Neuroregeneration in neurodegenerative disorders

Article (PDF Available)inBMC Neurology 11(1):75 · June 2011with30 Reads
DOI: 10.1186/1471-2377-11-75 · Source: PubMed
Abstract
Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration--implantation of viable cells as a therapeutical approach. Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies. In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.

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DEBATE Open Access
Neuroregeneration in neurodegenerative
disorders
Ana M Enciu
1
, Mihnea I Nicolescu
1,2
, Catalin G Manole
1,2
, Dafin F Mureşanu
3
, Laurenţiu M Popescu
1,2
and
Bogdan O Popescu
2,4*
Abstract
Background: Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and
neurorestoration - implantation of viable cells as a therapeutical approach.
Discussion: Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimers Disease
or Parkinsons Disease and correlate with low endogenous protection, as a result of a diminished growth factors
expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a
neuroregenerative reserve, that could be exploited by growth factors or stem cells-neurores toration therapies.
Summary: In this paper we revie w the current data regarding all three aspects of neuroregeneration in Alzheimers
Disease and Parkinsons Disease.
Background
Adult neuroregeneration is a complex concept, beyond
the common knowledge of neurogenesis that also com-
prises endogenous neuroprotection leading to neuro-
plasticity and neurorestoration -a therapeutical approach
of implantation of viable cells (Figure 1). Regeneration
in the central nervous system (CNS) implies that new
neurons, generated either through proliferation of endo-
genous stem/progenitor cells or by administration of
exogenous stem/precursor cells with potential to substi-
tute for lost tissue, will diffe rentiate , survive, and inte-
grate into existing neural networks [1]. Among the three
components of neuro regeneration previously mentioned,
neuroplasticity was the first one put forwar d, by Ramon
y Cajal, in 1894: associations already established among
certain groups of cells would be notably reinforced by
means of the multiplication of the small terminal
branches of the dendritic append ages and axo nal collat-
erals; but, in addition, completely new intercellular con-
nections could be established thanks to the new
formation of [axonal] collaterals and dendrites. [2].
However, Ramon y C ajal discards, in t he s ame p aper,
the possibility of cell renewal: it is known that the
nerve cells after the embryonic period have lost the
property of proliferation. Adult neurogenesis was pro-
posed by Joseph Altman in the 1960s, in a series of arti-
cles involving tritiated thymidine retaining cells in the
rat brain [3-5]. The newly emerged concept was a con-
troversy until the early 1990s, when several reports [6-9]
proved beyond doubt the ex istence of adult neural stem
cells.
The c oncepts of neuroplasticity and neural stem cells
led to the idea of neurorestoration as an alternative
the rapy for neurodegenerative di sorders such as Alzhei-
mers Disease (AD) and P arkinsonsDisease(PD),both
characterized by neuronal loss. Our review will attempt
to answer the question Is there any neuroregeneration
in neurodegeneration? taking into account the three
concepts mentioned above.
Discussion
Neurogenesis in neurodegenerative diseases
The adult mammalian brain retains a limited capacity of
neurogenesis, which manifests in the subventricular
zone (SVZ) and subgranular zone of the hippocampal
dentate gyrus. The neuronal precursors migrate into the
olfactory bulb, the granular cell layer, or, if necessary, to
the striatum, CA1 region of hippocampus or cerebral
cortex [10].
* Correspondence: bogdan.popescu@jcmm.org
2
Laboratory of Molecular Medicine, Victor Babeş National Institute of
Pathology, 99-101 Splaiul Independenţei, sector 5, Bucharest 050096,
Romania
Full list of author information is available at the end of the article
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© 2011 Enciu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provide d the original work is properly cited.
Alzheimers Disease animal models
Neurogenesis in AD transgenic mice is usually impaired,
but the results may differ from one transgenic strain to
another [11]. Haughey e t al. reported that proliferati on
and survival of neural precursor cells (NPC) was
reduced in the de ntate gyrus of APP mutant mice with
already constituted amyloid deposits [12]. Furthermore,
the decrement in NPC number w as correlated with
accumulation of Ab, e ven i n oli gomeric, diffusible form
[11]. Although Kolecki et al. confirmed the previous
results, they reported that overexpressing APP and Ab
in transgenic mice do not interfere with the mitotic
activity of NPC, as assessed by Ki-67 [13].
