Anaesth Crit Care Pain Med 34 (2015) 239245

Review

Adult neurogenesis and brain remodelling after brain injury:

From bench to bedside?
Herve Quintard a,*, Catherine Heurteaux b, Carole Ichai a,1
a
Intensive Care Unit, CHU Nice, 4, rue Pierre-Devoluy, 06000 Nice, France
b
Institut de Pharmacologie Moleculaire et Cellulaire (CNRS), Universite de Sophia-Antipolis, 660, route des Lucioles, 06560 Valbonne, France

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Brain trauma and stroke cause important disabilities. The mechanisms involved are now well
Received 13 June 2014 described, but all therapeutics developed thus far for neuro-protection are currently unsuccessful at
Accepted 19 February 2015 improving neurologic prognosis. The recently studied neuro-restorative time following brain injury may
Available online 29 July 2015
point towards a promising therapeutic approach. The purpose of this paper is to explain the mechanisms
of this revolutionary concept, give an overview of related knowledge and discuss its transfer into clinical
Keywords: practice.
Neurogenesis
Data sources and synthesis: An overview of the neurogenesis concept using MEDLINE, EMBASE and
Vasculogenesis
Brain injury
CENTRAL databases was carried out in May 2014. The clinicaltrials.gov registry was used to search for
Brain trauma ongoing clinical trials in this domain.
Stroke Conclusion: The concept of brain remodelling upset fundamental ideas concerning the neurologic system
Neuro-restorative treatment and opened new elds 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.
2015 Societe francaise danesthesie et de reanimation (Sfar). Published by Elsevier Masson SAS. All
rights reserved.

1. Introduction tissue. This endogenous remodelling of the cerebral nervous

The incidences of stroke and brain trauma have been estimated
in the US at 750,000 [1] and 1.5 million per year [2], respectively.
Brain damage related to these cerebral pathologies represents a
major cause of mortality, morbidity, cognitive impairment and
learning disability. The loss of autonomy in public health is
dramatic with a median disability-adjusted life year (DALY) of
781 per 100,000 habitants [1]. A better understanding of the
mechanisms involved in brain damage is necessary to improve
therapy. It is established that excitotoxicity, apoptosis, inamma-
tion and oxidative stress develop after stroke or brain trauma
[3]. Unfortunately, neuro-protective therapy focused on these
different mechanisms fails to improve functional recovery.
Beyond this neurodegenerative step, a promising neuro-
restorative period has recently been discovered based on complex
biochemical and micro-cellular mechanisms that develop in viable
* 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.
system (CNS) is not sufcient to restore neurological function, but
stimulation of the pathways involved could be a promising
approach. We briey summarize the endogenous mechanisms
involved in this process and review some different potential
therapies, which could improve this restorative mechanism.
2. The birth of a new concept: adult neurogenesis
Whereas the dogma of a xed number of neurons in the brain
was accepted worldwide over one century ago [4], a revolutionary
concept has been developed by Allen et al. [5]. The latter authors
rst described that some dividing cells persist in the postnatal
cerebral 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 dividing
cells, Altman et al. conrmed these data and described different
cerebral localizations for these dividing cells [68] in animal
models. Adult neurogenesis persists in two principal regions: the
subventricular zone of the lateral ventricle (SVZ) and the
subgranular zone (SGZ) of the hippocampal dentate gyrus (DG)
[9] (Fig. 1). Recent data suggest neurogenesis is present also in the

http://dx.doi.org/10.1016/j.accpm.2015.02.008
2352-5568/ 2015 Societe francaise danesthesie et de reanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.
240 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
Fig. 1. Germinal niches in the adult rat brain.
hypothalamus and the cortex [1013]. Erikson et al. [14] were the
rst to describe this cell proliferation in the DG of the human brain.
Cells from the SVZ that are nestin and glial brillary acidic
protein (GFAP) immunoreactive radial glia-like cells, migrate
along the rostral migratory stream to the olfactive bulb and
differentiate into granule and periglomerular neurons [15]. Adult
stem cell-generated progeny is essential for maintaining and
reorganizing the olfactory bulb [16]. Dividing cells are also
continuously generated from the SGZ and laterally migrate the
short distance into the granule cell layer of the dentate gyrus and
extend their axonal projection to the target CA3 region [17]. The
new synapse connections enhance long-term potentiation and
contribute to learning and memory functions [1821].
3. Neurogenesis and vascular remodelling in brain injury
During brain injury, these mechanisms are amplied. Several
studies have described that immature cells proliferate signicantly
in niches after stroke or TBI [2224]. This occurs within the DG
granular layer, where the newly generated cells differentiate into
mature DG granule neurons, form synapses and extend axons to
the CA3 regions 10 weeks after injury [25]. Depletion of this
hippocampal neurogenesis is associated with impaired hippo-
campal-dependent learning [26,27] after injury. In reality, only
a small percentage of cells differentiate into neurons [22].
Neuronal differentiation depends on several proteins (Noggin,
neurogenesin-1, Sox, Hes 6) that can modulate the endogenous
bone morphogenetic protein (BMP) signalling involved in
development [2830]. Newborn cells are also encountered
directly near the lesion where they can persist at least 2 months
after injury. This represents only a fraction of precursors because
most of them do not survive secondary to the inammatory
response in the microglia encountered during migration
[22,31]. The migration from niches to lesions has been described
as developing along blood vessels [32,33], which underlines the
extreme dependence of these newborn cells on the vasculature
system [32].
