesis,   probably   to   provide   an   appro-priate   microenvironment   for   neurogenic   progenitors.   The   increasein   endothelial   cells   begins   after   12   h   to   21   days,   depending   onspecies   [37]   and   is   mediated   by   vascular   endothelial   growth   factor(VEGF),   a   soluble   factor   secreted   by   vascular   cells,   up-regulated   inbrain   injury.   VEGF   expression   has   been   described   in   associationwith   the   proliferation   of    neural   progenitor   cells   (NPC),   increasedoutgrowth   from   cerebral   cortical   neurons,   the   survival   of    newborncells   [38]   and   the   initiation   of    angiogenesis.   A   correlation   betweenthis   angiogenesis   step   within   the   neuro-restorative   mechanismframework   and   survival   time   has   been   described   in   several   clinicalstudies   [39,40].   Thus,   VEGF,   due   to   its   crucial   role   in   activation   of angiogenesis,   could   represent   an   interesting   target   for   noveltherapy   strategies.Besides   the   vasculature,   the   vascular   environment   includingthe   endothelial   cells,   pericytes,   outer   vascular   adventitial   layer,soluble   factors   and   extracellular   matrix   (ECM)   appears   to   also   beintimately   linked   to   the   behaviours   of    NPC   and   a   regulator   of neurogenesis.   Interestingly,   the   extracellular   matrix   acts   as   animportant   regulator   of    proliferation,   differentiation,   migration   andneurite   growth.   In   particular,   laminin,   metalloproteinases   andintegrins   ( b 8   integrin,   N-Cadherin)   may   play   a   role   in   NPCmigration   [41],but   the   ECM   can   also   act   as   a   trap   for   growth   factorsto   enhance   neurogenesis   and   axonal   sprouting   [42].   Glial   cells,   andparticularly   astrocytes,   also   create   a   microenvironment   forsuccessful   brain   remodelling.   In   brain   injury,   they   down-regulatesecretion   of    proteoglycans,   which   modulate   neuronal   plasticityand   growth.After   injury,   axonal   sprouting   is   enhanced   in   the   ipsi-   andcontralesional   pyramidal   tract   systems   and   depends   on   differentmechanisms   to   regulate   its   expansion   [43,44].This   axonalremodelling   depends   on   neurofilaments   (NFs),   a   neuron-specificintermediate   filament   abundant   in   axons   and   dendrites   [45].   Invitro   data   have   demonstrated   that   the   PI3/Akt   pathway   is   involvedin   this   axonal   expansion   [46].   This   mechanism   is   thought   tocompensate   axon   loss   in   injured   zones.   Beside   these   interconnec-tions,   transcallosal   projections   connecting   the   two   motor   corticeshave   also   been   described   [47].   This   increased   axonal   density   ismaintained   for   at   least   1   year   after   stroke   [48].   Imaging   procedures,such   as   functional   MRI,   are   able   to   detect   this   reorganization   in   thebrain   [49].Synaptogenesis   is   also   enhanced   after   brain   injury   in   arestorative   way.   Indeed,   to   restore   loss   of    connections   betweenneurons   after   brain   injury,   the   surviving   neurons   can   develop   new Fig.   1.   Germinal   niches   in   the   adult   rat   brain. H.   Quintard   et    al.    /     Anaesth   Crit    Care   Pain   Med34   (2015)    239–245 240  synapses   [50].   This   has   been   described   in   the   CA3   region   of    theipsilateral   hippocampus   after   ischemia,   with   loss   of    afferents   to   theCA1   structure,   compensated   by   an   increase   in   synaptogenesis   [50].This   brief    overview   underlined   the   extreme   complexity   of    thisphenomenon   and   the   multiple   pathways   requiring   research.   Theimproved   understanding   of    neurogenesis,   angiogenesis,   andneuronal   plasticity   mechanisms   achieved   over   the   last   decadehave   paved   the   way   for   experiments   concerning   new   treatmentsthat   enhance   neuro-regenerative   pathways.   We   will   now   developan   overview   of    some   of    the   different   therapies   that   have   beenexperimentally   evaluated. 4.   ICU   therapies   and   neurogenesis Adequate   control   of    intracranial   pressure   (ICP)   is   one   of    the   maintherapeutic   goals   of    managing   critically   ill   neurologic   patients.Sedatives   may   reduce   ICP   by   decreasing   CMRO 2 ,   producing   areduction   in   CBF,   reducing   cerebral   blood   volume,   or   by   limiting   thenumber   of    agitation   episodes.   General   anaesthetics   arepowerfulmodulators   of    g -aminobutyric   acid   (GABA)-ergic   and   glutamatergicneurotransmission.   In   this   context,   these   drugs   could   influenceneurogenesis   mechanisms.   In   healthy   animals,   Stratmann   et   al.[51]described   an   immediate   decrease   in   the   number   of    proliferatingprogenitors   in   the   dentate   gyrus   of    animals   treated   with   Isoflurane,with   expression   of    an   early   neuronal   marker   in   dentate   gyrusprogenitors;   however,   none   of    the   above   changes   had   an   effect   onthe   number   of    new   neurons   4   weeks   after   anaesthesia.   