In vitro,Ab effects reported on mouse brain-derived
neurospheres are different with the type of peptide used:
i) Ab 25-35 induces neuronal differentiation and apop-
tosis in neural committed cells [14]; ii) Ab40 promotes
neurogenesis in NPCs [15]; iii) Ab42 stimulates neuro-
sphere formation and increases the number of neuronal
precursors [16]; it also has a reported effect of inducing
astrocytic differentiation [15].
Evidence of neurogenesis in AD human brain
An overexpression of neurogenesis markers (Doublecor-
tin - DCX, Polysialylated Neural Cell Adhesion Molecule
- PSA-NCAM and TUC-4) in hippocampus of AD
patients, without a correlated increase in mature neuro-
nal markers (NeuN, Calbinding D28k) is reported by Jin
et al. [17]. This expression disjunction sustains the
hypothesis of AD as a failed attempt of precursor cells to
neuronal differentiation [18], but Boekhoorn et al argue
that DCX is a nonspecific mar ker, increased due to reac-
tive gliosis [19]. Furthermore, Verwer et a l. questioned
whether DCX+ cells are indeed neuroblasts, presenting
arguments for their astrocytic origin [20]. I nvestigating
Musashi1 immunoreactivity in SVZ of AD patients, Ziab-
reva et al. also reported impaired neurogenesis, as com-
pared to controls [21]. In turn, although Lovell et al.
isolated viable NSC from AD patients hipp ocampi, they
obtained decreased viable NPC yields and altered division
rates, as compared to controls [22].
In vitro studies using human neurospheres reported,
unlike in vitro models using rodent NPCs, that Ab 1-40
treatment impaired proliferation and differentiation of
precursor cells [23].
In order to assess neurogenesis in AD brain, adding to
contradictory results in literature, one must further take
into account the neurogenesis-stimulating effect of AD
medication [24].
Neurogenesis in PD animal models
Adult mice subs tantia nigra contain s bromodeoxyuridine
(BrdU) incorporating cells that show dividing an d differ -
entiating properties. In vivo, this potential seems to mate-
rialize into glial li neage, wher eas in vitro,under
appropriate growth factors stimulation, neuronal pro-
genitors may b e identified [25]. Reports regarding neur o-
genesis in 6-hydroxydopamine (6-OHDA) models of PD
showed increased number of BrdU+ cells and a tendenc y
to migrate towards the lesioned striatal nuclei [26], but
without further differentiation on neural lineage [27].
Transgenic mice overexpressing human mutated a
synuclein exhibited reduce d BrdU+ cell s and decreased
survival of new ly generated neurons, as compared to
aged-matched controls. Interestingly, t he cessation of a
synuclein overexpression led to recovered neurogenesis
[28].
Neurogenesis in PD human brain
The numbers of proliferating cells in the subependymal
zone and neural precursor cells in the subgranular zone
and olfactory bulb are reduced in postmortem brains of
Parkinson s Disease patients [29]. However, there are
reports of newly generated neuroblasts PSA-NCAM + in
substantia nigra of PD patients, without a solid proof of
further dopaminergic neuronal differentiation or reinte-
gration in neuronal circuitry [30].
Endogenous neuroprotection and growth factors
Discovery of growth factors and their pro-surv ival effect
led to a closer investigation of specific nervous system
Figure 1 The large concept of neuroregeneration contains
three landmarks: endogenous protection by growth factors,
neurogenesis and neurorestoration. Rather than perceiving them
as isolated events, they should be viewed interrelated, one creating
the premises for generating the other.
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cytokines - Nerve Growth Factor (NGF), Brain-Derived
Nerve Factor (BDNF), Glial-Derived Nerve Factor
(GDNF) - involvement in the outcome of neurodegen-
erative diseases. Interestingly, different neuronal subpo-
pulations require different gr owth factors to thrive, for
example NGF protects cholinergic neurons from various
insults [31], whereas for dopaminergic neurons, this
effect is better sustained by BDNF [32].
