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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


system (CNS) is not sufcient to restore neurological function, but
The incidences of stroke and brain trauma have been estimated stimulation of the pathways involved could be a promising
in the US at 750,000 [1] and 1.5 million per year [2], respectively. approach. We briey summarize the endogenous mechanisms
Brain damage related to these cerebral pathologies represents a involved in this process and review some different potential
major cause of mortality, morbidity, cognitive impairment and therapies, which could improve this restorative mechanism.
learning disability. The loss of autonomy in public health is
dramatic with a median disability-adjusted life year (DALY) of 2. The birth of a new concept: adult neurogenesis
781 per 100,000 habitants [1]. A better understanding of the
mechanisms involved in brain damage is necessary to improve Whereas the dogma of a xed number of neurons in the brain
therapy. It is established that excitotoxicity, apoptosis, inamma- was accepted worldwide over one century ago [4], a revolutionary
tion and oxidative stress develop after stroke or brain trauma concept has been developed by Allen et al. [5]. The latter authors
[3]. Unfortunately, neuro-protective therapy focused on these rst described that some dividing cells persist in the postnatal
different mechanisms fails to improve functional recovery. cerebral nervous system (CNS) in rats. The adult brain continu-
Beyond this neurodegenerative step, a promising neuro- ously supplies new neurons to the olfactory bulb and hippocam-
restorative period has recently been discovered based on complex pus. With the development of new methods for labelling dividing
biochemical and micro-cellular mechanisms that develop in viable 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
* Corresponding author. Tel.: +33 4 92 03 33 00.
E-mail addresses: quintard.h@chu-nice.fr (H. Quintard), heurteaux@ipmc.cnrs.fr
subventricular zone of the lateral ventricle (SVZ) and the
(C. Heurteaux), ichai.c@chu-nice.fr (C. Ichai). subgranular zone (SGZ) of the hippocampal dentate gyrus (DG)
1
Tel.: +33 4 92 03 33 00. [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 begins earlier than neurogenesis, probably to provide an appro-
rst to describe this cell proliferation in the DG of the human brain. priate microenvironment for neurogenic progenitors. The increase
Cells from the SVZ that are nestin and glial brillary acidic in endothelial cells begins after 12 h to 21 days, depending on
protein (GFAP) immunoreactive radial glia-like cells, migrate species [37] and is mediated by vascular endothelial growth factor
along the rostral migratory stream to the olfactive bulb and (VEGF), a soluble factor secreted by vascular cells, up-regulated in
differentiate into granule and periglomerular neurons [15]. Adult brain injury. VEGF expression has been described in association
stem cell-generated progeny is essential for maintaining and with the proliferation of neural progenitor cells (NPC), increased
reorganizing the olfactory bulb [16]. Dividing cells are also outgrowth from cerebral cortical neurons, the survival of newborn
continuously generated from the SGZ and laterally migrate the cells [38] and the initiation of angiogenesis. A correlation between
short distance into the granule cell layer of the dentate gyrus and this angiogenesis step within the neuro-restorative mechanism
extend their axonal projection to the target CA3 region [17]. The framework and survival time has been described in several clinical
new synapse connections enhance long-term potentiation and studies [39,40]. Thus, VEGF, due to its crucial role in activation of
contribute to learning and memory functions [1821]. angiogenesis, could represent an interesting target for novel
therapy strategies.
3. Neurogenesis and vascular remodelling in brain injury Besides the vasculature, the vascular environment including
the endothelial cells, pericytes, outer vascular adventitial layer,
During brain injury, these mechanisms are amplied. Several soluble factors and extracellular matrix (ECM) appears to also be
studies have described that immature cells proliferate signicantly intimately linked to the behaviours of NPC and a regulator of
in niches after stroke or TBI [2224]. This occurs within the DG neurogenesis. Interestingly, the extracellular matrix acts as an
granular layer, where the newly generated cells differentiate into important regulator of proliferation, differentiation, migration and
mature DG granule neurons, form synapses and extend axons to neurite growth. In particular, laminin, metalloproteinases and
the CA3 regions 10 weeks after injury [25]. Depletion of this integrins (b8 integrin, N-Cadherin) may play a role in NPC
hippocampal neurogenesis is associated with impaired hippo- migration [41], but the ECM can also act as a trap for growth factors
campal-dependent learning [26,27] after injury. In reality, only to enhance neurogenesis and axonal sprouting [42]. Glial cells, and
a small percentage of cells differentiate into neurons [22]. particularly astrocytes, also create a microenvironment for
Neuronal differentiation depends on several proteins (Noggin, successful brain remodelling. In brain injury, they down-regulate
neurogenesin-1, Sox, Hes 6) that can modulate the endogenous secretion of proteoglycans, which modulate neuronal plasticity
bone morphogenetic protein (BMP) signalling involved in and growth.