The vasculature is activated after injury, followed by vascular
remodelling [34,35]. The latter includes angiogenesis, develop-
ment of new capillaries from vessels and vasculogenesis,
development of new vessels depending on endothelial progenitor
cells moving from bone narrow to the lesions. Angiogenesis is a
multistep process involving endothelial cell proliferation, migra-
tion, tube formation, branching and anastomosis [36] (Fig. 2). It
begins earlier than neurogenesis, probably to provide an appro-
priate microenvironment for neurogenic progenitors. The increase
in endothelial cells begins after 12 h to 21 days, depending on
species [37] and is mediated by vascular endothelial growth factor
(VEGF), a soluble factor secreted by vascular cells, up-regulated in
brain injury. VEGF expression has been described in association
with the proliferation of neural progenitor cells (NPC), increased
outgrowth from cerebral cortical neurons, the survival of newborn
cells [38] and the initiation of angiogenesis. A correlation between
this angiogenesis step within the neuro-restorative mechanism
framework and survival time has been described in several clinical
studies [39,40]. Thus, VEGF, due to its crucial role in activation of
angiogenesis, could represent an interesting target for novel
therapy strategies.
Besides the vasculature, the vascular environment including
the endothelial cells, pericytes, outer vascular adventitial layer,
soluble factors and extracellular matrix (ECM) appears to also be
intimately linked to the behaviours of NPC and a regulator of
neurogenesis. Interestingly, the extracellular matrix acts as an
important regulator of proliferation, differentiation, migration and
neurite growth. In particular, laminin, metalloproteinases and
integrins (b8 integrin, N-Cadherin) may play a role in NPC
migration [41], but the ECM can also act as a trap for growth factors
to enhance neurogenesis and axonal sprouting [42]. Glial cells, and
particularly astrocytes, also create a microenvironment for
successful brain remodelling. In brain injury, they down-regulate
secretion of proteoglycans, which modulate neuronal plasticity
and growth.
After injury, axonal sprouting is enhanced in the ipsi- and
contralesional pyramidal tract systems and depends on different
mechanisms to regulate its expansion [43,44]. This axonal
remodelling depends on neurolaments (NFs), a neuron-specic
intermediate lament abundant in axons and dendrites [45]. In
vitro data have demonstrated that the PI3/Akt pathway is involved
in this axonal expansion [46]. This mechanism is thought to
compensate axon loss in injured zones. Beside these interconnec-
tions, transcallosal projections connecting the two motor cortices
have also been described [47]. This increased axonal density is
maintained for at least 1 year after stroke [48]. Imaging procedures,
such as functional MRI, are able to detect this reorganization in the
brain [49].
Synaptogenesis is also enhanced after brain injury in a
restorative way. Indeed, to restore loss of connections between
neurons after brain injury, the surviving neurons can develop new
 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
Fig. 2. Vasculogenesis and angiogenesis cascade after brain injury. BDNF: brain-derived neurotrophic factor; VEGF: vascular endothelial growth factor.
synapses [50]. This has been described in the CA3 region of the
ipsilateral hippocampus after ischemia, with loss of afferents to the
CA1 structure, compensated by an increase in synaptogenesis [50].
This brief overview underlined the extreme complexity of this
phenomenon and the multiple pathways requiring research. The
improved understanding of neurogenesis, angiogenesis, and
neuronal plasticity mechanisms achieved over the last decade
have paved the way for experiments concerning new treatments
that enhance neuro-regenerative pathways. We will now develop
an overview of some of the different therapies that have been
experimentally evaluated.
4. ICU therapies and neurogenesis
Adequate control of intracranial pressure (ICP) is one of the main
therapeutic goals of managing critically ill neurologic patients.
Sedatives may reduce ICP by decreasing CMRO2, producing a
reduction in CBF, reducing cerebral blood volume, or by limiting the
number of agitation episodes. General anaesthetics are powerful
modulators of g-aminobutyric acid (GABA)-ergic and glutamatergic
neurotransmission. In this context, these drugs could inuence
neurogenesis mechanisms. In healthy animals, Stratmann et al. [51]
described an immediate decrease in the number of proliferating
progenitors in the dentate gyrus of animals treated with Isourane,
with expression of an early neuronal marker in dentate gyrus
progenitors; however, none of the above changes had an effect on
the number of new neurons 4 weeks after anaesthesia. The effect of
sedation on neurogenesis is not well studied in brain injured
patients, but Propofol has been described as limiting reparative
processes in the early phase post-injury after a cortical impact
in animals [52] and ketamine has been described as improving
growing factors such as brain-derived neurotrophic factor (BDNF)
[53].
