The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development
Abstract: Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.
Abdipranoto A, Wu S, Stayte S, Vissel B. The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development. CNS & Neurological Disorders - Drug Targets, 2008, 7, 187-210.
INTRODUCTION
Neurodegenerative diseases such as Parkinson’s disease,
Alzheimer’s disease, or Amyotrophic Lateral Sclerosis
(ALS), are characterized by a loss of neurons in particular
regions of the nervous system. It is believed that this nerve
cell loss underlies the subsequent decline in cognitive or
motor function that patients experience in these diseases. A
range of mutant genes and environmental toxins have been
implicated in the cause of neurodegenerative diseases, but
the mechanisms remain largely unknown. Nevertheless, cur-
rent therapeutic strategies have focused on slowing cell loss
by antagonizing processes that have been implicated in the
degenerative process.
The recent discovery of neurogenesis in the adult nervous
system has profound implications for our understanding of
brain function and pathology. Neurogenesis refers to the
process by which new neurons are generated in the nervous
system. The discovery of adult neurogenesis raises the pos-
sibility that the nervous system has an intrinsic capacity for
repair. Perhaps more controversially, it also raises the ques-
tion as to whether impaired or failed neurogenesis may con-
tribute to the decline in neurodegenerative diseases. Cer-
tainly evidence suggests that neurogenesis is impaired in
neurodegenerative diseases such as Parkinson’s, Alzheimer’s
and ALS [1-4]. And, because neurogenesis is enhanced fol-
lowing stroke [5-7], the emerging question is whether this
may underlie some of the recovery that is observed in pa-
tients following a stroke.
This review proposes that the successful development of
new therapeutics for neurodegenerative diseases will depend
on understanding neurogenesis. Indeed, as we will discuss
below, literature data suggests that many of the processes
implicated in degeneration are equally important in the re-
generative process. Thus, many drugs, designed to block
degeneration by antagonizing these processes, potentially
also impair neurogenesis, making them unlikely to be suc-
cessful in the clinical setting. In support of this argument
many of the drugs that successfully entered into the clinic
have in fact rarely been found to impair neurogenesis and
indeed in some cases appear to stimulate neurogenesis. Even
more importantly, evidence is now mounting that stimulating
neurogenesis by various means can bring about functional
recovery in animal models of neurodegenerative diseases.
Thus, a key aim of this review is to suggest that drugs that
enhance neuroregeneration may offer hope for therapy in
neurodegenerative diseases.
To build our case we will first review neurogenesis in
general terms, before highlighting the antidepressants as an
example of a clinically practised strategy - albeit not by de-
sign - to combat a neurological disorder by enhancing neu-
rogenesis. We will then discuss neuroinflammation to dem-
onstrate the emerging link between inflammation, neuro-
genesis and neurodegenerative diseases, before discussing
literature on selected neurodegenerative diseases in more
detail. We will describe the therapeutic strategies in use and
in scope for these neurodegenerative diseases and summarize
their effects on neurogenesis, where this is known. Before
finishing the review with a short discussion of the limitations
of animal models in neurodegenerative diseases, we will
highlight the role of selected ion channels in neurodegenera-
tive diseases and neurogenesis, and review their suitability as
therapeutic targets.
NEUROGENESIS IN THE ADULT CNS IS A FUNCTIONALLY SIGNIFICANT PROCESS
This review emphasises that the study of neurogenesis in
the adult central nervous system (CNS) is important to un-
derstand the actions of current therapeutics and for develop-
ment of future drugs against neurodegenerative diseases. It
thus seems appropriate to first discuss neurogenesis in more
general terms.
Neurogenesis is the process by which new neurons are
formed from populations of neural stem or progenitor cells
residing in discrete regions of the CNS [8-14]. Neurogenesis
occurs in four main stages. Firstly, the stem or progenitor
cells proliferate; secondly, they migrate into areas of the
CNS; where thirdly, they differentiate into the specific neu-
ronal cell type. The fourth and final stage during neurogene-
sis is the integration of these newly formed neuronal cell
types into the pre-existing circuitry. All of these processes
play an important role in neurogenesis and contribute to the
success of regenerating CNS tissue both in normal and dis-
ease states.
Adult neural stem/progenitor cells reside in at least three
main areas of the brain, in the anterior part of the subven-
tricular zone (SVZ) along the walls of the lateral ventricles
[13, 15, 16], in the hippocampus in the subgranular zone
(SGZ) of the dentate gyrus and along the posterior periven-
tricular area (pPV), an extension of the SVZ [17-32].
Studies show that neural stem/progenitor cells exhibit
proliferative capacity [25, 33-35]. In vitro and in vivo studies
have shown that adult neural stem/progenitor cells differen-
tiate mainly into neurons with a proportion differentiating
into glial cells [18, 20, 32, 36]. These newly generated neu-
rons displayed the morphology of typical neurons and ex-
pressed the cell surface markers PSA-NCAM, -III tubulin,
MAP2a, MAP2b and NeuN [18, 20, 32, 36]. They also dis-
played the electrophysiological properties typical of neurons
and made synaptic connections to host neurons and vice
versa [18, 20, 32, 36].
It was shown in vitro and in vivo that newly generated
neurons derived from the adult hippocampus exhibited func-
tional properties typical for neurons in the hippocampal for-
mation. Song and colleagues in 2002 [30] showed that adult
neural stem/progenitor cells differentiated into neurons that
firstly, exhibited the correct neuronal polarity with the for-
mation of dendrites and axons; secondly, expressed the ma-
ture neuronal markers; thirdly, formed synapses with pri-
mary hippocampal neurons in a co-culture system; and
lastly, displayed electrophysiological properties indistin-
guishable from mature neurons [30]. These in vitro studies
were supported by studies conducted in vivo by van Praag
and colleagues (2002) [32] and Shors and colleagues (2001)
[37]. Furthermore, on a behavioral level, it has been sug-
gested that neurogenesis in the adult CNS may be important
in processes such as memory and learning [27, 32, 37-40].
This postulated functional significance of adult neuro-
genesis for memory and learning, for example, may have
direct consequences for the etiology of some neurological
disorders. In fact, numerous studies increasingly point to the
idea that depression might be a case in point for this hy-
pothesis.
ANTIDEPRESSANTS INFLUENCE NEUROGENESIS
During the past decade, a series of reports indicated that
major depression is frequently associated with significant
atrophy within the hippocampus, which can persist for sev-
eral years after remission from depression episodes [41]. In
congruence with this observation, both a reduction in hippo-
campal volume and a decrease in neurogenesis have been
reported in subordinate tree shrews subjected to social inter-
action stress [41-43]. The hypothesis is that depression and
declining neurogenesis in the hippocampus formation is
causally connected [44].