The   effect   of sedation   on   neurogenesis   is   not   well   studied   in   brain   injuredpatients,   but   Propofol   has   been   described   as   limiting   reparativeprocesses   in   the   early   phase   post-injury   after   a   cortical   impactin   animals   [52]   and   ketamine   has   been   described   as   improvinggrowing   factors   such   as   brain-derived   neurotrophic   factor   (BDNF)[53].Hypothermia   has   been   used   to   control   the   rise   in   ICP   associatedwith   brain   injury   [54].   Cooling   has   been   shown   to   differentiallyaffect   neurogenesis   in   injured   animals.   In   the   developing   brain,   atemperature   of    30   8 C   decreased   the   number   of    proliferating   cells   inthe   SGZ   [55],whereas   in   other   hypoxic   conditions,   hypothermia(33   8 C)   enhanced   maturation   of    neuronal   progenitor   cells   in   thestriatum   [56].   Neuronal   connectivity,   angiogenesis   and   gliogenesisare   stimulated   by   hypothermic   conditions   [57–61].   Although   theeffect   of    hypothermia   in   brain   regeneration   is   far   from   clear,   itseems   to   have   beneficial   effects   and   more   research   is   needed   in   thisarea   to   reach   any   kind   of    conclusion.   To   our   knowledge,   no   data   areavailable   concerning   the   neural   plasticity   effects   associated   withosmotic   therapies   (such   as   mannitol   and   hypertonic   saline). 5.   Neuro-restorative   therapy  5.1.   Bone   mesenchymal   stromal   cells   (MSC)   [62] To   enhance   the   number   of    immature   cells,   implementation   of bone   mesenchymal   stroma   cells   has   been   experimented   in   severalstudies   (Fig.   3).A   mixed   population   of    stem   and   progenitor   cellscan   be   isolated,   and   expanded   in   culture.   Routes   of    administrationcan   be   intravenous,   intra-ventricular   or   intranasal.   Local   adminis-tration   could   prevent   diffuse   localization   and   potential   toxiceffects   of    MSCs.   In   a   rat   model   of    traumatic   brain   injury,   anintravenous   administration   of    MSCs   induces   a   migration   of    thesecells   in   the   brain   and   a   reduction   of    motor   and   neurological   deficit[63,64].An   intracranial   injection   of    MSCs   near   the   brain   lesion   hasalso   been   described   as   improving   neurological   outcomes   [64].   In-deed,   animals   treated   with   MLCs   tested   with   the   rotarod   techniqueimprove   their   scores   29   days   after   trauma.   It   seems   that   the   resultsare   improved   by   MSCs   cultured   with   neurotrophic   factors   such   asBDNF   and   NGF   [65].   Neurogenesis,   angiogenesis,   synaptogenesisand   axonal   remodelling   have   been   discussed   in   an   attempt   toexplain   the   action   of    MSC   [66]   but   recent   data   seems   to   confirmthat   MSCs   do   not   directly   differentiate   into   neuron   cells,   butrather   secrete   factors   that   promote   neurogenic   and   regenerativeprocesses   [67].Neuronal   plasticity   has   also   been   enhanced   withMLCs   [44].Actually,   the   feasibility   of    this   procedure   has   beenassessed   in   two   human   studies   with   interesting   results   [68,69].Apaediatric   study   demonstrated   a   GOS   improvement   180   days   aftertrauma   in   children   treated   intravenously   with   MLCs   [68].Similarresults   are   observed   in   an   adult   population   receiving   combinedintravenous   and   near-lesion   injection   of    MLCs   during   surgery   aftertrauma   [69]. 5.2.   Erythropoietin   (EPO) EPO,   an   haematopoietic   growth   factor,   stimulates   proliferationand   differentiation   of    erythroid   precursor   cells   and   exertsneurotrophic   activity   in   the   central   nervous   system.   First   described Fig.   2.   Vasculogenesis   and   angiogenesis   cascade   after   brain   injury.   BDNF:   brain-derived   neurotrophic   factor;   VEGF:   vascular   endothelial   growth   factor. H.   Quintard   et    al.    /     Anaesth   Crit    Care   Pain   Med    34   (2015)    239–245   241  by   Masuda   and   al.[70],EPO   levelsincrease   after   brain   injury.   Itincreases   in   penumbra   after   experimental   stroke   in   a   model   of    focalischaemia   [71].   Exogenous   recombinant   human   erythropoietin(rhEPO)   has   been   used   in   severalstudies   to   understand   itsmechanism   of    action.   Beside   its   neuro-protective   effect   (anti-apoptotic,   inhibition   of    exocytosis,   inhibition   of    oxidative   stress,inhibition   of    nitric   oxide   formation,   action   on   blood   brain   barrier),rhEPO   also   promotes   angiogenesis   and   the   long-term   restoration   of local   cerebral   blood   flow   (lCBF)   [72].Several   studies   confirmed   itsneuro-restorative   effect.   Indeed,   use   of    an   antimitotic   agent   such   asAra-C,   can   abolish   the   recovery   observed   after   administration   of rhEPO   in   animals   suffering   from   traumatic   brain   injury   [73].   