Hypothermia has been used to control the rise in ICP associated
with brain injury [54]. Cooling has been shown to differentially
affect neurogenesis in injured animals. In the developing brain, a
temperature of 30 8C decreased the number of proliferating cells in
the SGZ [55], whereas in other hypoxic conditions, hypothermia
(33 8C) enhanced maturation of neuronal progenitor cells in the
striatum [56]. Neuronal connectivity, angiogenesis and gliogenesis
are stimulated by hypothermic conditions [5761]. Although the
effect of hypothermia in brain regeneration is far from clear, it
241
seems to have benecial effects and more research is needed in this
area to reach any kind of conclusion. To our knowledge, no data are
available concerning the neural plasticity effects associated with
osmotic 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 several
studies (Fig. 3). A mixed population of stem and progenitor cells
can be isolated, and expanded in culture. Routes of administration
can be intravenous, intra-ventricular or intranasal. Local adminis-
tration could prevent diffuse localization and potential toxic
effects of MSCs. In a rat model of traumatic brain injury, an
intravenous administration of MSCs induces a migration of these
cells in the brain and a reduction of motor and neurological decit
[63,64]. An intracranial injection of MSCs near the brain lesion has
also been described as improving neurological outcomes [64]. In-
deed, animals treated with MLCs tested with the rotarod technique
improve their scores 29 days after trauma. It seems that the results
are improved by MSCs cultured with neurotrophic factors such as
BDNF and NGF [65]. Neurogenesis, angiogenesis, synaptogenesis
and axonal remodelling have been discussed in an attempt to
explain the action of MSC [66] but recent data seems to conrm
that MSCs do not directly differentiate into neuron cells, but
rather secrete factors that promote neurogenic and regenerative
processes [67]. Neuronal plasticity has also been enhanced with
MLCs [44]. Actually, the feasibility of this procedure has been
assessed in two human studies with interesting results [68,69]. A
paediatric study demonstrated a GOS improvement 180 days after
trauma in children treated intravenously with MLCs [68]. Similar
results are observed in an adult population receiving combined
intravenous and near-lesion injection of MLCs during surgery after
trauma [69].
5.2. Erythropoietin (EPO)
EPO, an haematopoietic growth factor, stimulates proliferation
and differentiation of erythroid precursor cells and exerts
neurotrophic activity in the central nervous system. First described
242 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
Fig. 3. Erythropoietin (EPO) and statin actions on neurogenesis processes.
by Masuda and al. [70], EPO levels increase after brain injury. It
increases in penumbra after experimental stroke in a model of focal
ischaemia [71]. Exogenous recombinant human erythropoietin
(rhEPO) has been used in several studies to understand its
mechanism 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 ow (lCBF) [72]. Several studies conrmed its
neuro-restorative effect. Indeed, use of an antimitotic agent such as
Ara-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 have
also been conrmed after rhEPO injection [74]. Moreover, rhEPO up-
regulates VEGF expression in the penumbra region 321 days after
focal ischemia [74]. Unfortunately, human studies are conducted at
the early time of brain injury, explaining difculties in distinguish-
ing the neuro-protective and neuro-restorative actions of EPO. Two
prospective studies on the efciency of rhEPO against stroke report
controversial results. The rst one described an improvement in
neurological outcome one month after stroke, with no reduction of
infarct size but a decrease in PS1OOB secretion in a small population
of patients treated with rhEPO for 3 days following the ischemic
injury [75]. A second study, with a larger number of patients, did not
nd similar results, with an increase in the number of side effects in
the rhEPO group [76]. Increases in thromboembolic complications
due to blood viscosity and platelet activation, have been described
[77]. The EPO-ACR 2 (NCT00999583) study, testing the efciency of a
high dose of epoetin alpha at the early stage of cardiac arrest
resuscitation, did not nd any improvement in neurological
outcome. The effect of early administration of low and high doses
of recombinant human Epo on long-term neurological outcomes is
also 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. The
mechanism of action of statins appears to be more complex than
just a single reduction of cholesterol and more in relation with a
lowering of isoprenoid complexes, derived from cholesterol in the
mevalonate 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 vary
from toxic to protective. Similar to rhEPO, statins have neuro-
protective (anti-apoptotic, anti-inammatory, increase in cerebral
blood ow. . .) and neuro-restorative effects. Synaptogenesis and
angiogenesis are also increased in an experimental study using a
rat model of TBI associated with an increase in BDNF [80]. In a
model of experimental stroke in rat, Chen et al. dispense
atorvastatin one day after injury and observe an activation of
neurogenesis and angiogenesis pathways [81]. They identied an
increase in VEGF and an activation of Pi3k/Akt pathways known to
control synaptic plasticity. Analogous work carried out in TBI
conrmed 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 has
been conrmed in others studies [83]. Simvastatin and Pravastatin
have the same effect as atorvastatin in traumatic and ischemic
models [84,85]. A therapeutic association with MSC, based on
enhancement of brain receptivity, has been proposed with
promising results [86]. However, though promising results are
found in experimental data, clinical results are presently lacking.