Neurotrophins (NGF , BDNF , ne urotrophin 3 - NT 3
and neurotrophin 4 - NT 4) are most studied for their
involvement in norma l central nervous system (CNS)
development [33-36] and in normal [37] or pathological
ageing [38-40]. They exert their effect through tropo-
myosin-related kinase (Trk) receptors and activ ation of
several signaling cascades: i) IP3-DAG and subsequent
release of calcium, leading to synaptic plastic ity; ii)
PI3K/Akt and transcription of prosurvival genes and iii)
MAPK/ERK and activation of differentiation promoting
substrates [41]. With l ow affinity and also in immature
form (as proneurotrophins) they interact with p75
NTR
-
a tumor necrosis factor receptor which, in turn, upon
activation, leads to apoptosis in neuronal and non-neu-
ronal cells [42]. Glial -Derived Neurotrophic Factor
(GDNF) is a growth factor from the transforming
growth factor b (TGFb) superfamily, with documented
neuroprotective effects in dopaminergic neurons cell
cultures [43], in vivo studies on laboratory animals [44]
and in animal models of PD [45,46]. It exerts its effects
through Ret receptor tyrosine kinase and GDNF family
receptor a1 (GFRa1) complex [47], although the role o f
Ret signaling is controversial [48,49]. Mesencephalic
Astrocyte-Derived Neurotrophic Factor (MANF) and
Conserved Dopamine Neurotrophic Factor (CDNF) are
members of a novel, evolutionarily conserved neuro-
trophic factor family with specific protective properties
on dopaminergic neurons, as shown in 6-hydroxydopa-
mine (6-OHDA) animal models of PD [50]. Further-
more, they seem to act more effectively than GDNF and
use a different protective mechanism [51].
Neurotrophins and growth factors in neurodegeneration
In both AD and PD human brains, levels of BDNF [52]
and its mRNA [53] are low. Furthermore, BD NF serum
levels correlat e with AD severity [54]. Correlated altera-
tion in TrkB expression in AD is also reported in corti-
cal neurons, but not in glial cells, which, surprisingly,
upregulate a truncated form of the receptor [55].
According to Tong et al., BDNF signaling pathway
seems also to be negatively affected in AD, by Ab 1-42
peptide interference with gene transcription. Treatment
of rat cort ical neurons cultureswithsublethaldosesof
Ab peptide, interfered with the CREB activation-induced
transcription of the BDNF gene and suppressed BDNF-
induced activation of selective signaling pathways such
as Ras-MAPK/ERK and PI3-K/Akt [56].
The reports regarding NGF mRNA and protein levels
in AD brain are contra dictory [57-59]. NGF deficiency
has been proposed as ethiopatogenic factor in sporadic
AD, and the AD11 a nti-NGF mice recreate the pheno-
type and the functional impairment of early AD stages
[55]. Also, in early stages, a loss of TrkA has been
reported [60], while Cuello et Bruno proposed the exis-
tence of a failure of the NGF maturation cascade in AD
[61]. Ab load recreates the same NGF dismetabolism
in the hippocampus of laboratory rats, as proposed by
Cuel lo et al. [62]. In vitro model s showed Ab peptide as
a potent NGF -secretion stimulator in astrocytic rat cul-
tures and, in turn, NGF was shown to increase neuro-
toxic p otency o f am yloid p eptide i n prim ary rat
hippocampal cultures via p75 induction [63].
It is well documented that brains of PD patients
express lower GDNF levels [64] and growth factor deliv-
ery in brain of PD animal models exert s neuroprotective
effects and improves clinical outcome [65,66]. Further-
more, S un et al. demonstra ted in a rat model t hat
GDNF is more efficient than BDNF in protecting striatal
neurons from 6-hydroxydopamine (6-OHDA), compa red
to the control group o r BDNF group. M oreover, simul-
taneous administration of both growth factors showed
no benefit over GDNF treatment alone [67]. However,
using vector-induced striatal neuron-restricted expres-
sion of both GDNF and BDNF genes, Cao et al.
reported an improved protein expression as to either
approach alone [68].
In human AD studies, there are controversial reports
of GDNF protein levels. Straten et al. reported higher
CSF concentration than age-matched controls along
with decreased serum concentration [69], whereas
Marksteiner s et al. results showed increased plasma
levels in AD and mild cognitive impairment (MCI)
patients [70]. However, in light of the serious side
effects reported after intracerebroventricular infu sion of
GDNF in parkinsonian patients [71], attention was
drown toward MANF and CDNF, which will hopefully
make good candidates for novel therapies in PD.
Neuroplasticity in neurodegeneration
Neuroplasticity is a comprehensive term that illustrates
the brain s c apacity to adapt, structurally and functio n-
ally, to environmental enhancement. According to
Thickbroom and Mastaglia, the molecular mechanisms
underlying neuroplasticity are both neuronal and non-
neuronal and, furthermo re, neuronal plasticity may be
synaptic or non-synaptic [72]. Neuroplasticity is substrate
for learning and memory formation, cognitive abilities
progressively lost in AD and in late stages of PD.