development [2830]. Newborn cells are also encountered After injury, axonal sprouting is enhanced in the ipsi- and
directly near the lesion where they can persist at least 2 months contralesional pyramidal tract systems and depends on different
after injury. This represents only a fraction of precursors because mechanisms to regulate its expansion [43,44]. This axonal
most of them do not survive secondary to the inammatory remodelling depends on neurolaments (NFs), a neuron-specic
response in the microglia encountered during migration intermediate lament abundant in axons and dendrites [45]. In
[22,31]. The migration from niches to lesions has been described vitro data have demonstrated that the PI3/Akt pathway is involved
as developing along blood vessels [32,33], which underlines the in this axonal expansion [46]. This mechanism is thought to
extreme dependence of these newborn cells on the vasculature compensate axon loss in injured zones. Beside these interconnec-
system [32]. tions, transcallosal projections connecting the two motor cortices
The vasculature is activated after injury, followed by vascular have also been described [47]. This increased axonal density is
remodelling [34,35]. The latter includes angiogenesis, develop- maintained for at least 1 year after stroke [48]. Imaging procedures,
ment of new capillaries from vessels and vasculogenesis, such as functional MRI, are able to detect this reorganization in the
development of new vessels depending on endothelial progenitor brain [49].
cells moving from bone narrow to the lesions. Angiogenesis is a Synaptogenesis is also enhanced after brain injury in a
multistep process involving endothelial cell proliferation, migra- restorative way. Indeed, to restore loss of connections between
tion, tube formation, branching and anastomosis [36] (Fig. 2). It neurons after brain injury, the surviving neurons can develop new
H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245 241

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 seems to have benecial effects and more research is needed in this
ipsilateral hippocampus after ischemia, with loss of afferents to the area to reach any kind of conclusion. To our knowledge, no data are
CA1 structure, compensated by an increase in synaptogenesis [50]. available concerning the neural plasticity effects associated with
This brief overview underlined the extreme complexity of this osmotic therapies (such as mannitol and hypertonic saline).
phenomenon and the multiple pathways requiring research. The
improved understanding of neurogenesis, angiogenesis, and 5. Neuro-restorative therapy
neuronal plasticity mechanisms achieved over the last decade
have paved the way for experiments concerning new treatments 5.1. Bone mesenchymal stromal cells (MSC) [62]
that enhance neuro-regenerative pathways. We will now develop
an overview of some of the different therapies that have been To enhance the number of immature cells, implementation of
experimentally evaluated. bone mesenchymal stroma cells has been experimented in several
studies (Fig. 3). A mixed population of stem and progenitor cells
4. ICU therapies and neurogenesis can be isolated, and expanded in culture. Routes of administration
can be intravenous, intra-ventricular or intranasal. Local adminis-
Adequate control of intracranial pressure (ICP) is one of the main tration could prevent diffuse localization and potential toxic
therapeutic goals of managing critically ill neurologic patients. effects of MSCs. In a rat model of traumatic brain injury, an
Sedatives may reduce ICP by decreasing CMRO2, producing a intravenous administration of MSCs induces a migration of these
reduction in CBF, reducing cerebral blood volume, or by limiting the cells in the brain and a reduction of motor and neurological decit
number of agitation episodes. General anaesthetics are powerful [63,64]. An intracranial injection of MSCs near the brain lesion has
modulators of g-aminobutyric acid (GABA)-ergic and glutamatergic also been described as improving neurological outcomes [64]. In-
neurotransmission. In this context, these drugs could inuence deed, animals treated with MLCs tested with the rotarod technique
neurogenesis mechanisms. In healthy animals, Stratmann et al. [51] improve their scores 29 days after trauma. It seems that the results
described an immediate decrease in the number of proliferating are improved by MSCs cultured with neurotrophic factors such as
progenitors in the dentate gyrus of animals treated with Isourane, BDNF and NGF [65]. Neurogenesis, angiogenesis, synaptogenesis
with expression of an early neuronal marker in dentate gyrus and axonal remodelling have been discussed in an attempt to
progenitors; however, none of the above changes had an effect on explain the action of MSC [66] but recent data seems to conrm