5.4. MLC 601 (NeuroAid) and MLC 901 (NurAid II)
MLC601 and its simplied formula MLC901, two components of
Traditional Chinese Medicine, which is used in China following
stroke [87], was recently described to be protective in rodent
models of stroke and cardiac arrest [88,89]. It also enhances
neurogenesis and stimulates BDNF expression in focal and global
ischemia [88,89]. A preclinical study on a brain trauma model is
currently ongoing. To date, the rst clinical trials involving MLC601
have been conducted in Asia on stroke patients. These trials, as well
as clinical reports, have demonstrated a high level of safety and
efciency [90] in improving cerebral blood ow velocity and stroke
rehabilitation, even when taken several months after stroke onset
[87]. A multicentre, randomized, double-blind placebo-controlled
study to investigate Chinese Medicine MLC601 Efcacy on Stroke
 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
recovery (CHIMES) has been conducted in Asia. This study failed to
conrm an enhancement in recovery in the general population
when the treatment was conducted early after stroke, but
described promising results for later treatment and in reducing
the risk of vascular secondary events [91]. Investigation on the
delayed action of NeuroAid is ongoing. In a multicentre study
conducted in Australia and New Zealand, TBI patients experiencing
cognitive impairment after 2-3 months of a mild to moderate
TBI are presently randomized to receive NeuroAid or Placebo
(BRAINS Study).
5.5. Other treatments
Thymosin Beta 4 (TB4) is a 43 amino acid polypeptide that has a
G-actinsequestration function. It promotes neurite proliferation
and angiogenesis with functional recovery in animal models
[92]. Few data are available on this molecule in clinical practice. In
experimental studies, proliferation can be also modulated by
different growth factor secretions (broblast growth factor-2 [FGF-
2], epidermal growth factor [EGF] [93], vascular endothelial
growth factor [VEGF], BDNF [94], Hes 1 and Notch [95]), estrogens
[96], serotonin, norepinephrine, antidepressants, lithium [97],
corticosteroids [98]. These types of therapeutics have yet to be
evaluated via clinical studies.
Immunosuppression alone or in combination with other
therapy could potentially play a central role in the development
of successful neural regenerative therapies. Indeed, in an
experimental study, Cyclosporine A treatment leads to increased
numbers of endogenous neural precursor cells and regenerated
cortical tissue containing neural stem cells with an enhancement
of functional recovery [99]. No clinical data are presently available
in this setting.
In addition to these pharmacological therapeutics, sensory
motor stimulation seems to have, by the way of Apolipoprotein E
(Apo E) modulation, a direct impact on regeneration near the injury
zone [100]. Exercise enhances the production of new DG neurons,
with an increase of BDNF levels [101]. The positive effects of
exercise are likely the result of a combination of factors including
neurogenesis, modications in synaptic plasticity or spine density.
An enriched environment has effects on synaptic plasticity, such as
increased dendritic complexity of young granule neurons [102],
enhanced arborization of cortical neurons [103], elevated synap-
tophysin levels in the hippocampus and cortex [104] and
angiogenesis that may mediate the benecial effects on learning
and memory.
Transcranial magnetic stimulation (TMS) has been described to
promote axonal regeneration after injury [105], but the mecha-
nisms involved in this effect are not well identied.
These promising results in experimental studies have to be
mitigated in different ways because humans have many char-
acteristics that differ from rodents, such as brain size, lesion
heterogeneity (particularly in brain trauma), genetics, etc.
Moreover, patients often present risk factors associated with
brain injury, whereas rodents present no comorbidities. For
example, recent data demonstrated that the efcacy of neuro-
restorative therapy might be compromised in ageing animals with
vascular risk factors [106,107]. Another problem encountered is
disentangling the neuro-protective and neuro-regenerative effects
of most of the proposed treatments, such as EPO or MLC901. The
direct action of neuro-restorative pathways is consequently
difcult to conrm. Finally, the therapeutic window seems to be
an important tool requiring investigation. As neuro-restorative
pathways are secondary to neuro-protection, early treatment after
injury may lead to the conclusion of an absence of effect while the
same treatment administered later may have a real one [108]. For
example, the CHIMES study carried out with MLC901 in stroke
243
patients found a positive treatment effect in a sub group of patients
receiving delayed and prolonged treatment compared to the
others. Pharmacodynamic knowledge is of major interest before
starting clinical studies. Development of markers specic to neuro-
restorative phases could be helpful in this way.
During the last decade, progress in understanding brain damage
physiopathology during stroke or traumatic brain injury has been
made. The concept of brain remodelling upset fundamental ideas
concerning the neurologic system and opened new elds 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.
Disclosure of interest
The authors declare that they have no conicts of interest
concerning this article.
Acknowledgements
Authors thank Pr N. Bruder for his help in writing this review.
References
[1] Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and
mortality: estimates from monitoring, surveillance, and modelling. Lancet
Neurol 2009;8:34554.
[2] Faul M, Wald MM, Rutland-Brown W, Sullivent EE, Sattin RW. Using a cost-
benet analysis to estimate outcomes of a clinical treatment guideline:
testing the Brain Trauma Foundation guidelines for the treatment of severe
traumatic brain injury. J Trauma 2007;63:12718.
[3] Conti AC, Raghupathi R, Trojanowski JQ, McIntosh TK. Experimental brain
injury induces regionally distinct apoptosis during the acute and delayed
post-traumatic period. J Neurosci 1998;18:566372.
[4] Cajal RY. Degeneration and regeneration of the nervous system. Oxford
University Press; 1913.
[5] Allen E. The cessation of mitosis in the central nervous system of albino rat. J
Comp Neurol 1912;19:54768.