Synaptic loss is one of the neurobiological hallmarks
of AD, from the first stages of t he disease [ 73]. The
synaptic dysfunction is apparently due to soluble Ab
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oligomers, as proven by studies on human AD brains
[74] and AD animal models [75]. Soluble Ab oligomers
have a proven inhibitory effect on NMDA-R - depen-
dent LTP [76], impairing even further the neuroplasti-
city, besides their roles in morphological and structural
degeneration of the synapse [77].
Synapse alteration is initially compensated by
dynamic synaptic reorganization,emphasizedbya
paradoxical initial increase in synapt ic markers [78]. The
proof of network reorganization is sustained by studies
on AD brains showing increased polysialylated neural
cell adhesion molecule (PSA-NCAM) in dentate gyrus,
as compared to controls [79]. Also investigating NCAM,
Jørgensen et al hypothesize that AD brain uses neuro-
plasticity as a compensatory measure for neuronal loss
[80]. Furthermore, inflammatory environment - a con-
stant finding in AD brain - impairs neuronal plasticity
by inhibiting both (NMDA-R) - induced and voltage-
dependent calcium channel (VDCC)-induced LTP [81].
The other neuropathological hallmark of AD, tau hyper-
phosphorylation, correlates with low neuronal plastici ty
and synaptic disorganization, as proven by studies on
hibernating animals [82]. Possibly a protective mechanism
against neuronal apoptosis in unfavorable conditions, per-
sistent hyperphosphorylation will eventually lead to forma-
tion of paired helical filaments and cell destruction.
PD animal models also show impaired neuroplasticity.
Studies in mice o verexpressing human a-synuclein
report both short-term and long -term altered p resynap-
tic plasticity in the corticostriatal pathway [83]. Trans-
genic m ice bearing mutated a-synuclein - (A30P) a-
synuclein - also showed impaired short-time synaptic
plasticity [84] and the (6-OHDA) PD animal models
develop defective synaptic plasticity induction [85].
Morphological studies of idiopathic PD b rains and PD
animal models reported that lo ss of dopaminergic input
on medium spiny neurons of striatum resulted in lower-
ment of dendritic length, dendritic spine density, and
total number of dendritic spines [86].
Toconcludesofar,thereisevidenceofimpaired
neural plasticity in both AD [87] and PD [86] brains,
which occurs on various molecula r lev els, from growth
factors signaling to synaptic malfunction, disorganization
and cytoskeletal rearrangement. However, the brain pos-
sesses a latent recovery capacity and in early stages
some compensatory mechanisms are triggered (see
Table 1). Furthermore, the brains capacity to compen-
sate these structural and functional deficits is exploited
by neurorestoration attempts in animal models and
patients, as discussed below.
Neurorestoration
At the base of initial neurorestoration attempts lies the
idea of enhancing the endogenous neuroprotective effect
of growth fa ctors in the CNS. At first, genetically modi-
fied fibrob lasts to prod uce eith er BD NF, or NGF have
been transplanted in laboratory rats [88,89] and pri-
mates [90]. The experiments were successful in rescuing
functional and cellular loss. The same type of experi-
men t was conducted, in 2005, on human patients, diag-
nosed with AD [91]. The delivery system consisted of
induced pluripotent stem cells (iPS), generated from the
recipients fibroblast population and genetically modified
into secreting NGF. The authors reported significant
progress at 22 months follow-up, quantified by cognitive
scales and PET -Scan.
For PD patients, there are reports since the 1980sof
fetal midbrain dopamine cells implants [92]. The clinical
Table 1 Evidences of impaired neuroregeneration in AD and PD
Neurorestorative
field
Evidence of impairment Evidence of compensatory mechanism
Neurogenesis AD Decreased number of NPCs and altered division rates [21] Increased neuroproliferation markers [16]
PD Reduced number of NPCs [28] Increased number of PSA-NCAM + cells [29]
Neuroprotection AD Low BDNF mRNA and protein levels [37] Upregulation of glial truncated TrkB [40]
Controversed data on NGF levels [40,48,49] Possibly upregulation of NGF with ageing and
dementia [61,62,87]
Ab stimulates NGF astrocytic secrection [51]
High GDNF levels in cerebrospinal fluid
PD Low BDNF mRNA and protein levels [37] BDNF pretreatment protects dopaminergic neurons
[34]
Low GDNF protein levels [66]
Neuroplasticity AD Synaptic loss [77] Dynamic synaptic reorganization [82].