Antidepressant treatment can increase neural plasticity,
promote de-novo adult neurogenesis, block stress-induced
decrease of neurogenesis and upregulate the cyclic AMP-
CREB cascade with proliferative effects [45]. Ablation of
hippocampal neurogenesis renders antidepressants inactive
in behavioural paradigms for antidepressant responses and
anxiety-like behaviours in mice [46, 47]. However, ablating
neurogenesis in mice does not evoke an increase in depres-
sion or anxiety like behaviours indicating that adult-born
neurons in hippocampal physiology may be involved in anti-
depressant therapy rather than in the pathogenesis of depres-
sion [46-49]. The only study to date in humans did not detect
a difference in proliferation of stem cells in the hippocampus
of depressed patients compared to normal subjects [49, 50].
The implications of this for understanding the role of neuro-
genesis in depression is yet to be resolved.
Among the mechanisms by which antidepressants may
exert their effects is by increasing cell proliferation in order
to reverse or offset the deleterious effects of stress on the
brain [51]. It has been shown that long-term antidepressant
therapy is needed to increase hippocampal cell proliferation
and reverse the stress and depression-induced decreases in
neurogenesis and hippocampal volume, respectively [41,
51]. The mechanism through which antidepressant therapy
increases hippocampal cell proliferation may be through the
upregulation of brain derived neurotrophic factor (BDNF)
[51, 52].
Multiple classes of antidepressants have been shown to
increase hippocampal neurogenesis such as selective sero-
tonin reuptake inhibitors (SSRIs), noradrenaline reuptake
inhibitors (NRI), monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants, lithium, thyroxine, electroconvul-
sive therapy (ECT) and exercise [53]. One antidepressant
therapy that has been used in models of neurodegenerative
diseases is fluoxetine. Fluoxetine treatment has been shown
to not only reverse learned helplessness but has also been
shown to restore normal neurogenesis [53, 54].
In summary, there is increasing evidence that the benefi-
cial action of several commonly used antidepressants does
not only depend on their originally described mechanism of
action, but is also, at least partially, due to the stimulation of
adult neurogenesis. Thus, it is reasonable to assume that al-
tered neurogenesis may be involved in other neurological
disorders, and that stimulation of neurogenesis might have
beneficial effects in such conditions. We will start to explore
this line of thought further by reviewing the emerging link
between neurogenesis and CNS inflammation that is increas-
ingly implicated in the pathology of neurodegenerative dis-
eases.
THE EFFECT OF CNS INFLAMMATION ON NEUROGENESIS AND NEURODEGENERATIVE DISEASES
The CNS has been traditionally thought of as an immune-
privileged system [55, 56]. However, it is known that the
healthy adult CNS contains a population of cells called micro-
glia. Microglia are inflammatory cells that are ubiquitously
distributed throughout the nervous system. Microglia respond
to pathological events such as injury or disease by becoming
activated, releasing pro-inflammatory mediators and phagocy-
tosing cellular debris, microorganisms or foreign bodies [57,
58].
CNS inflammation has been shown to play a pivotal role in
the disease characteristics of Alzheimer’s disease [59, 60],
Parkinson’s disease [61-63], stroke [64-69], and ALS [70-75].
Studies of post-mortem brain tissue from patients as well as
animal models of Parkinson’s disease [76-85], Alzheimer’s
disease [86-92] ischemia/stroke [64-69] and ALS [70-75]
showed increased number of activated microglia and upregu-
lated expression of pro-inflammatory cytokines compared to
control tissue.
Likewise, studies using animal models of these neurode-
generative diseases show that stimulation of inflammation
contributed to the pathology in these models following deposi-
tion of -synuclein in a Parkinson’s disease model [93] and
formation of A plaques and neurofibrillary tangles in Alz-
heimer’s disease models [94-97]. Furthermore, inhibition of
harmful inflammatory processes through non-steroidal anti-
inflammatory drugs (NSAIDs) or antibodies directed against
pro-inflammatory cytokines in animal models of Parkinson’s
disease [98-103], Alzheimer’s disease [96, 97, 104, 105], and
ischemia [66, 67] have resulted in attenuation of neuronal loss,
delay of onset and progression of disease and in some cases
functional recovery.
Recent studies have demonstrated that inflammation in the
CNS regulates neurogenesis, making it possible that altered
neurogenesis is at least partially responsible for the effects
described above [36, 106-109]. Activation of microglia by
systemic inflammation [108] and in models of neurological
disease and injury, such as Alzheimer’s disease [110], Parkin-
son’s disease, ischemia/stroke, epilepsy [106] and cranial ra-
diation therapy [108], have been shown to have an inhibitory
effect on the brain’s ability for repair.
A particularly important and influential study by Monje
and colleagues in 2003 demonstrated that systemic inflamma-
tion stimulated by Lipopolysaccharide (LPS) increased micro-
glial activation in the dentate gyrus and decreased the number
of newly generated (BrdU+/Dcx+) neurons as a result of dis-
ruption to the microenvironment and the inability of neural
stem/progenitor cells to associate with the vasculature [108].
When systemic inflammation was inhibited by the administra-
tion of the NSAID indomethacin, the effect was reversed, re-
sulting in increased neurogenesis. The study further confirmed
the negative effect of inflammation on neurogenesis in vitro
using co-culture systems of microglia and neural
stem/progenitor cells derived from the adult hippocampus
[108]. Furthermore, this study also noted that patients under-
going cranial radiation therapy experienced a decline in cogni-
tive function, which was accompanied by chronic inflamma-
tion that was linked to impaired neurogenesis [108]. It was
also demonstrated that irradiated hippocampi displayed in-
creased microglial activation and increased infiltration of the
brain by peripheral inflammatory cells such as monocytes.
Finally, administration of indomethacin following cranial ra-
diation decreased microglial activation correlating with in-
creased neurogenesis [108].
A second study conducted by Ekdahl and colleagues in
2003 also showed that injection of LPS increased microglial
activation and inhibited the formation of new neurons [106].
These authors looked at the role of inflammation in a model of
status epilepticus (SE) as acute brain insults have been linked
with inflammation and contribute to the pathogenesis of dis-
ease and the propagation of neuropathological events. The
study found that in SE there was a significant increase in mi-
croglial activation in the hippocampus, which also correlated
with a decline in neurogenesis [106]. In order to confirm these
results, Ekdahl and colleagues showed that inhibition of in-
flammation observed following SE by administration of mino-
cycline reversed the detrimental effects of inflammation re-
sulting in a decline in microglial activation, which correlated
with increased neurogenesis in dentate gyrus [106].
It is clear through these studies that neuroinflammation
and more specifically microglia play an important role in the
regulation of brain repair by mediating stem cell activity and
the microenvironment. Understanding the mechanisms that
regulate inflammation in the adult injured and intact hippo-
campus will aid in the development of therapeutics for neuro-
logical diseases where it has recently been shown that inflam-
mation plays an important role in the pathology and progres-
sion of the disease. Since CNS inflammation has been increas-
ingly implicated in the pathology of neurodegenerative dis-
eases, inflammation provides a potential mechanism by which
neurogenesis is suppressed in these diseases. Whilst targeting
inflammation is an increasingly important goal for slowing
neurodegeneration, it should also be recognised that this same
approach is likely to promote neurogenesis by inhibiting in-
flammatory mechanisms.