[6] Altman J. Autoradiographic and histological studies of postnatal neurogen-
esis. IV. Cell proliferation and migration in the anterior forebrain, with special
reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol
1969;137:43357.
[7] Altman J, Das GD. Autoradiographic and histological evidence of postnatal
hippocampal neurogenesis in rats. J Comp Neurol 1965;124:31935.
[8] Altman J, Das GD. Autoradiographic and histological studies of postnatal
neurogenesis. I. A longitudinal investigation of the kinetics, migration and
transformation of cells incorporating tritiated thymidine in neonate rats,
with special reference to postnatal neurogenesis in some brain regions. J
Comp Neurol 1966;126:33789.
[9] Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult
neurogenesis. Cell 2008;132:64560.
[10] Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex
of adult mice. Nature 2000;405:9515.
[11] Gould E. How widespread is adult neurogenesis in mammals? Nat Rev
Neurosci 2007;8:4818.
[12] Bonfanti L, Ponti G. Adult mammalian neurogenesis and the New Zealand
white rabbit. Vet J 2008;175:31031.
[13] Migaud M, Batailler M, Segura S, Duittoz A, Franceschini I, Pillon D. Emerging
new sites for adult neurogenesis in the mammalian brain: a comparative
study between the hypothalamus and the classical neurogenic zones. Eur J
Neurosci 2014;32:204252.
[14] Eriksson PS, Perlieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson
DA, et al. Neurogenesis in the adult human hippocampus. Nat Med
1998;4:13137.
[15] Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult
mammalian brain. Science 1994;264:11458.
[16] Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, et al.
Roles of continuous neurogenesis in the structural and functional integrity of
the adult forebrain. Nat Neurosci 2008;11:115361.
[17] Tanaka R, Yamashiro K, Mochizuki H, Cho N, Onodera M, Mizuno Y, et al.
Neurogenesis after transient global ischemia in the adult hippocampus
visualized by improved retroviral vector. Stroke 2004;35:14549.
[18] van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional
neurogenesis in the adult hippocampus. Nature 2002;415:10304.
[19] Bendel O, Bueters T, von Euler M, Ove Ogren S, Sandin J, von Euler G.
Reappearance of hippocampal CA1 neurons after ischemia is associated with
244 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
recovery of learning and memory. J Cereb Blood Flow Metab 2005;25:
158695.
[20] Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the
adult is involved in the formation of trace memories. Nature 2001;410:3726.
[21] Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in
hippocampal function. Physiology (Bethesda) 2004;19:25361.
[22] Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement
from endogenous precursors in the adult brain after stroke. Nat Med
2002;8:96370.
[23] Gu W, Brannstrom T, Wester P. Cortical neurogenesis in adult rats after
reversible photothrombotic stroke. J Cereb Blood Flow Metab 2000;20:
116673.
[24] Jiang W, Gu W, Brannstrom T, Rosqvist R, Wester P. Cortical neurogenesis in
adult rats after transient middle cerebral artery occlusion. Stroke 2001;
32:12017.
[25] Sun D, McGinn MJ, Zhou Z, Harvey HB, Bullock MR, Colello RJ. Anatomical
integration of newly generated dentate granule neurons following traumatic
brain injury in adult rats and its association to cognitive recovery. Exp Neurol
2007;204:26472.
[26] Wang S, Kee N, Preston E, Wojtowicz JM. Electrophysiological correlates of
neural plasticity compensating for ischemia-induced damage in the hippo-
campus. Exp Brain Res 2005;165:25060.
[27] Jin K, Wang X, Xie L, Mao XO, Greenberg DA. Transgenic ablation of dou-
blecortin-expressing cells suppresses adult neurogenesis and worsens stroke
outcome in mice. Proc Natl Acad Sci U S A 2010;107:79938.
[28] Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-
Buylla A. Noggin antagonizes BMP signaling to create a niche for adult
neurogenesis. Neuron 2000;28:71326.
[29] Ueki T, Tanaka M, Yamashita K, Mikawa S, Qiu Z, Maragakis NJ, et al. A novel
secretory factor. Neurogenesin-1, provides neurogenic environmental cues
for neural stem cells in the adult hippocampus. J Neurosci 2003;23:1173240.
[30] Jhas S, Ciura S, Belanger-Jasmin S, Dong Z, Llamosas E, Theriault FM, et al.
Hes6 inhibits astrocyte differentiation and promotes neurogenesis through
different mechanisms. J Neurosci 2006;26:110617.
[31] Ekdahl CT, Kokaia Z, Lindvall O. Brain inammation and adult neurogenesis:
the dual role of microglia. Neuroscience 2009;158:10219.
[32] Zhang RL, Chopp M, Gregg SR, Toh Y, Roberts C, Letourneau Y, et al. Patterns
and dynamics of subventricular zone neuroblast migration in the ischemic
striatum of the adult mouse. J Cereb Blood Flow Metab 2009;29:124050.
[33] Kernie SG, Erwin TM, Parada LF. Brain remodeling due to neuronal and
astrocytic proliferation after controlled cortical injury in mice. J Neurosci
Res 2001;66:31726.
