Review Article Treatment of multiple system atrophy - the past, present and future - the past, present ...
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Am J Clin Exp Immunol 2018;7(5):88-94
www.ajcei.us /ISSN:2164-7712/AJCEI0083748
Review Article
Treatment of multiple system
atrophy - the past, present and future
Haiyan Yu1*, Xiaoling Yuan1*, Lifeng Liu1, Tian Wang2, Dianrong Gong1
1
Department of Neurology, Liaocheng People’s Hospital, Liaocheng Clinical School, Taishan Medical University,
Liaocheng, PR China; 2Taishan Medical University, Liaocheng, PR China. *Equal contributors.
Received August 8, 2018; Accepted August 12, 2018; Epub October 5, 2018; Published October 15, 2018
Abstract: Multiple system atrophy is a sporadic progressive degenerative disease which is characterized by multiple
central nervous systems involved. So far, there is no effective medicine to cure MSA. The main research direction
of treatment includes immunization transplantation and cytotherapy. Human umbilical cord blood is the residue
of blood in the placenta and umbilical cord after fetal delivery. It is the most abundant cell bank and its usage is
not limited to treat hematological diseases. The researches about hUCB-MNC treatment on MSA are increasing
gradually. The potential of other MSC is also discussed. Lateral atlanto-occipital space puncture is an ingenious way
created by Professor Dianrong Gong. More than 30 cases of MSA have been treated by this method with fine clini-
cal effect and without serious complications. It indicates that stem cells treatment is a valid method for refractory
nerve system diseases.
Keywords: Multiple system atrophy, lateral atlanto-occipital space puncture, stem cells, human umbilical cord
blood-mononuclear cell
Multiple system atrophy (MSA), also named types can combine with autonomic nervous
Parkinsonism plus syndrome in the past, is a dysfunction [4]. The 2008 second consensus
sporadic progressive degenerative disease statement established by Gilman etc defined
which is characterized by multiple central MSA as sporadic, progressive and adult-onset
nervous systems involved [1]. Epidemiologic (>30 year old) neurodegenerative disease, and
data showed the MSA morbidity is 0.60- included imaging characteristics such as atro-
3.00/100,000 per year, and the prevalence phy of putamen, middle cerebellar peduncle,
rate is 1.90-4.90/100,000 per year [2, 3]. pons and cerebellum in MRI and hypometabo-
Once the onset, the condition of MSA progress- lism of putamen, brain stem and cerebellum in
es continuously, then leads to death or dis- FDG-PET.
abled, and the mean survival time is about 7-9
years. Based on the pathogenesis and patho- Pathology features and pathogenesis
logical features, we reviewed the treatment and
In 1989, Papp et al [5] found inclusion bodies in
research highlights of MSA as follows.
Oligodendrocyte are typical pathological chang-
Diagnostic criteria es in MSA patients. In 1998, Wakabayashi et al
[6] found α-synuclein is the main ingredient of
The previous diagnostic criteria was according inclusion bodies in Oligodendrocyte. And inclu-
to symptoms and signs. The clinical symptoms sion bodies with α-synuclein inside were also
include the different combination about stria- found in the neurons of Parkinson disease,
tum nigra degeneration, olivopontocerebellar Alzheimer’s disease, and Huntington dementia
atrophy and Shy-Drager syndrome. It can be patients, which indicates that there is a same
derived into MSA-P type which is manifested pathogenesis in these diseases and MSA,
with Parkinsonian symptoms and dopamine and they are called α-synuclein disease. The
poor outcome, and MSA-C type which has main α-synuclein is in inferior olivary nucleus, pon-
manifestations of cerebellar ataxia. Both of two tine nucleus, cerebellum, substantia nigra,Treatment of multiple system atrophy
locus coeruleus, putamen, pallidum, subtha- In recent years, many kinds of stem cells have
lamic nucleus and intermediolateral column of been found by researchers and they are trying
thoracic spinal cord, lower motor neuron and to treat MSA and other degenerative diseases
cortical cone neurons [7], and the distribution which hope to relieve the degeneration of
density is positively correlated with degree of neurons.