ROLE OF NEUROGENESIS IN NEURODEGENERATIVE DISEASE
Recent literature has suggested that in neurodegenerative
diseases such as Parkinson’s disease, Alzheimer’s disease,
ischemia/stroke and amyotrophic lateral sclerosis (ALS), neu-
ral stem/progenitor cell proliferation and neuronal differentia-
tion is altered [1-5, 17, 19, 27, 111-114]. In the following sec-
tion of the review we will outline the evidence that in particu-
lar neurogenesis appears to be impaired in Alzheimer’s dis-
ease, Parkinson’s disease and ALS, raising the question as to
whether impaired neurogenesis contributes to the disease pro-
gression. We also provide evidence that enhanced neurogene-
sis following an ischemic-induced neural loss may in fact un-
derlie the partial recovery that occurs after the ischemic epi-
sode, although it is presumably not upregulated sufficiently to
bring about full recovery.
Evidence for Altered Neurogenesis in Parkinson’s Disease
Parkinson’s disease is a chronic and progressive move-
ment disorder that is characterised by motor impairments
including limb tremors, muscle rigidity, bradykinesia, akine-
sia and postural instability [115, 116]. The motor symptoms
arise as a result of loss of dopaminergic neurons in the sub-
stantia nigra and the subsequent loss of the neurotransmitter
dopamine [116]. The loss of dopamine neurons appears to
follow from mutations in a range of genes [116, 117] or from
exposure to certain neurotoxins [118, 119], although how
these different factors lead to cell loss is unknown [116,
120].
-- Neurogenesis in Animal Models of Parkinson’s Disease
It has been suggested that the substantia nigra contains a
population of neural stem/progenitor cells and exhibits a
basal level of neurogenesis [1-4]. In the 6-hydroxydopamine
(6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
dine (MPTP) models of Parkinson’s disease, lesions of the
substantia nigra stimulated proliferation of neural stem/pro-
genitor cells residing in the substantia nigra [2-4] and in-
creased differentiation of these neural stem/progenitor cells
into neurons that expressed the dopaminergic marker tyro-
sine hydroxylase (TH) [1-4]. However the notion that neuro-
genesis gives rise to new dopamine neurons is controversial.
Indeed some studies suggest lesioning to the substantia nigra
following 6-OHDA or MPTP administration, decreased the
number of proliferating neural stem/progenitor cells in the
SVZ correlating with the extent of dopaminergic denervation
[121-123]. Other studies in models of Parkinson’s disease
have suggested that whilst lesioning the substantia nigra re-
sulted in increased neural stem/progenitor cell proliferation,
there was no evidence of differentiation of these neural
stem/progenitor cells into dopaminergic neurons [88, 121,
123-131]. The neural stem/progenitor cells, instead, adopted
glial phenotypes [125-127, 132].
-- Effects of Stimulating Neurogenesis in Parkinson’s Disease Models
Studies have shown that dopaminergic neurogenesis can
be stimulated in animal models of Parkinson’s disease
through treatments with exogenous factors, which stimulate
endogenous populations of neural stem/progenitor cells [128,
129, 133]. Differentiation of endogenous neural stem/pro-
genitor cells into neurons in the substantia nigra was also
stimulated in Parkinsonian animals that were housed in en-
riched environments [134]. Steiner and colleagues showed
that enriched environments along with physical activity re-
sulted in increased cell proliferation in the substantia nigra of
6-OHDA injected animals. This housing in enriched envi-
ronments also led to alleviation of Parkinsonian symptoms
including rotational behaviour [134].
The conclusions that can be cautiously drawn from these
studies are that the protocols which lead to enhanced neuro-
genesis seem to bring about functionally beneficial effects.
This does not prove that enhanced neurogenesis is responsi-
ble for these beneficial effects. While much work still needs
to be done, the hope is that neurogenesis leading to repair
could offer hope for sufferers Parkinson’s disease.
Altered Neurogenesis in Alzheimer’s Disease
Alzheimer’s disease that presents in patients in their late
40s to mid 50s is characterised in the early stages by pro-
gressive memory impairment and cognitive decline, altered
behaviour and language deficits [135-138]. In later stages,
Alzheimer’s disease is characterised by global amnesia and
the slowing of motor functions, with death typically occur-
ring within 9 years of diagnosis [136, 138]. Alzheimer’s dis-
ease is pathologically characterised by neurofibrillary tangles
consisting of phosphorylated tau and amyloid (A ) protein
deposition forming plaques [137-141].
-- Neurogenesis is Decreased in Humans with Alzheimer’s Disease
Analysis of human brain tissue from Alzheimer’s disease
patients using immunohistochemistry revealed the presence
of neural stem/progenitor cells in the SVZ, dentate gyrus and
CA1, CA2 and CA3 regions of the hippocampus [112, 142,
143], with the number of neural stem/progenitor cells in the
SVZ being significantly decreased compared to control brain
tissue [143]. This suggests that in humans, neuronal degen-
eration following onset of Alzheimer’s disease may result in
inhibition of neural stem/progenitor cells and may indicate
inhibition of neurogenesis.
Analysis of human hippocampal tissue from Alzheimer’s
disease patients by Boekhoorn and colleagues in 2006
showed there was not only a significant decrease in the num-
ber of neurons in the CA1 and CA2 areas but there was also
a significant increase in the number of proliferating cells in
the entire hippocampus [142]. However, when specific re-
gions were compared between Alzheimer’s disease patients
and control patient, there appeared to be no significant
changes in cell proliferation [142].
-- Neurogenesis is Altered in Animal Models of Alzheimer’s Disease
This observation in human brain tissue from Alzheimer’s
disease and control patients is supported by a number of
studies using animal models of Alzheimer’s disease that also
showed decreased neural stem/progenitor cell populations
and decreased neurogenesis [144-155]. However, some
authors have reported increased neurogenesis in animal
models of Alzheimer’s disease [142, 156-161]. It is not yet
possible to resolve the discrepancies between these studies
although one possibility is that the extent of neurogenesis
depends on the age of the animal studied. The other possibil-
ity is that evidence of enhanced neurogenesis does not mean
that the neurogenesis is necessarily proceeding normally.
In vitro studies suggest that proliferation of neural
stem/progenitor cells is inhibited by A protein, which in
Alzheimer’s disease accumulates to form the characteristic
A plaques that are believed to contribute to the pathology
of the disease [148]. It was further suggested that addition of
A protein to cultured neural stem/progenitor cells resulted
in decreased migration and differentiation of the neural
stem/progenitor cells [148]. These results obtained in vitro
have been supported by studies conducted in animals models
where it was observed that neurogenesis is impaired in mice
co-expressing mutant forms of amyloid precursor protein
and presenilin1 (APP/PS1 mice) [148, 155, 162-165], or
where mutant APP and PS1 are expressed separately
(PDAPP, Tg2576, APP Tg, PS1-KO mice) [145, 146, 148,
152-154, 156, 166, 167].