[34] Sawada M, Matsumoto M, Sawamoto K. Vascular regulation of adult neuro-
genesis under physiological and pathological conditions. Front Neurosci
2014;8:53.
[35] Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature 2005;
438:9549.
[36] Risau W. Mechanisms of angiogenesis. Nature 1997;386:6714.
[37] Jin X, Bookstein R, Wills K, Avanzini J, Tsai V, LaFace D, et al. Evaluation of
endostatin antiangiogenesis gene therapy in vitro and in vivo. Cancer Gene
Ther 2001;8:9829.
[38] Lee C, Agoston DV. Vascular endothelial growth factor is involved in mediat-
ing increased de novo hippocampal neurogenesis in response to traumatic
brain injury. J Neurotrauma 2010;27:54153.
[39] Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Some remarks on the
growth-rate and angiogenesis of microvessels in ischemic stroke. Morpho-
metric and immunocytochemical studies. Patol Pol 1993;44:2039.
[40] Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in
patients with cerebral ischemic stroke. Stroke 1994;25:17948.
[41] Shen J, Xie L, Mao X, Zhou Y, Zhan R, Greenberg DA, et al. Neurogenesis after
primary intracerebral hemorrhage in adult human brain. J Cereb Blood Flow
Metab 2008;28:14608.
[42] Kerever A, Schnack J, Vellinga D, Ichikawa N, Moon C, Arikawa-Hirasawa E,
et al. Novel extracellular matrix structures in the neural stem cell niche
capture the neurogenic factor broblast growth factor 2 from the extracel-
lular milieu. Stem Cells 2007;25:214657.
[43] Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci
2006;7:61727.
[44] Liu Z, Li Y, Zhang X, Savant-Bhonsale S, Chopp M. Contralesional axonal
remodeling of the corticospinal system in adult rats after stroke and bone
marrow stromal cell treatment. Stroke 2008;39:25717.
[45] Li S, Overman JJ, Katsman D, Kozlov SV, Donnelly CJ, Twiss JL, et al. An age-
related sprouting transcriptome provides molecular control of axonal sprout-
ing after stroke. Nat Neurosci 2010;13:1496504.
[46] Ueno Y, Chopp M, Zhang L, Buller B, Liu Z, Lehman NL, et al. Axonal outgrowth
and dendritic plasticity in the cortical peri-infarct area after experimental
stroke. Stroke 2012;43:22218.
[47] Liu Z, Li Y, Zhang RL, Cui Y, Chopp M. Bone marrow stromal cells promote
skilled motor recovery and enhance contralesional axonal connections after
ischemic stroke in adult mice. Stroke 2011;42:7404.
[48] Shen LH, Xin H, Li Y, Zhang RL, Cui Y, Zhang L, et al. Endogenous tissue
plasminogen activator mediates bone marrow stromal cell-induced neurite
remodeling after stroke in mice. Stroke 2011;42:45964.
[49] Grefkes C, Nowak DA, Eickhoff SB, Dafotakis M, Kust J, Karbe H, et al. Cortical
connectivity after subcortical stroke assessed with functional magnetic
resonance imaging. Ann Neurol 2008;63:23646.
[50] Scheff SW, Price DA, Hicks RR, Baldwin SA, Robinson S, Brackney C. Synapto-
genesis in the hippocampal CA1 eld following traumatic brain injury. J
Neurotrauma 2005;22:71932.
[51] Stratmann G, Sall JW, May LD, Bell JS, Magnusson KR, Rau V, et al. Isourane
differentially affects neurogenesis and long-term neurocognitive function in
60-day-old and 7-day-old rats. Anesthesiology 2009;110:83448.
[52] Thal SC, Timaru-Kast R, Wilde F, Merk P, Johnson F, Frauenknecht K, et al.
Propofol impairs neurogenesis and neurologic recovery and increases mor-
tality rate in adult rats after traumatic brain injury. Crit Care Med 2014;
42:12941.
[53] Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA
receptor blockade at rest triggers rapid behavioural antidepressant
responses. Nature 2011;475:915.
[54] Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL. Marked
protection by moderate hypothermia after experimental traumatic brain
injury. J Cereb Blood Flow Metab 1991;11:11421.
[55] Kanagawa T, Fukuda H, Tsubouchi H, Komoto Y, Hayashi S, Fukui O, et al. A
decrease of cell proliferation by hypothermia in the hippocampus of the
neonatal rat. Brain Res 2006;1111:3640.
[56] Xiong M, Cheng GQ, Ma SM, Yang Y, Shao XM, Zhou WH. Post-ischemic
hypothermia promotes generation of neural cells and reduces apoptosis by
Bcl-2 in the striatum of neonatal rat brain. Neurochem Int 2011;58:62533.
[57] Feng JF, Zhang KM, Jiang JY, Gao GY, Fu X, Liang YM. Effect of therapeutic mild
hypothermia on the genomics of the hippocampus after moderate traumatic
brain injury in rats. Neurosurgery 2010;67:73042.
[58] Xie YC, Li CY, Li T, Nie DY, Ye F. Effect of mild hypothermia on angiogenesis in
rats with focal cerebral ischemia. Neurosci Lett 2007;422:8790.