LTP impairment by Abeta oligomers and inflammatory
environment [85]
NCAM increase in dentate gyrus [83]
PD Loss of dendritic spines following loss of dopaminergic input [90]
Impaired synaptic plasticity in several models of PD [87-89]
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outcome was improved [93,94] and engraftment of trans-
planted cells was successful [95,96], although some
authors questioned the utility of t he procedure in older
patients [97]. However, two double-blinded, randomized,
controlled trials set back the initial positivism, showing
cell transplantation to be less effective than deep brain sti-
mulation [98], in preventing recurrent dyskinesia. It seems
however, that reported improvement is due to r eplace-
ment by graft cells of aged brain cells [99], rather than sti-
mulation of the brains own neurorestorative mechanism.
Other restorative models, tested in vitro or in animal
models of AD and PD, use stem cells therapy: i) embryo-
nic stem cells [100]; ii) embryonic stem cells-derived neu-
rospheres [101]; iii) transdifferentiated stem cells (stem
cells forced to differentiate outside their lineage by special
growth media and specific stimuli) (e.g. hematopoietic
stem cells), or iv) mesenchimal stem cells induced into
secreting increased quantities of growth factors [102].
Apel et al. report neuroprotective effects of dental pulp
cells co-cultured with hippocampal and mesencephalic rat
neurons, in in vitro AD and PD models [103]. Murell et al
used human olfactory mucosa-derived neuronal progeni-
tors to obtain dopaminergic neurons and transplant them
in a rat PD model brain. The outcome was favorable and
no difference was noted between transplants received
form healthy donors or from Parkinson patients [104].
Summary
As expected, most reports inc line towards progressive
impairment of neuroregeneration resources in AD and
PD brains, as proven on human post-mortem analysis,
animal models and in vi tro studies. However, due to
increased a mount of evidence that proper stimulation or
supply of growth factors restores some of the cognitive
loss and ameliorates behavioral skills, we hypothesize
that the brain possess, at least in early and medium stages
of disease, a neuroregenerative reserve, that may be and
begins to be, targeted as a therapeutical perspective.
List of abbreviations
AD: Alzheimers Disease; PD: Parkinsons Disease; NPCs: neural precursor cells;
PSA-NCAM: Polysialylated Neural Cell Adhesion Molecule; BDNF: Brain
Derived Nerve Factor; TrkB: tropomyosin-related kinase receptor B; NGF:
Nerve Growth Factor; GDNF: Glial Derived Nerve Factor
Acknowledgements
This paper is supported by the Sectorial Operational Programme Human
Resources Development (SOP HRD), financed from the European Social Fund
and by the Romanian Government under the contract number POSDRU/89/
1.5/S/64109 and by the Executive Unit for Financing Higher Education,
Research, Development and Innovation - Romania (UEFISCDI), Program 4
(Partnerships in Priority Domains), grant nr. 41-013/2007.
Author details
1
Department of Cellular and Molecular Medicine, Carol Davila University of
Medicine and Pharmacy, School of Medicine, 8 Eroilor Sanitari, sector 5,
Bucharest 050474, Romania.
2
Laboratory of Molecular Medicine, Victor Babeş
National Institute of Pathology, 99-101 Splaiul Independenţei, sector 5,
Bucharest 050096, Romania.
3
Department of Neurology, Iuliu Hatieganu
University of Medicine and Pharmacy, 8, Victor Babeş, Cluj Napoca 400023,
Romania.
4
Department of Neurology, University Hospital Bucharest, Carol
Davila University of Medicine and Pharmacy, 169 Splaiul Independenţei,
sector 5, Bucharest 050098, Romania.
Authors contributions
All authors contributed equally to elaboration of the manuscript, read and
approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 5 March 2011 Accepted: 23 June 2011
Published: 23 June 2011
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Pre-publication history
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doi:10.1186/1471-2377-11-75
Cite this article as: Enciu et al.: Neuroregeneration in neurodegenerative
disorders. BMC Neurology 2011 11:75.
Enciu et al . BMC Neurology 2011, 11:75
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    • "This can be achieved by utilizing means that can enhance adult hippocampal neurogenesis and neuronal and synaptic plasticity. Several different approaches have been employed in rodent models of AD with reasonable success to enhance neurogenesis and neuronal and synaptic plasticity [105] . Neural stem cells-based replacement approach for AD is currently the focus of intense research and has shown promising results in animal models of AD [106, 107]. "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood–brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.