the number of new neurons 4 weeks after anaesthesia. The effect of that MSCs do not directly differentiate into neuron cells, but
sedation on neurogenesis is not well studied in brain injured rather secrete factors that promote neurogenic and regenerative
patients, but Propofol has been described as limiting reparative processes [67]. Neuronal plasticity has also been enhanced with
processes in the early phase post-injury after a cortical impact MLCs [44]. Actually, the feasibility of this procedure has been
in animals [52] and ketamine has been described as improving assessed in two human studies with interesting results [68,69]. A
growing factors such as brain-derived neurotrophic factor (BDNF) paediatric study demonstrated a GOS improvement 180 days after
[53]. trauma in children treated intravenously with MLCs [68]. Similar
Hypothermia has been used to control the rise in ICP associated results are observed in an adult population receiving combined
with brain injury [54]. Cooling has been shown to differentially intravenous and near-lesion injection of MLCs during surgery after
affect neurogenesis in injured animals. In the developing brain, a trauma [69].
temperature of 30 8C decreased the number of proliferating cells in
the SGZ [55], whereas in other hypoxic conditions, hypothermia 5.2. Erythropoietin (EPO)
(33 8C) enhanced maturation of neuronal progenitor cells in the
striatum [56]. Neuronal connectivity, angiogenesis and gliogenesis EPO, an haematopoietic growth factor, stimulates proliferation
are stimulated by hypothermic conditions [5761]. Although the and differentiation of erythroid precursor cells and exerts
effect of hypothermia in brain regeneration is far from clear, it 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 just a single reduction of cholesterol and more in relation with a
increases in penumbra after experimental stroke in a model of focal lowering of isoprenoid complexes, derived from cholesterol in the
ischaemia [71]. Exogenous recombinant human erythropoietin mevalonate pathway, which is particularly present in the brain
(rhEPO) has been used in several studies to understand its [78]. Lipophilic statins seem to easily cross the blood brain barrier
mechanism of action. Beside its neuro-protective effect (anti- [79]. Depending on statin concentrations, their effects can vary
apoptotic, inhibition of exocytosis, inhibition of oxidative stress, from toxic to protective. Similar to rhEPO, statins have neuro-
inhibition of nitric oxide formation, action on blood brain barrier), protective (anti-apoptotic, anti-inammatory, increase in cerebral
rhEPO also promotes angiogenesis and the long-term restoration of blood ow. . .) and neuro-restorative effects. Synaptogenesis and
local cerebral blood ow (lCBF) [72]. Several studies conrmed its angiogenesis are also increased in an experimental study using a
neuro-restorative effect. Indeed, use of an antimitotic agent such as rat model of TBI associated with an increase in BDNF [80]. In a
Ara-C, can abolish the recovery observed after administration of model of experimental stroke in rat, Chen et al. dispense
rhEPO in animals suffering from traumatic brain injury [73]. Neuro- atorvastatin one day after injury and observe an activation of
proliferation in SVZ and migration of immature cells to lesions have neurogenesis and angiogenesis pathways [81]. They identied an
also been conrmed after rhEPO injection [74]. Moreover, rhEPO up- increase in VEGF and an activation of Pi3k/Akt pathways known to
regulates VEGF expression in the penumbra region 321 days after control synaptic plasticity. Analogous work carried out in TBI
focal ischemia [74]. Unfortunately, human studies are conducted at conrmed the effect of statin on neurogenesis, with an improve-
the early time of brain injury, explaining difculties in distinguish- ment in spatial learning at Day 31 after injury [82]. Improvement of
ing the neuro-protective and neuro-restorative actions of EPO. Two neurogenesis in the hippocampus and in perilesional zones has
prospective studies on the efciency of rhEPO against stroke report been conrmed in others studies [83]. Simvastatin and Pravastatin
controversial results. The rst one described an improvement in have the same effect as atorvastatin in traumatic and ischemic
neurological outcome one month after stroke, with no reduction of models [84,85]. A therapeutic association with MSC, based on
infarct size but a decrease in PS1OOB secretion in a small population enhancement of brain receptivity, has been proposed with
of patients treated with rhEPO for 3 days following the ischemic promising results [86]. However, though promising results are
injury [75]. A second study, with a larger number of patients, did not found in experimental data, clinical results are presently lacking.