[59] Kao CH, Chio CC, Lin MT, Yeh CH. Body cooling ameliorating spinal cord injury
may be neurogenesis-, anti-inammation- and angiogenesis-associated in
rats. J Trauma 2011;70:88593.
[60] Kuo JR, Lo CJ, Chang CP, Lin HJ, Lin MT, Chio CC. Brain cooling-stimulated
angiogenesis and neurogenesis attenuated traumatic brain injury in rats. J
Trauma 2010;69:146772.
[61] Imada S, Yamamoto M, Tanaka K, Seiwa C, Watanabe K, Kamei Y, et al.
Hypothermia-induced increase of oligodendrocyte precursor cells: possible
involvement of plasmalemmal voltage-dependent anion channel 1. J Neu-
rosci Res 2010;88:345766.
[62] Liu S, Li C, Xing Y, Tao F. Effect of transplantation of human embryonic stem
cell-derived neural progenitor cells on adult neurogenesis in aged hippo-
campus. Am J Stem Cells 2014;3:216. eCollection 2014.
[63] Lu D, Li Y, Wang L, Chen J, Mahmood A, Chopp M. Intraarterial administration
of marrow stromal cells in a rat model of traumatic brain injury. J Neuro-
trauma 2001;18:8139.
[64] Mahmood A, Lu D, Yi L, Chen JL, Chopp M. Intracranial bone marrow
transplantation after traumatic brain injury improving functional outcome
in adult rats. J Neurosurg 2001;94:58995.
[65] Mahmood A, Lu D, Wang L, Chopp M. Intracerebral transplantation of marrow
stromal cells cultured with neurotrophic factors promotes functional recov-
ery in adult rats subjected to traumatic brain injury. J Neurotrauma 2002;
19:160917.
[66] Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet
Neurol 2002;1:92100.
[67] van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Nasal administration of
stem cells: a promising novel route to treat neonatal ischemic brain damage.
Pediatr Res 2010;68:41922.
[68] Cox Jr CS, Baumgartner JE, Harting MT, Worth LL, Walker PA, Shah SK, et al.
Autologous bone marrow mononuclear cell therapy for severe traumatic
brain injury in children. Neurosurgery 2011;68:588600.
[69] Zhang ZX, Guan LX, Zhang K, Zhang Q, Dai LJ. A combined procedure to deliver
autologous mesenchymal stromal cells to patients with traumatic brain
injury. Cytotherapy 2008;10:1349.
[70] Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas Jr F, Tabira T, et al.
Functional erythropoietin receptor of the cells with neural characteristics.
Comparison with receptor properties of erythroid cells. J Biol Chem 1993;
268:1120816.
[71] Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, et al.
A potential role for erythropoietin in focal permanent cerebral ischemia in
mice. J Cereb Blood Flow Metab 1999;19:64351.
[72] Li Y, Lu ZY, Ogle M, Wei L. Erythropoietin prevents blood brain barrier damage
induced by focal cerebral ischemia in mice. Neurochem Res 2007;32:
213241.
[73] Zhang Y, Chopp M, Mahmood A, Meng Y, Qu C, Xiong Y. Impact of inhibition of
erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the
hippocampus on restoration of spatial learning after traumatic brain injury.
Exp Neurol 2012;235:33644.
[74] Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with
erythropoietin enhances neurogenesis and angiogenesis and improves neu-
rological function in rats. Stroke 2004;35:17327.
[75] Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M,
et al. Erythropoietin therapy for acute stroke is both safe and benecial. Mol
Med 2002;8:495505.
[76] Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg
K, et al. Recombinant human erythropoietin in the treatment of acute
ischemic stroke. Stroke 2009;40:e64756.
[77] Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efcacy and
safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:96576.
 H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245
[78] Ostrowski SM, Wilkinson BL, Golde TE, Landreth G. Statins reduce amyloid-
beta production through inhibition of protein isoprenylation. J Biol Chem
2007;282:2683244.
[79] Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, et al.
Chronic administration of statins alters multiple gene expression patterns in
mouse cerebral cortex. J Pharmacol Exp Ther 2005;312:78693.
[80] Lu D, Goussev A, Chen J, Pannu P, Li Y, Mahmood A, et al. Atorvastatin reduces
neurological decit and increases synaptogenesis, angiogenesis, and neuro-
nal survival in rats subjected to traumatic brain injury. J Neurotrauma
2004;21:2132.
[81] Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, et al. Statins induce
angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol
2003;53:74351.
[82] Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, et al. Statins increase
neurogenesis in the dentate gyrus, reduce delayed neuronal death in the
hippocampal CA3 region, and improve spatial learning in rat after traumatic
brain injury. J Neurotrauma 2007;24:113246.
[83] Wu H, Jiang H, Lu D, Qu C, Xiong Y, Zhou D, et al. Induction of angiogenesis and
modulation of vascular endothelial growth factor receptor-2 by simvastatin
after traumatic brain injury. Neurosurgery 2014;68:136371 [discussion 1371].
[84] Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, et al. Simvastatin-mediated
upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and
increase of neurogenesis are associated with therapeutic improvement after
traumatic brain injury. J Neurotrauma 2008;25:1309.
[85] Zheng Z, Chen B. Effects of Pravastatin on neuroprotection and neurogenesis
after cerebral ischemia in rats. Neurosci Bull 2007;23:18997.