    Full-text · Article · Jul 2016
    • "In all these cases, brain repair is necessary and neuroregenerative mechanisms to restore neuronal function exist, although most of them still remain unveiled. In addition, the hypothesis that neurodegeneration is a failure of neuroregeneration, increases the importance and complexity of the regenerative process (Armstrong and Barker, 2001; Enciu et al., 2011; Gage and Temple, 2013; Lim and Alvarez-Buylla, 2014). It is to emphasize that a broad heterogeneity among adult neural stem cells exists, their regional specification emerging in early embryonic development . "
    [Show abstract] [Hide abstract] ABSTRACT: Brain injury generates the release of a multitude of factors including extracellular nucleotides, which exhibit bi-functional properties and contribute to both detrimental actions in the acute phase and also protective and reparative actions in the later recovery phase to allow neuroregeneration. A promising strategy toward restoration of neuronal function is based on activation of endogenous adult neural stem/progenitor cells. The implication of purinergic signaling in stem cell biology, including regulation of proliferation, differentiation, and cell death has become evident in the last decade. In this regard, current strategies of acute transplantation of ependymal stem/progenitor cells after spinal cord injury restore altered expression of P2X4 and P2X7 receptors and improve functional locomotor recovery. The expression of both receptors is transcriptionally regulated by Sp1 factor, which plays a key role in the startup of the transcription machinery to induce regeneration-associated genes expression. Finally, general signaling pathways triggered by nucleotide receptors in neuronal populations converge on several intracellular kinases, such as PI3K/Akt, GSK3 and ERK1,2, as well as the Nrf-2/heme oxigenase-1 axis, which specifically link them to neuroprotection. In this regard, regulation of dual specificity protein phosphatases can become novel mechanism of actions for nucleotide receptors that associate them to cell homeostasis regulation.
    Full-text · Article · May 2016
    • "Indeed, over the past decade or two, increasing evidence has been generated that earlier intervention may be the key to achieving effective disease-modifying therapies for many neurodegenerative diseases. Studies in animal models, which incorporate major genetic and/or pathogenic variables and mimic important pathogenic elements in human diseases as diverse as ALS, AD, PD, lysosomal storage diseases and autism, have consistently shown that more robust therapeutic effects are achieved with earlier as opposed to later intervention (Golde et al., 2011; Tovar-y-Romo et al., 2014; Enciu et al., 2011; Sondhi et al., 2008; Giacometti et al., 2007). Moreover, the clinical effort to treat Parkinson's and Alzheimer's diseases with neurotrophic factors and other disease-modifying therapies has yielded information that provides even further empirical support for the concept that earlier intervention may be very important -possibly the most important variable not yet addressed in any of the neurotrophic trials, to date. "
    [Show abstract] [Hide abstract] ABSTRACT: The therapeutic potential of neurotrophic factors has been recognized for decades, with clinical trials in human neurodegenerative diseases extending back at least 25 years. While improvements in clinical dosing paradigms have reduced the side effects commonly seen in the earlier trials, efficacy has remained a serious disappointment (reviewed in Bartus and Johnson, 2016). This lengthy clinical effort stands in contrast to robust effects consistently achieved from different neurotrophic factors in a variety of animal models of neurodegeneration. This review discusses the prevailing assumption and supporting data that the major reason for the disappointing efficacy of past clinical trials is related to suboptimal dosing methods. It is concluded that while further improvements in dosing parameters might be useful, a much greater problem centers around a number of specific morphologic and functional changes in neurons in human neurodegenerative disease that mitigate the ability of neurotrophic factors to exert their effects. Moreover, the biological substrate which neurotrophic factors depend upon to exert their effects continues to erode as time progresses, due to the progressive nature of these diseases. For this reason, most of the empirically-supported reasons contributing to the weak neurotrophic responses in human patients can be mitigated by enrolling less severely advanced cases. It is further concluded that recent clinical trials of neurotrophic factors have generated important evidence that shifts risk: benefit assessments to support enrolling earlier-stage patients. While the Alzheimer's field has begun to shift attention toward much earlier-stage (even prodromal) patients in trials intended to modify disease progression, other neurodegenerative diseases (e.g., Parkinson's, ALS and possibly HD) must now consider similar changes in approach.
    Full-text · Article · Apr 2016
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