neuropathy. According to the studies, research-
ers found the possible pathogenesis of MSA is Stem cells
because of abnormally gathering of hyperphos-
Stem cell as “universal cell” has significant
phorylation of α-synuclein which leading to
superiority in treatment of neurodegenerative
degeneration of Oligodendrocyte, and inducing
diseases because of its particular biological
degeneration and loss of myelin, activating
characteristic. In recent years, researches
microglia, causing oxidative stress and inflam-
about stem cells increase quickly both in basic
matory reaction, and leading to degeneration
and clinical trials. In 2010, FDA approved the
and death of neurons [8-10]. Besides, immuno-
global first case of Oligodendrocyte precursor
inflammatory response is also found in the
cell in human embryonic stem cells for treat-
pathogenesis of MSA [11, 12]. Additionally, the
ment of acute spinal cord injury in human test-
intravenous injection of immunoglobulin can
ing. Soon afterwards, stem cell was approved
relieve the symptoms of MSA patients in clinical
in clinical trials in many countries such as
study [13], which indicates that the immune-
England, Swiss, Korea and China, and in last
mediated mechanism may also involve in the
year, umbilical cord blood cell was also
pathogenesis of MSA.
approved in enlarging clinical treatment by
Treatment in current situation FDA. In China, since 2016, 114 stem cell
clinical research record organizations were
Now there is no effective medicine to cure MSA, supported of clinical application transforma-
most part of methods are symptomatic treat- tion by Chinese National Health and Family
ment and enhanced care. The main research Planning Commission and the Food and Drug
direction of treatment includes immunization Administration.
transplantation and cytotherapy.
Stem cells are derided into embryo stem cells
1. Parkinsonism: Levodopa, monoamine oxi- and adult stem cells according to their sources.
dase inhibitor, or combination of them, but has The later one includes neural stem cells, mes-
no apparent results [14]. enchymal stem cells, induced pluripotent stem
cells [18] and umbilical cord blood mononucle-
2. Orthostatic hypotension: Midodrine Hydro- ar cells. Otherwise, embryo stem cells were
chloride or Pyridostigmine Bromide can reduce restricted in basic researches because of its
the difference of blood pressure between erect ethical issues and induced teratomas [19].
posiont and supine positon [15]. Adult stem cells are approved to use in both
preclinical and clinical trials.
3. Urinary and bowel disorders: Antidiuretic
hormone analogues or Trospium Chloride is for Neural stem cells
urinary incontinence, but with caution because
of its central nervous system side effect. Neural stem cells exist in cerebral ventricles,
Catheterization is for much residual urine, and hippocampus and striatum of brain tissues,
Laxative is for astriction [16]. and they have self-renewing ability and differ-
4. Cerebellum ataxia: Cholinergic agents are entiation potentiality [20]. In vitro and in vivo
advised for a try by some studies, which could trials it has shown that they can differentiate
increase cholinergic transmitter in the brain into neurons and gliocytes. The researchers
[17] and improve the symptoms, but there is no found that in mice models of neurodegenera-
any effect to confirm it. tive diseases, the stem cells can migrate into
the lesions of the brain (cortex, hippocampus
5. Change the life style and increase the and striatum) to proliferate and differentiate
rehabilitation and exercises: Stretch socks, into three kinds of nerve cells including neu-
avoiding hot environment, changing the posi- rons [21, 22]. Neural stem cells are ideal
tion slowly, balance exercises and other reha- donors for MSA by replacement treatment.