[86] Cui X, Chopp M, Shehadah A, Zacharek A, Kuzmin-Nichols N, Sanberg CD, et al.
Therapeutic benet of treatment of stroke with simvastatin and human
umbilical cord blood cells: neurogenesis, synaptic plasticity, and axon
growth. Cell Transplant 2012;21:84556.
[87] Chen C, Venketasubramanian N, Gan RN, Lambert C, Picard D, Chan BP, et al.
Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke
recovery. Stroke 2009;40:85963.
[88] Quintard H, Borsotto M, Veyssiere J, Gandin C, Labbal F, Widmann C, et al.
MLC901, a Traditional Chinese Medicine protects the brain against global
ischemia. Neuropharmacology 2011;61:62231.
[89] Heurteaux C, Gandin C, Borsotto M, Widmann C, Brau F, Lhuillier M, et al.
Neuroprotective and neuroproliferative activities of NeuroAid (MLC601,
MLC901), a Chinese medicine, in vitro and in vivo. Neuropharmacology
2010;58:9871001.
[90] Young SH, Zhao Y, Koh A, Singh R, Chan BP, Chang HM, et al. Safety prole of
MLC601 (Neuroaid) in acute ischemic stroke patients: a Singaporean sub-
study of the Chinese medicine neuroaid efcacy on stroke recovery study.
Cerebrovasc Dis 2010;30:16.
[91] Chen Y, Sun FY. Age-related decrease of striatal neurogenesis is associated
with apoptosis of neural precursors and newborn neurons in rat brain after
ischemia. Brain Res 2007;1166:919.
[92] Xiong Y, Mahmood A, Meng Y, Zhang Y, Zhang ZG, Morris DC, et al. Treatment
of traumatic brain injury with thymosin beta in rats. J Neurosurg 2011;
114:10215.
245
[93] Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A. EGF
converts transit-amplifying neurogenic precursors in the adult brain into
multipotent stem cells. Neuron 2002;36:102134.
[94] Leventhal C, Rai S, Rai D, Shahar A, Goldman SA. Endothelial trophic
support of neuronal production and recruitment from the adult mammalian
subependyma. Mol Cell Neurosci 1999;13:45064.
[95] Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial
cells stimulate self-renewal and expand neurogenesis of neural stem cells.
Science 2004;304:133840.
[96] Galea LA, Spritzer MD, Barker JM, Pawluski JL. Gonadal hormone modula-
tion of hippocampal neurogenesis in the adult. Hippocampus 2006;16:
22532.
[97] Boku S, Nakagawa S, Koyama T. Glucocorticoids and lithium in adult hippo-
campal neurogenesis. Vitam Horm 2010;82:42131.
[98] Kempermann G. Regulation of adult hippocampal neurogenesis - implica-
tions for novel theories of major depression. Bipolar Disord 2002;4:
1733.
[99] Erlandsson A, Lin CH, Yu F, Morshead CM. Immunosuppression promotes
endogenous neural stem and progenitor cell migration and tissue regenera-
tion after ischemic injury. Exp Neurol 2011;230:4857.
[100] Ruscher K, Johannesson E, Brugiere E, Erickson A, Rickhag M, Wieloch T.
Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes
and attenuates inammation of the peri-infarct tissue after experimental
stroke. J Cereb Blood Flow Metab 2009;29:1796805.
[101] Kobilo T, Liu QR, Gandhi K, Mughal M, Shaham Y, van Praag H. Running is the
neurogenic and neurotrophic stimulus in environmental enrichment. Learn
Mem 2011;18:6059.
[102] Beauquis J, Roig P, De Nicola AF, Saravia F. Short-term environmental
enrichment enhances adult neurogenesis, vascular network and dendritic
complexity in the hippocampus of type 1 diabetic mice. PLoS One 2010;
5:e.13993.
[103] Ip EY, Giza CC, Griesbach GS, Hovda DA. Effects of enriched environment and
uid percussion injury on dendritic arborization within the cerebral cortex of
the developing rat. J Neurotrauma 2002;19:57385.
[104] Lambert TJ, Fernandez SM, Frick KM. Different types of environmental
enrichment have discrepant effects on spatial memory and synaptophysin
levels in female mice. Neurobiol Learn Mem 2005;83:20616.
[105] Gordon T, Brushart TM, Amirjani N, Chan KM. The potential of electrical
stimulation to promote functional recovery after peripheral nerve injury
comparisons between rats and humans. Acta Neurochir Suppl 2007;
100:311.
[106] Chen J, Ye X, Yan T, Zhang C, Yang XP, Cui X, et al. Adverse effects of bone
marrow stromal cell treatment of stroke in diabetic rats. Stroke 2011;
42:35518.
[107] Duan J, Murohara T, Ikeda H, Sasaki K, Shintani S, Akita T, et al. Hyperho-
mocysteinemia impairs angiogenesis in response to hindlimb ischemia.
Arterioscler Thromb Vasc Biol 2000;20:257985.
[108] Kilic E, ElAli A, Kilic U, Guo Z, Ugur M, Uslu U, et al. Role of Nogo-A in neuronal
survival in the reperfused ischemic brain. J Cereb Blood Flow Metab
2010;30:96984.