APP/PS1 mice developed A plaques at 6 months of age
and displayed decreased neural stem/progenitor cell prolif-
eration and decreased differentiation into mature neurons in
the dentate gyrus [151, 155]. It was also shown that overpro-
duction of APP/A exacerbated cell death of newborn neu-
rons as they approached maturity [151, 155]. This indicates
that decreased neurogenesis and neural stem/progenitor cell
population may be due to the increased deposition of A and
the subsequent development of A plaques.
Individual expression of mutant APP and PS1 in the
Tg2576, PDAPP, and the APP23 models or the PS1 P117L,
PS1 knock out (KO) and PS1 M146V knock in (KI) models,
respectively, has also been shown to increase A 42 produc-
tion and A plaques [144-146, 148, 152-154, 166]. In the
PDAPP model, there is increased deposition of A plaques
as well as decreasing number of proliferating neural
stem/progenitor cells in the SGZ and the granule cell layer
(GCL) of the dentate gyrus compared to wild-type controls
[145]. These results were supported by studies conducted in
other APP Tg models including the Tg2576 model [144,
148, 166].
Studies using animal models where mutant PS1 (preseni-
lin1) is expressed, such as the PS1 P117L and PS1 MS146V
KI models, also show significant increases in A 42 levels,
decreased number of neural stem/progenitor cells and de-
creased differentiation of these neural stem/progenitor cells
into neurons in the dentate gyrus when compared to wild
type controls [144, 145, 148, 152-154, 166]. These studies
together indicate that PS1 plays an important role in the
regulation of neurogenesis in models of Alzheimer’s disease.
Whilst most studies using animal models of Alzheimer’s
disease show that mutations of APP and PS1 are linked to
the production and accumulation of A 42 protein and A
plaques, as well as decreased neural stem/progenitor cell
populations and differentiation into neurons in the dentate
gyrus, some studies also exist that show increased neural
stem/progenitor cell number and neurogenesis [142, 156-
159, 161]. In a study by Chevallier and colleagues in 2005,
mutant PS1 was shown to stimulate proliferation of neural
stem/progenitor cells in the SGZ of the dentate gyrus with no
significant difference in their rate of survival or differentia-
tion into mature neurons [158]. Another study also observed
that loss of functional PS1 led to premature differentiation of
neural stem/progenitor cells into neurons but no changes in
the neural stem/progenitor cell proliferation and apoptosis
[159]. The effect of loss of both PS1 and PS2 in a double
knock out model of Alzheimer’s disease strengthens the evi-
dence for a role of presenilin molecules in the regulation of
adult neural stem/progenitor cell proliferation and neuro-
genesis. Regional specific loss of PS1 and PS2 was associ-
ated with enhanced proliferation in the dentate gyrus with
aging along with increased neuronal differentiation and glio-
sis in the dentate gyrus of double knock out mice when com-
pared to wild type control mice [157].
-- There is a Positive Correlation Between Neurogenesis and Functional Recovery in Animal Models of Alzheimer’s Disease
Following the studies that showed altered neurogenesis in
animal models of Alzheimer’s disease and in human brain
tissue from Alzheimer’s disease patients, it has been demon-
strated that neurogenic processes are able to be stimulated,
leading to the astounding observation that recovery of the
neuronal population is associated with the functional recov-
ery of memory and learning [113, 146, 154, 163, 164, 167-
169]. This is perhaps the most important and exciting evi-
dence to date that neurogenesis is functionally important in
Alzheimer’s disease. By inference, this underpins the pro-
posal of this review that drugs or factors that impair neuro-
genesis are likely to be detrimental to an Alzheimer’s disease
patient.
Previous studies have detailed the use of growth factors
or environmental enrichment to stimulate neurogenesis in
models of Alzheimer’s disease. A study by Tsai and col-
leagues in 2007 detailed the administration of growth-colony
stimulating factor (G-CSF) to the Tg2576 mouse model of
Alzheimer’s disease. It was found that the administration of
G-CSF resulted in significantly increased cell proliferation in
the dentate gyrus and also induced differentiation of these
neural stem/progenitor cell populations into mature neurons.
Furthermore, the treatment of Alzheimer’s disease mice with
G-CSF not only increased neurogenesis but also resulted in
improvement of cognitive function indicated by decreased
latency time in the Morris water maze test for memory and
learning [169].
Several studies investigating Alzheimer’s disease models
have detailed the benefits of environmental enrichment in
stimulating neurogenesis and functional recovery of memory
and learning [163, 164, 167]. It has been well documented
that environmental enrichment significantly stimulates neu-
rogenesis in the normal adult rodent brain and also signifi-
cantly improves the memory and learning capabilities of the
animal [170-174]. It has also been demonstrated that animals
with mutant APP or PS1 housed in an enriched environment
had reduced levels of A protein and amyloid deposits [163,
164, 167].
-- Neurogenesis as a Therapeutic Target for Alzheimer’s Disease
Stimulating neurogenesis in models of Alzheimer’s dis-
ease reduces the appearance of the amyloid plaques charac-
teristic of Alzheimer’s disease and appears to contribute to
functional recovery with improvement of memory and learn-
ing capabilities. Therefore, methods of stimulating neuro-
genesis are promising therapeutic approaches for treating
Alzheimer’s disease and other neurodegenerative diseases.
The effects of current therapies for neurodegenerative dis-
ease on levels of neurogenesis must also be considered in
light of the evidence that neurogenesis plays an important
role in the recovery of function.
Evidence for Neurogenesis in Ischemia/Stroke
Cerebral ischemia occurs when the brain or parts of the
brain do not receive enough blood flow to maintain essential
neurological function [175, 176]. The loss of blood supply to
the brain results in impairment of glutamate transporters
leading to accumulation of glutamate and therefore excessive
activation of glutamate receptors and excitotoxic neuronal
cell death [176]. When this occurs in humans this is referred
to as stroke.
Common deficits that are exhibited following ischemic
injury include dysphasia, dysarthria, hemianopia, weakness,
ataxia, sensory loss and neglect [177]. At the cellular level,
pyramidal cells of the CA1 region are especially sensitive to
global ischemia and the duration of ischemia has a direct
effect on the progression of CA1 cell death such that shorter
duration of ischemia results in slower progression of the neu-
ronal cell death [178].
-- Neurogenesis in Humans Following Stroke
Analysis of human stroke tissue demonstrated the expres-
sion of markers associated with newborn neurons such as
Dcx and -III tubulin as well as markers of mature neurons
such as Map2 and NeuN in the ischemic penumbra surround-
ing the cerebral cortical infarcts [179]. These findings sug-
gest that stroke-induced compensatory neurogenesis may
occur in the human brain and contribute to post-ischemic
recovery [179].
-- Neurogenesis is also Stimulated in Animal Models of Ischemia
Focal ischemia induced by middle cerebral artery occlu-
sion in animal models, results in loss of neurons in the py-
ramidal regions of the hippocampus and the striatum, and
alters the normal pattern of adult neurogenesis. It has been
shown that ischemia stimulates cell proliferation within the
SVZ and SGZ and migration of newly born immature neu-
rons into the areas of damage [27, 180-184].