bilitation methods. Nonetheless, it is difficult to obtain the neural
89 Am J Clin Exp Immunol 2018;7(5):88-94Treatment of multiple system atrophy
stem cells because they are in the central nerve lar endothelial growth factor (VEGF), brain-
system. Moreover, it is restricted by ethics derived neurotrophic factor (BDNF), IL-6, Glial
problems if taking them from the brain of the cell line-derived neurotrophic factor (GDNF)
aborted fortus and using the embryonic stem and so on. These secretion substances were
cells. injected into substantia nigra and striatum of
the animal mode, the dopaminergic neurons
Mesenchymal stem cells (MSCs) increased and the motor behavior got improved
in the animal mode [41]. It indicates that MSCs
MSCs mainly include bone marrow MSCs, not only can differentiate into and replace the
umbilical cord MSCs, adipose tissue-derived damaged nerve cells, but have secretion and
MSCs and gingiva-derived MSCs [23-31]. The secretagogue function. We speculate MSCs
MSCs are widely used because they are easy to secret neuroprotective substances which can
obtain, and they have powerful self-renewing change the microenvironment of the lesions of
and differentiation ability, quick ex-vivo expan- MSA patients, regulate immunity, inhibit inflam-
sion, easy mediated gene transfer and other matory reaction, protect nerve cells, and pro-
advantages, and they have very little possibility mote the endogenous neural stem cells to gain
of oncogenicity [32-34]. In a mice trial, the bone the differentiation and secretion functions,
marrow MSCs were transplanted into the MSA- which contributes to treat and improve the
P type mice, the Parkinsonism symptoms got symptoms of MSA.
improved because of the neuroprotective and
immune-regulation effects [35]. Some similar Human umbilical cord blood-mononuclear cell
animal experiments have verified that MSCs (hUCB-MNC)
could decrease cytokines of TNF-α and IL-1
releasing, inhibit immuno-inflammatory reac- Human umbilical cord blood is the residue of
tions, and reduce the activation of astrocytes blood in the placenta and umbilical cord after
and gliocytes in the brain of MSA animal mode. fetal delivery. It is the most abundant cell bank
It has been confirmed that the proliferation of and its usage is not limited to treat hemato-
astrocytes and gliocytes is negatively correlat- logical diseases. In October 2017, a compre-
ed with survival levels of the neurons [36, 37]. hensive clinical research of umbilical cord
blood cells was developed at Duke University
In a recent study, the MSCs were injected into School of Medicine, which included patients
the internal carotid artery of MSA animal mode with autism, cerebral palsy, hydrocephalus, lan-
to observe the security and effectivity, and the guage disorders and cerebral ischemia. They
results were that there was no ischemic chang- found the most important cells in the umbilical
es in brain MRI, and in the treatment group, the cord blood are mononuclear cells which had
survival amount of neurons in striatum and nerve regeneration function [42]. Besides of
substantia nigra increased significantly and the proliferation and differentiation functions,
dyskinesia symptoms relieved obviously, which hUCB-MNC also has many advantages such as
indicates that this method could be safe and simple and convenient collection and separa-
effective [38]. Lee [39] found that after 1 year tion, noninvasive, no ethics controversy, low
follow-up, in the treatment group of 33 MSA antigenicity and longer survival time [43, 44].
patients, the UMSARS and cognitive ability are The researches about hUCB-MNC treatment
better than the control group, and the glucose on α-synucleinisopathies diseases such as
metabolism rate and grey matter concentration Parkinson disease, dementia and MSA, or on
in cerebellum and cerebral cortex were higher neuron motor disease increased gradually.