nd similar results, with an increase in the number of side effects in
the rhEPO group [76]. Increases in thromboembolic complications 5.4. MLC 601 (NeuroAid) and MLC 901 (NurAid II)
due to blood viscosity and platelet activation, have been described
[77]. The EPO-ACR 2 (NCT00999583) study, testing the efciency of a MLC601 and its simplied formula MLC901, two components of
high dose of epoetin alpha at the early stage of cardiac arrest Traditional Chinese Medicine, which is used in China following
resuscitation, did not nd any improvement in neurological stroke [87], was recently described to be protective in rodent
outcome. The effect of early administration of low and high doses models of stroke and cardiac arrest [88,89]. It also enhances
of recombinant human Epo on long-term neurological outcomes is neurogenesis and stimulates BDNF expression in focal and global
also currently being investigated in a population of trauma patients ischemia [88,89]. A preclinical study on a brain trauma model is
(NCT00313716). currently ongoing. To date, the rst clinical trials involving MLC601
have been conducted in Asia on stroke patients. These trials, as well
5.3. Statins as clinical reports, have demonstrated a high level of safety and
efciency [90] in improving cerebral blood ow velocity and stroke
Initially developed to lower cholesterol levels, the discovery of rehabilitation, even when taken several months after stroke onset
additional statin effects on the brain have been described. The [87]. A multicentre, randomized, double-blind placebo-controlled
mechanism of action of statins appears to be more complex than study to investigate Chinese Medicine MLC601 Efcacy on Stroke
H. Quintard et al. / Anaesth Crit Care Pain Med 34 (2015) 239245 243

recovery (CHIMES) has been conducted in Asia. This study failed to patients found a positive treatment effect in a sub group of patients
conrm an enhancement in recovery in the general population receiving delayed and prolonged treatment compared to the
when the treatment was conducted early after stroke, but others. Pharmacodynamic knowledge is of major interest before
described promising results for later treatment and in reducing starting clinical studies. Development of markers specic to neuro-
the risk of vascular secondary events [91]. Investigation on the restorative phases could be helpful in this way.
delayed action of NeuroAid is ongoing. In a multicentre study During the last decade, progress in understanding brain damage
conducted in Australia and New Zealand, TBI patients experiencing physiopathology during stroke or traumatic brain injury has been
cognitive impairment after 2-3 months of a mild to moderate made. The concept of brain remodelling upset fundamental ideas
TBI are presently randomized to receive NeuroAid or Placebo concerning the neurologic system and opened new elds of
(BRAINS Study). research. Therapies currently under evaluation hold promising
results and could have a real prognostic impact in future years, but
5.5. Other treatments the translation of these therapies from the laboratory to the clinic
is still far from completion.
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 Disclosure of interest
[92]. Few data are available on this molecule in clinical practice. In
experimental studies, proliferation can be also modulated by The authors declare that they have no conicts of interest
different growth factor secretions (broblast growth factor-2 [FGF- concerning this article.
2], epidermal growth factor [EGF] [93], vascular endothelial
growth factor [VEGF], BDNF [94], Hes 1 and Notch [95]), estrogens Acknowledgements
[96], serotonin, norepinephrine, antidepressants, lithium [97],
corticosteroids [98]. These types of therapeutics have yet to be Authors thank Pr N. Bruder for his help in writing this review.
evaluated via clinical studies.
Immunosuppression alone or in combination with other
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