Further studies conducted in animal models of ischemia
have also provided evidence of stimulated neurogenesis in
the hippocampus and in the striatum following ischemia [5,
114, 182, 184-198]. Hence, novel therapeutics aimed at fur-
ther increasing stroke-induced neurogenesis may contribute
to enhanced functional recovery and therefore should be
considered in drug development.
Middle cerebral artery occlusion in animals induces loss
of pyramidal neurons in the CA1 region of the hippocampus.
This is concurrent to increased cell proliferation in the SVZ
and SGZ of the dentate gyrus observed between 3 and 28
days after the ischemic episode [27, 187, 192, 198]. Fur-
thermore, neural stem/progenitor cells in the SVZ and SGZ
migrate towards regions that exhibit neurodegeneration such
as the CA3 and CA1 pyramidal regions [27, 182, 185, 195,
197, 198]. In vitro, stroke-derived SVZ neural stem/proge-
nitor cells also exhibited faster migration when compared to
non-stroke derived SVZ neural stem/progenitor cells [197].
Finally, the neural stem/progenitor cells differentiated into
newborn neurons expressing neuronal markers such as cal-
bindin and formed synapses with neighbouring cells 4-6
weeks after ischemia [114, 185, 187, 195, 199].
-- Positive Correlation Between Neurogenesis and Recovery in Models of Ischemia
A pioneering study conducted by Nakatomi and col-
leagues in 2002 showed that stimulation of neural
stem/progenitor cells into neurons in the hippocampus fol-
lowing ischemia led to functional recovery in rodents [27].
Treatment of ischemic mice with different growth factors
including fibroblast growth factor 2 (FGF-2), epidermal
growth factor (EGF), and vascular endothelial growth factor
(VEGF) stimulated neurogenesis in the striatum and hippo-
campus of ischemic mice [27, 200-204]. Nakatomi and col-
leagues also showed that the newly generated neurons
formed functional glutamatergic synaptic connections to
neurons in the pre-existing circuitry [27]. The study investi-
gated further and showed that ischemic animals that received
growth factor treatment improved in memory and learning
tasks. Therefore, endogenous neural stem/progenitor cells
have extraordinary regenerative capabilities and are able to
form functional neurons to repopulate areas of degeneration
and induce functional recovery [27]. Furthermore, treatment
of ischemic hippocampi with VEGF resulted in the signifi-
cant reduction in infarct volume as well as a marked increase
in neural stem/progenitor cell proliferation and differentia-
tion into cortical neurons in the SVZ 14-28 days after ische-
mia [203]. Increased neurogenesis contributed to improved
post-ischemic motor function, thus supporting the regenera-
tive potential of endogenous neural stem/progenitor cells in
models of neurodegeneration.
Environmental enrichment is also capable of increasing
the level of neurogenesis in the hippocampus and striatum of
ischemic animals [27, 201, 202, 204-207]. Environmental
enrichment stimulates neurogenesis in normal animals result-
ing in improvement of memory and learning ability [40, 170-
173]. Ischemic mice housed in an enriched environment dis-
played increased neural stem/progenitor cell proliferation in
the SVZ and dentate gyrus and increased number of imma-
ture neurons, however, there was no affect on lesion size
[208, 209].
Therefore neuronal degeneration following ische-
mia/stroke stimulates endogenous recovery through neural
stem/progenitor cell proliferation and differentiation in re-
gions of degeneration thus indicating the potential that the
CNS has to induce functional repair. Further stimulation of
neurogenesis may therefore be beneficial and further en-
hance neuronal and functional recovery.
Evidence for Neurogenesis in ALS
Amyotrophic Lateral Sclerosis (ALS) is a progressive
neurodegenerative disease that is associated with loss of up-
per and lower motor neurons in the cortex, brainstem, and
spinal cord [210]. Symptoms typically start in middle life
(40-60 years) and progress rapidly to death, due mostly to
respiratory failure, within 2-5 years of diagnosis [211]. For
approximately 50% of patients, survival is about 30 months
from the onset of symptoms, although there are some that
survive beyond 10 years [210].
Patients with ALS present with symptoms that are di-
rectly related to the death of motor neurons, such as wasting,
weakness, spasticity, difficulty in communicating, dyspnoea,
chronic hypoventilation, excessive saliva, fasciculations and
cramps, persistent secretions, dysphagia, and emotional la-
bility [210]. In addition there are many symptoms that are
indirectly related, such as depression, anxiety, insomnia,
fatigue, constipation, pain, and discomfort [210]. However
there is relative sparing of the muscles controlling eye
movement and the urinary sphincters [212].
-- Neurogenesis in Animal Models of ALS
Many theories on the underlying ALS pathogenesis have
been proposed, including oxidative stress, excitotoxicity,
mitochondrial dysfunction, defective axonal transport and
abnormal protein aggregation. The identification of muta-
tions encoding the Cu/Zn superoxide dismustase 1 (SOD1)
gene have led to the discovery that these mutations are the
cause of approximately 10-20% of familial ALS and there-
fore 2% of all cases [213]. SOD1 knockout mice do not de-
velop overt ALS [214], however, transgenic mice that over-
express the mutant forms of the human SOD1 protein de-
velop an adult onset progressive motor neuropathy pheno-
type [215]. This model is therefore the most widely used
animal model in the study of ALS.
There is evidence of a widespread regenerative response
in the spinal cord of ALS transgenic mice [216]. Specifi-
cally, there was a significant increase in the number of
BrdU-positive proliferative cells in the central canal, grey
matter and white matter in the cervical, thoracic and lumbar
regions of the spinal cord of ALS mice compared to wild
type controls [216]. Despite the presence of a regenerative
response, it appears to be largely unproductive as convincing
evidence of neurogenesis is absent [216]. Therefore, in ALS
mice the neurodegenerative process stimulates a regenerative
response, which suggests that the adult spinal cord has at
least a limited ability for regeneration [216] but it is inade-
quate to regenerate the spinal cord.
In studies using the nestin promoter driven LacZ reporter
transgenic (pNes-Tg) mice and G93A-SOD1 bi-transgenic
mice, it was shown that neural stem/progenitor cell prolifera-
tion, migration and neurogenesis occurred in the lumbar re-
gion of the adult spinal cord in response to motor neuron
degeneration [217]. The neural stem/progenitor cells were
restricted to the ependymal zone surrounding the central ca-
nal with a significant increase in symptomatic bi-transgenic
mice compared to presymptomatic bi-transgenic and pNesTg
mice [217]. Once the neural stem/progenitor cells left the
ependymal zone of the central canal they lost their prolifera-
tive capacity but maintained their migratory function [217].