Neuro-proliferation   in   SVZ   and   migration   of    immature   cells   to   lesions   havealso   been   confirmed   after   rhEPO   injection   [74].   Moreover,   rhEPO   up-regulates   VEGF   expression   in   the   penumbra   region   3–21   days   afterfocal   ischemia   [74].   Unfortunately,   human   studies   are   conducted   atthe   early   time   of    brain   injury,   explaining   difficulties   in   distinguish-ing   the   neuro-protective   and   neuro-restorative   actions   of    EPO.   Twoprospective   studies   on   the   efficiency   of    rhEPO   against   stroke   reportcontroversial   results.The   first   one   described   an   improvement   inneurological   outcome   one   month   after   stroke,   with   no   reduction   of infarct   size   but   a   decrease   in   PS1OOB   secretion   in   a   smallpopulationof    patients   treated   with   rhEPO   for   3   days   following   the   ischemicinjury   [75].   A   second   study,   with   a   larger   number   of    patients,   did   notfind   similar   results,   with   an   increase   in   the   number   of    side   effects   inthe   rhEPO   group   [76].   Increases   in   thromboembolic   complicationsdue   to   blood   viscosity   and   plateletactivation,   have   been   described[77].   The   EPO-ACR    2   (NCT00999583)   study,   testing   the   efficiency   of    ahigh   dose   of    epoetin   alpha   at   the   early   stageof    cardiac   arrestresuscitation,   did   not   find   any   improvement   in   neurologicaloutcome.   The   effect   of    early   administration   of    low   and   high   dosesof    recombinant   human   Epo   on   long-term   neurological   outcomes   isalso   currently   being   investigated   in   a   population   of    trauma   patients(NCT00313716). 5.3.   Statins Initially   developed   to   lower   cholesterol   levels,   the   discovery   of additional   statin   effects   on   the   brain   have   been   described.   Themechanism   of    action   of    statins   appears   to   be   more   complex   than just   a   single   reduction   of    cholesterol   and   more   in   relation   with   alowering   of    isoprenoid   complexes,   derived   from   cholesterol   in   themevalonate   pathway,   which   is   particularly   present   in   the   brain[78].   Lipophilic   statins   seem   to   easily   cross   the   blood   brain   barrier[79].   Depending   on   statin   concentrations,   their   effects   can   varyfrom   toxic   to   protective.   Similar   to   rhEPO,   statins   have   neuro-protective   (anti-apoptotic,   anti-inflammatory,   increase   in   cerebralblood   flow .   .   . )   and   neuro-restorative   effects.   Synaptogenesis   andangiogenesis   are   also   increased   in   an   experimental   study   using   arat   model   of    TBI   associated   with   an   increase   in   BDNF   [80].   In   amodel   of    experimental   stroke   in   rat,   Chen   et   al.   dispenseatorvastatin   one   day   after   injury   and   observe   an   activation   of neurogenesis   and   angiogenesis   pathways   [81].They   identified   anincrease   in   VEGF   and   an   activation   of    Pi3k/Akt   pathways   known   tocontrol   synaptic   plasticity.   Analogous   work   carried   out   in   TBIconfirmed   the   effect   of    statin   on   neurogenesis,   with   an   improve-ment   in   spatial   learning   at   Day   31   after   injury   [82].Improvement   of neurogenesis   in   the   hippocampus   and   in   perilesional   zones   hasbeen   confirmed   in   others   studies   [83].Simvastatin   and   Pravastatinhave   the   same   effect   as   atorvastatin   in   traumatic   and   ischemicmodels   [84,85].A   therapeutic   association   with   MSC,   based   onenhancement   of    brain   receptivity,   has   been   proposed   withpromising   results   [86].   However,   though   promising   results   arefound   in   experimental   data,   clinical   results   are   presently   lacking. 5.4.   MLC    601   (NeuroAid)   and   MLC    901   (NurAid   II) MLC601   and   its   simplified   formula   MLC901,   two   components   of Traditional   Chinese   Medicine,   which   is   used   in   China   followingstroke   [87],was   recently   described   to   be   protective   in   rodentmodels   of    stroke   and   cardiac   arrest   [88,89].It   also   enhancesneurogenesis   and   stimulates   BDNF   expression   in   focal   and   globalischemia   [88,89].A   preclinical   study   on   a   brain   trauma   model   iscurrently   ongoing.   To   date,   the   first   clinical   trials   involving   MLC601have   been   conducted   in   Asia   on   stroke   patients.   These   trials,   as   wellas   clinical   reports,   have   demonstrated   a   high   level   of    safety   andefficiency   [90]   in   improving   cerebral   blood   flow   velocity   and   strokerehabilitation,   even   when   taken   several   months   after   stroke   onset[87].   A   multicentre,   randomized,   double-blind   placebo-controlledstudy   to   investigate   Chinese   Medicine   MLC601   Efficacy   on   Stroke Fig.   3.   Erythropoietin   (EPO)   and   statin   actions   on   neurogenesis   processes. H.   Quintard   et    al.    /     Anaesth   Crit    Care   Pain   Med34   (2015)    239–245 242
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