than in the control group. He also found there
was no any serious side effects correlating with HUCB-MNC is a mixed cell group. Besides some
MSCs during treatment and follow-up period. kinds of stem cells and ancestral cells such as
hematopoietic stem cells, MSCs and endothe-
The basic research found that MSCs also have lial progenitor cells, it also includes regulatory T
secretion ability [40]. Some proteomic analysis cells, natural killer cells, T lymphocytes and
was made about the substances secreted by dendritic cells, and these cells have protective
MSCs. The researchers found that there were functions in generating and developing process
many important neuromodulators including of neurodegenerative diseases [45]. Human
cystatin C, glia-derived nexin, galectin-1, vascu- umbilical cord blood cells have high level of
90 Am J Clin Exp Immunol 2018;7(5):88-94Treatment of multiple system atrophy
CD34+ and CD105+ cytological markers, which than 20 years. In 2011, Professor Gong trans-
means they have high regenerative potentiality planted stem cells into the brain by lateral
[46]. This was also found in many in vitro stud- atlanto-occipital space puncture. The needle is
ies, and it even has higher directional differen- inserted through lateral atlanto-occipital space
tiation functions. It can differentiate into nerve behind the ear, and hUCB-MNC is injected into
cells and replace the degenerative ones in cisterna magna. More than 200 kinds of refrac-
special environment [47-49]. In animal experi- tory nerve system diseases have been treated
ments, after hUCB-MNC was transplanted into by this method, which included more than 30
the brain, it could not only secret nerve growth cases of MSA with fine clinical effect and with-
factors [50-52], but promote endogenous neu- out serious complications. It indicates that
rotrophic factors to release [53], to protect neu- stem cells treatment may be valid for refractory
rons and repair the damaged cells, and rebuild nerve system diseases.
the regeneration microenvironment. Professor
Gong [54, 55] and her colleagues found the Conclusions
clinical scores of MSA improved significantly,
their daily life skills enhanced obviously. The MSA is a neurodegenerative disease with
conditions of 3 cases got significantly improve- extensive lesions, gradual progress and poor
ment in 3 days, and it was impossible for the prognosis. Some common methods used in
stem cells to differentiate into nerve cells, so it clinic could only improve few symptoms of
was probably because hUCB-MNC changed the patients but it could not cure it radically and
pathogenic micro-environment. Other studies improve the outcomes. Stem cell has many
also indicated that hUCB-MNC has positive characteristics such as self-replication, self-
effect in nerve system diseases treatment by renewal, differentiation and secreting neuro-
regulating immunity [56-58]. In recent years, trophic factors, and it can serve as a more
some researches showed that inflammatory effective intervention method for MSA and
and immune mechanisms were involved in the other refractory neurological diseases. Though
pathogenesis of MSA. So hUCB-MNC may play the basic experiments and clinical researches
roles by many aspects including differentiation, of stem cell are increasing gradually, we should
replacement, secretion, changing micro-envi- concern about its safety and validity, if it can
ronment, inhibiting inflammation and regulating survive after transplantation into human body,
immunity and so on. how it can integrate well with host, how it can
play therapeutic effect. Furthermore, there is
It is important to choose the appropriate way of no standardization about choice of stem cell
stem cell transplantation treatment for MSA. types, stem cell amounts, choice of treatment
The effective treatment not only depends on method and so on. In spite of many difficulties
the characteristics of the donor cells, but relies of treatment of neurodegenerative diseases
on if the stem cells can migrate to central nerve such as MSA, stem cell treatment would be a
system and integrate into the lesion tissues. prospective method in the future.
Some researchers found stem cells which were
transplanted by intravenous injection partly Disclosure of conflict of interest
passed through blood-brain barrier, and the
ones transplanted by carotid artery led to minor None.
cerebral embolism [59]. The lateral ventricle
Address correspondence to: Dianrong Gong, De-
puncture would damage the brain and may
partment of Neurology, Liaocheng People’s Hos-
have complications such as intracerebral infec-
pital, Liaocheng Clinical School, Taishan Medical
tion and cerebrospinal fluid fistula. The stereo-
University, No. 67, Dongchang West Road, Liaocheng
tactic technique usually used in the neurosur-
252000, PR China. E-mail: 13346256059@163.
gery operation is chosen for limited lesions, but
com
it is difficult to use in MSA patients because
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