During disease onset and progression, neural stem/progenitor
cells in the ependymal zone of the central canal migrated
initially toward the dorsal horn direction then to the ventral
horn regions where the motor neurons have degenerated
[217]. There was also increased de novo neurogenesis from
neural stem/progenitor cells during ALS-like disease onset
and progression [217]. This was demonstrated through a
significant increase in the percentage of mature neurons in
bi-transgenic mice compared to nestin reporter mice [217].
Another study conducted by Chi and colleagues in 2007 also
showed significant increases in neural stem/progenitor cells
in the dorsal horn in the cervical, thoracic and lumbar re-
gions of the spinal cord at disease onset and in progression
stages in bi-transgenic mice compared to age matched
pNesTg control mice [218].
Despite the absence of substantial evidence of neuro-
genesis occurring in ALS, the above two studies do show
that there is at least the potential for regeneration in animal
models of ALS and therefore, future drug development
should consider the possibility of harnessing this potential
regenerative ability as a therapeutic target.
CURRENT THERAPIES IN NEURODEGENERATIVE DISEASES AND THEIR ROLE IN NEUROGENESIS AND INFLAMMATION
Currently, therapeutic strategies for neurodegenerative
diseases including Parkinson’s disease, Alzheimer’s disease,
stroke and ALS are directed at protecting neurons from de-
generation and providing symptom relief. As discussed
above, neurogenesis and inflammation may play an impor-
tant role in these conditions. Therefore we will discuss cur-
rent therapeutic strategies, their known applications and any
possible influences on neurogenesis. Because this connection
has not previously been comprehensively investigated, the
intention of this review, though controversial, is to highlight
this possible relationship and its implications for future
therapeutic development
Current Therapeutic Strategies for Parkinson’s Disease
Current therapeutic strategies for Parkinson’s disease are
targeted at providing symptomatic relief via replenishing
dopamine levels, which are lost as a result of the degenera-
tion of nigrostriatal dopaminergic neurons. However, none
of these drugs have yet to been shown to halt or retard do-
paminergic neuron degeneration [219].
Levodopa (L-DOPA) is currently the gold standard for
Parkinson’s disease as it is the most effective therapy in
treating the symptoms of the disease [220]. However its ef-
fectiveness is limited as long term use over 5-10 years is
associated with the development of motor complications in
up to 80% of patients [115]. As a result, there are a number
of possible alternative therapies which can be used as an
adjunct to L-DOPA or as a monotherapy.
-- Evidence for MAO Inhibitors Influencing Neurogenesis in Parkinson’s Disease
Monoamine oxidase (MAO) is an enzyme that catalyses
the oxidative deamination of biogenic amines in peripheral
tissues and the brain. There are two types of monoamine
oxidases: MAO-A and MAO-B. MAO-A preferentially
deaminates norepinephrine, serotonin and epinephrine while
MAO-B preferentially deaminates benzylamine and phen-
ylethylamine. Dopamine is equally catabolized by both
forms of MAO [221]. MAO inhibitors such as rasagiline
mesylate and selegiline have been used as monotherapies in
patients with early Parkinson’s disease and as adjunctive
therapies in Parkinson’s disease patients receiving treatment
with L-DOPA [222] by smoothing out L-DOPA related mo-
tor fluctuations and prolonging dopamine-induced responses
in midbrain dopaminergic neurons [223].
In models of Parkinson’s disease, MAO inhibitors exert
neuroprotection against the neurotoxins 6-OHDA and par-
ticularly MPTP [224]. Specifically in the MPTP model,
MAO catalyses the conversion of MPTP to the neurotoxic
MPP+ form and therefore, administration of MAO inhibitors
prevents generation of MPP+ and the subsequent degenera-
tion of dopaminergic neurons [224].
Furthermore, a study by Sagi and colleagues (2007)
investigated the possible neurogenic activity of rasagiline in
post-MPTP induced nigrostriatal lesioned mice. The study
demonstrated that a continuous administration of rasagiline
following MPTP lesion, restored the severe reduction in do-
paminergic cell count, striatal dopamine content and tyrosine
hydroxylase activity [225]. This demonstrates that rasagiline
may have therapeutic use in stimulating neurogenesis.
-- Evidence for Dopamine Agonists Influencing Neurogenesis in Parkinson’s Disease
Experimental studies have provided evidence that the
activation of dopamine receptors (D1, D2, D3 and D4) is
important in mediating the beneficial anti-parkinsonian ef-
fects of dopamine agonists [226]. Dopamine agonists exert
their therapeutic effect by directly activating dopamine re-
ceptors, bypassing the presynaptic synthesis of dopamine
[226]. Some dopamine receptor agonists used in the treat-
ment of Parkinson’s disease include bromocriptine, per-
golide, ropinirole, pramipexole and cabergoline [226-228].
The dopamine receptor agonists are highly selective for D2
or D3 receptors and improve parkinsonian symptoms such as
bradykinesia, rigor and tremor [228, 229].
There is a growing body of evidence that dopamine re-
ceptor agonists exert a neuroprotective role [226, 229, 230].
In vitro studies have shown that addition of dopamine ago-
nists to neuronal dopaminergic cell lines protects the dopa-
minergic neurons against cell loss induced by rotenone,
MPP+, dopamine and hydrogen peroxide [230]. The protec-
tion of dopaminergic neurons is not only dependent on the
actions of the drugs as dopamine receptor agonists but also
on their antioxidant capacity in preventing oxidative stress-
induced neuronal cell death [229].
The neuroprotective effect of dopamine receptor agonists
observed in in vitro studies was supported by studies con-
ducted in vivo. Administration of dopamine receptor agonists
such as pergolide preserved the integrity of nigrostriatal neu-
rons in the ageing rat brain and protected against the reduc-
tion of striatal dopamine and its metabolites following the
injection of 6-OHDA [123, 229]. In experimental models of
Parkinson’s disease, it has been found that dopamine recep-
tor agonists reversed the motor and behavioural deficits in-
duced by MPTP [229].
Recently, it was shown that striatal dopaminergic inner-
vations are important for the proliferation of precursors in
the SVZ which is reduced in Parkinson’s disease [231]. The
mechanism by which these dopaminergic innervations regu-
late proliferation may be through activation of the D2/D3
dopamine receptors [231]. There is some evidence that the
D2/D3/D4 dopamine receptors are capable of influencing
proliferation and neural stem/progenitor cells [231]. Specifi-
cally, it was shown that D2/D3/D4 transmission stimulated
subependymal zone proliferation and D2/D3/D4 activation
increased proliferation in neurospheres [123].
Two papers published in 2004 [130, 232], indicated that
both in vitro and in vivo dopamine agonists augmented SVZ
cell numbers via a recruitment of D3 receptors and that this
effect reflects enhanced mitogenesis and not decreased apop-
tosis [233]. Therefore dopamine receptors may provide an
exciting potential therapeutic target for both neuroprotection
and neurogenesis in the treatment of Parkinson’s disease.
-- Other Therapies in Parkinson’s Disease
The anticholinergics, including the tricyclics, have long
been believed to be a successful therapy in the early stages of
Parkinson’s disease due to their ability to correct the imbal-
ance between the dopaminergic and cholinergic pathways in
less advanced forms of the disease by reducing the neuro-
transmission mediated by nigrostriatal acetylcholine [234].
Amantadine, an antiviral, has been found to enhance re-
lease of dopamine from presynaptic terminals and also has
modest anti-cholinergic properties [220]. There is recent
evidence suggesting a role for amantadine as a potential neu-
roprotective agent through its ability to block NMDA recep-
tors [220]. Presently there is no evidence that shows that
amantadine plays a role in neurogenesis and/or inflamma-
tion. However, as there is evidence that some anticholinergic
drugs used in Alzheimer’s disease promote neurogenesis
[113], further work needs to be done to determine whether
the modest anticholinergic effects of amantadine and the
anticholinergics used in Parkinson’s disease may also influ-
ence neurogenesis.
Catechol O-methyltransferase (COMT) inhibitors, such
as tolcapone and entacapone, are used in the treatment of
Parkinson’s disease due to the fact that, in the presence of
carbidopa, a significant quantity of orally administered L-
DOPA is metabolised by COMT in the gastrointestinal tract
[220]. This results in a measurable reduction in the amount
of levodopa that will ultimately enter the brain. Even though
there is currently no evidence that COMT inhibitors affect
regeneration, it should be kept in mind that there could still
be a possibility of these inhibitors influencing neurogenesis.
-- Future Therapeutic Targets for Parkinson’s Disease
There are a number of other drug targets that are being
investigated as potential new therapeutic agents to be used in
Parkinson’s disease. For example, adenosine A2a receptor
antagonists have attracted interest as potential symptomatic
drugs for Parkinson’s disease [235, 236]. The symptomatic
effect of A2a receptor antagonists can be explained by
blockade of the A2a receptors on the D2 receptor-expressing
striatopallidal neurons, which inhibits their release of GABA
in the globus pallidus, ultimately leading to enhanced motor
function through the so called indirect motor pathway of the
basal ganglia [235, 236]. A2a receptor antagonists affect the
release of acetylcholine from striatal cholinergic interneu-
rons as well as affecting the release of dopamine from the
nigro-striatal tract [235]. It has also been suggested that A2a
receptors might possess neuroprotective properties [236].
Some other potential therapeutics for Parkinson’s disease
include nicotine which has been shown to protect against
degeneration in both the 6-OHDA [237] and MPTP [238]
models, however nicotine itself seems to have no anti-
parkinsonian effects [236]. Serotonergic receptor agonists
may also provide neuroprotective effects as well as extend-
ing the duration of L-DOPA action while dramatically reduc-
ing levodopa-induced dyskinesias [236]. Other interesting
candidates are allosteric potentiators of group III me-
tabotropic glutamate receptors, which have been shown to
markedly reverse reserpine-induced akinesia [239]. Many of
these drug targets are still currently under investigation or
undergoing clinical trials. However the results of these stud-
ies should be considered with the possibility that effects of
these therapies on neurogenesis may have an influence on
their outcomes.
Current Therapeutic Strategies for Alzheimer’s Disease
Reduced levels of acetylcholine in the brain are believed
to be responsible for some of the symptoms of Alzheimer’s
disease. Therefore cholinesterase inhibitors (ChEI), like
tacrine, donepezil, rivastigmine and galantamine, are used as
the primary sources of symptomatic treatment for this disor-
der. However, tacrine is no longer in widespread clinical use
because it is associated with an unacceptable degree of hepa-
totoxicity [240].
It has been suggested that cholinesterase inhibitors may
also play a neuroprotective role, because the addition of a
ChEI to cell culture protects the cells against damage in-
duced by oxygen-glucose deprivation and glutamate-
mediating cytotoxicity [240]. Cholinesterase inhibitors could
conceivably be used to stimulate neurogenesis because cho-
linergic receptors are expressed on neuronal progenitor cells
and are also coupled to cell proliferation [113]. In the study
by Jin and colleagues in 2006, tacrine and galantamine were
administered at maximally effective concentrations to corti-
cal cultures and it was shown that basal levels of BrdU in-
corporation was increased by approximately 40% [113].
However the key question of whether these newly produced
cells actually become functional neurons still remains to be
answered.
Memantine, a non-competitive NMDA antagonist, is
another drug used in the treatment of moderate to severe
Alzheimer’s disease. Memantine allows normal physiologi-
cal function of the NMDA receptor while blocking its patho-
logical activation and providing neuroprotection [241]. The
use of memantine is associated with significant improve-
ments in measures of cognition, function, and behaviour in
both Alzheimer’s disease and vascular dementia [242]. Me-
mantine was found to increase BrdU labelling in the dentate
gyrus and the SVZ, showing promise of the drug in stimulat-
ing neurogenesis in Alzheimer’s disease [113]. This is how-
ever a rather unexpected result given that NMDA receptor
antagonists have been found to inhibit neurogenesis. How-
ever, memantine has been recently shown to have numerous
other actions and its primary role as an NMDA antagonist at
therapeutic doses has been drawn into question [243]. We
further explore the role of memementine and NMDA recep-
tor antagonists in neurogenesis later in this review.
Although the two therapeutic strategies discussed above
have shown promise in stimulating neurogenesis in vitro,
more studies need to be conducted in order to investigate this
in animal models and humans. In any case, these intriguing
examples highlight previously unknown effects on neuro-
genesis of drugs used clinically. Hence we suggest that fail-
ure of some drugs in clinical trials may be due to unpredicted
adverse effects on neurogenesis. This concept may need to
be at least considered in future therapeutic development.
-- Potential Future Therapies for Alzheimer’s Disease
Tumour Necrosis Factor alpha (TNF-alpha) has been demon-
strated to play a major role in CNS neuroinflammation-
mediated cell death in Alzheimer’s disease, Parkinson’s dis-
ease and ALS [244]. There is increasing evidence that sug-
gests that microscopic inflammation resulting from the re-
lease of inflammatory cytokines, including TNF-alpha by A -
activated microglia plays a central role in the neurotoxicity
that occurs in Alzheimer’s disease [245]. Therapeutic agents
that selectively inhibit the biological activity of TNF-alpha have
recently become available for human use and include the
dimeric fusion protein called etanercept. Etanercept binds
specifically to TNF and blocks its interaction with cell-
surface TNF receptors [245]. TNF-alpha antagonists such as
etanercept may therefore be useful in combating inflamma-
tion in Alzheimer’s disease and possibly in other neurode-
generative diseases. As noted previously, therapeutics that
block inflammation could be predicted to enhance neuro-
genesis. The extent to which TNF-alpha antagonists promote neu-
rogenesis needs to be investigated.
Several new compounds are now being tested for safety
and efficacy in clinical trials. These include strategies to re-
duce the pathogenicity of A peptides which are widely be-
lieved to play a key role in Alzheimer’s disease. For exam-
ple, in a phase II clinical trial, active immunisation with
A 42 plus adjuvant appeared to reduce amyloid deposits in
some brain regions and improved certain cognitive measures.
However, the trial was halted because 6% of immunised pa-
tients developed meningoencephalitis [246].
There are a number of other drugs and treatment strate-
gies that are currently undergoing clinical trials and pre-
clinical investigations. These therapeutic agents and targets
will not be comprehensively reviewed here but include
apoE4, Lithium, which inhibit tau phosphorylation, the anti-
oxidant Q10 [247], zinc, NSAIDs, cholesterol lowering
agents [248], nicotine, M2 receptor antagonism, the MAO-B
inhibitors and ladostigil [249]. Whilst investigating the neu-
roprotective effects of these future therapies, the possible
influence of these drugs on neurogenesis should also be con-
sidered.
Current Therapeutic Strategies for ALS
Currently, there are a number of treatment options avail-
able for the treatment of ALS, but Riluzole is the only ap-
proved disease-modifying drug. However the effects of rilu-
zole are only modest, with the drug having no effect on mus-
cle strength, quality of life, or functional capacity [250] and
prolonging survival by approximately only 3 months after 18
months of treatment [210].
There are a number of drugs that are used to specifically
target the symptoms of ALS and as such will only be briefly
mentioned in this review. These include compounds such as
baclofen, dantolene and tizanidine which act as antispasmod-
ics [251], atropine and hyoscine hydrobromide which are
used to control sialorrhea and drooling [252], Cox-2 inhibi-
tors [253], and lorazepam for dyspnoea [210] amongst oth-
ers. Trials of cocktails of therapies – combining agents such
as minocycline, riluzole and nimodipine, have given excel-
lent results in the mouse model [254] and may provide an
alternative therapy. An interesting question is whether the
use of GABA drugs such as baclofen as adjunct therapy may
have some detrimental effect on neurogenesis, given the
critical role of GABA in this process (as discussed further
later in this review).
-- Future Therapeutic Strategies for ALS
As Riluzole is currently the only approved disease-
modifying drug available in the treatment of ALS, much
study is being conducted to try to find additional therapies
for this devastating disease. There has been much interest in
the tetracycline antibiotic minocycline, as this has been the
most effective agent in prolonging survival in the rodent
mutant SOD1 model [211] when administered pre-
symptomatically [250]. Minocycline works independent of
its antibacterial actions, reducing microglial activation and
modulating apoptosis [250]. Surprisingly this did not trans-
late to patients when tested in the clinical setting [255]. Gene
therapy is another treatment that has garnered more interest
recently. In SOD1 mice, intraspinal [256] or intramuscular
[257] injection of a lentiviral vector that produces RNA in-
terference-mediated silencing of SOD1 reduced SOD1 ex-
pression, causing a delay in disease onset and progression
[250]. However, this approach cannot be taken for the major-
ity of sporadic ALS patients and so offers a limited scope of
beneficial outcomes. As oxidative stress is one of the key
factors claimed to underlie ALS pathology, antioxidant com-
pounds have been considered as potential therapeutics and
include examples such as vitamin E, N-acetyl cystein, and
catalase. For example, catalase has been shown to delay the
onset of the disease and improve survival in SOD1 mice
[258]. N-acetyl cystein has also shown benefits in a cell cul-
ture model of ALS and in SOD1 transgenic mice, but unfor-
tunately this benefit has not transferred to human clinical
trials [259]. Another interesting treatment that may prove
beneficial in ALS is erythropoietin, which has been shown to
exhibit neurotrophic effects in in vivo and in vitro studies
[259]. Studies completed on cultured neurons show that
erythropoietin inhibits dopamine release [260], protects neu-
rons from glutamate excitotoxicity and has also been shown
to modulate inflammation [212].
In light of the evidence above that many of the therapies
used or tried for treatment of ALS have shown promise in
animal studies but failed in the clinical setting, it must be
considered that they are having as yet other unknown effects
on the neurological system. Further studies of the effects of
these drugs in neurogenesis will need to be conducted.
Current Therapeutic Strategies for Stroke
There are a vast number of pharmacological drugs that
are used in the treatment of stroke. However the first line of
defence are the thrombolytics, such as tissue plasminogen
activator (tPA), which is effective at restoring blood flow
after an ischemic attack but must be administered within 3
hours of the ischemic episode to be the most effective [176].
-- Future Therapeutic Strategies for Stroke
As highlighted above, thrombolytic therapy is the only
effective available clinical option for immediate post-stroke
treatment. Hence there is currently high interest in finding
agents capable of protecting neurons from further post-
ischemic degeneration. Below are some examples of cur-
rently investigated therapeutic options.
Glutamate receptors such as NMDA receptors and
AMPA receptors have been implicated in neurodegenerative
conditions such as stroke, Alzheimer’s disease and Parkin-
son’s disease. Studies that administered glutamate receptor
antagonists in animal studies found greatest efficacy when
the antagonist was administered prior to ischemia onset.
However these results were not replicated in clinical trials
[176]. One potential limitation of such drugs is that they may
impair regeneration due to the important role of these ion
channels in neurogenesis, as reviewed further below.
Studies have found that transplanted neural stem cells
genetically modified to secrete nerve growth factor (NGF)
were able to ameliorate the death of striatal projection neu-
rons caused by transient focal ischemia in the adult rat [261].
Although the transplanted cells can survive and partly re-
verse some behavioural deficits, mechanisms underlying the
improvement remain unclear and there is little evidence for
neuronal replacement [262]. In most cases only a few grafted
cells survive and these do not show the phenotype of the
dead neurons, which might indicate an influence on neuro-
genesis
According to McCulloch and Dewar in 2001, mitogen-
activated protein kinases are also an attractive target for drug
development because of their multiplicity of actions, which
influence not only cell survival and apoptosis but also in-
flammatory mechanisms [263]. There are still further treat-
ments for stroke that have received interest over the years,
such as adenosine 3 receptor agonists [264] and acid-sensing
ion channel antagonists [176], but these will not be discussed
further in this review.
As has been discussed above, current drug development
aimed at treating neurodegenerative diseases is directed at
developing therapeutics that either protect neurons from de-
generation or focus on relieving the symptoms associated
with these disorders. Among the vast number of drugs that
have been developed, several have shown effects on neuro-
genesis. In general, most of the drugs that have been success-
ful clinically have not adversely affected neurogenesis, and
have in some cases even increased neurogenesis. Thus, fu-
ture drug development should in our opinion consider stimu-
lation of neurogenesis, or at the very least, focus on develop-
ing therapies that do not inadvertently block neurogenesis.
ION CHANNELS AS THERAPEUTIC TARGETS FOR NEURODEGENERATIVE DISEASES
Below we will focus on ion channel targets currently
being considered for treating neurodegeneration and demon-
strate how these ion channels also play a role in neurogenesis
and/or inflammation. For the sake of argument and brevity,
we have focused on a few examples to emphasize these
points.
NMDA Receptors
NMDA receptors (NMDARs) are hetero-oligomeric
ligand-gated cation channels which are comprised of a gly-
cine-binding NR1 subunit along wit
