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1.
Oki C Watanabe Y Yokoyama H Shimoda T Kato H Araki T 《Cellular and molecular neurobiology》2008,28(3):417-430
The authors investigated the protective effects of a novel astrocyte-modulating agent, arundic acid, in a 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine
(MPTP) mouse model of Parkinson’s disease. Male mice received four intraperitoneal (i.p.) injections of MPTP (20 mg/kg) at
2 h intervals. The content of dopamine and its metabolites in the striatum was reduced markedly 7 days after MPTP treatment.
The delayed treatment with arundic acid (30 mg/kg, i.p.) administered 3, 4, 5 and 6 days after MPTP treatment did not affect
the depletion of dopamine and its metabolites in the striatum. Our immunohistochemical study with anti-tyrosine hydroxylase
antibody, anti-neuronal nuclei antibody, anti-glial fibrillary acidic protein antibody, anti-S100β antibody and anti-nestin
antibody showed that the delayed treatment with arundic acid had a protective effect against MPTP-induced neuronal damage
in the striatum and the substantia nigra of mice. Furthermore, this agent ameliorated the severe reductions in number of isolectin
reactive microglia in the striatum and the substantia nigra 7 days after MPTP treatment. These results demonstrate that the
inhibition of S100β synthesis in astrocytes may be the major component of the beneficial effect of arundic acid. Thus, our
present findings provide that the therapeutic strategies targeted to astrocytic modulation with arundic acid offers a great
potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with Parkinson’s
disease. 相似文献
2.
The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease
afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of
the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies
that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of
some of the most devastating diseases of old age. 相似文献
3.
Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene–environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and prion diseases.) and discuss possible links of gene–environment interplay including, where implicated, mitochondrial genes. 相似文献
4.
The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective
was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors
in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most
frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral
amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four
degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide
dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD,
HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF
and appeared to be a good biomarker of PD. 相似文献
5.
α-Synuclein and dopamine metabolism 总被引:4,自引:0,他引:4
α-Synuclein (α-Syn), a 140-amino-acid protein richly expressed in presynaptic terminals in the central nervous system, has
been shown to play a central role in the pathogenesis of Parkinson’s disease. Although the normal functions of α-Syn remain
elusive, accumulating evidence shows that the molecule is involved in multiple steps related to dopamine metabolism, including
dopamine synthesis, storage, release, and uptake. The regulatory effect of α-Syn on dopamine metabolism is likely to tone
down the amount of cytoplasmic dopamine at nerve terminals, thereby limiting its conversion to highly reactive oxidative molecules.
Formation of α-Syn protofibrils triggered by factors such as gene mutations and environmental toxins can make the molecule
lose its normal functions, leading to disrupted homeostasis of dopamine metabolism, increased cytoplasmic dopamine levels,
and enhanced oxidative stress in dopaminergic neurons. The enhanced oxidative stress will, in turn, exacerbate the formation
of α-Syn protofibrils and drive the neurons into a vicious cycle, which will finally result in the selective degeneration
of the dopaminergic neurons associated with Parkinson’s disease. 相似文献
6.
Münch C Zhu BG Mink A Seefried U Riepe MW Ludolph AC Meyer T 《Neurochemical research》2008,33(6):1005-1010
Hypoxia is one of the major common components of vascular risk factors for pathogenesis of Alzheimer’s disease. This study
investigated the possible relationship between hypoxia and alternative splicing of the excitatory amino acid transporter 2
(EAAT2) in a transgenic model for Alzheimer’s disease. We used an APP23 mouse model prior to amyloid deposition and subjected
it to chemical hypoxia treatment as induced by 3-nitropropionic acid. One hour after administration of 3-nitropropionic acid
changes in the expression of the 5′-splice forms mEAAT2/5UT3, mEAAT2/5UT4, and mEAAT2/5UT5 were found in the frontal cortex,
hippocampus and cerebellum of the APP23 model. In untreated APP23 animals the expression of EAAT2 splice variants was unchanged.
Our results demonstrate that hypoxia facilitates alternative splicing of EAAT2 in the APP23 model. This may be a molecular
mechanism linking vascular factors to early pathophysiology of Alzheimer’s disease. 相似文献
7.
Agmatine treatment is known to exert neuroprotective effects in several models of neurotoxic and ischemic brain and spinal
cord injuries. Here we sought to find out whether agmatine treatment would also prove to be neuroprotective in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) model of Parkinson’s disease. Concomitant daily treatment (intraperitoneal injections) with agmatine (100 mg/kg for
5 days) and MPTP (40 mg/kg for 2 days) exacerbated MPTP-related toxicity as evidenced by a larger reduction in dopamine uptake
into striatal synaptosomes (42.4% as compared to 58.3% of control, respectively). In contrast, agmatine treatment commencing
after MPTP, produced partial protection (31%) against MPTP dopaminergic toxicity. The findings implicate agmatine in mechanisms
regulating MPTP neurotoxicity, but underscore the characteristic neuroprotective efficacy of agmatine when applied after the
insult. 相似文献
8.
Beal MF 《Amino acids》2011,40(5):1305-1313
There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro
and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies
examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic
lesions produced by N-methyl-d-aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic
acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent
neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic
neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic
mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor
performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS).
Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the
R6/2 and the N-171-82Q transgenic mouse models of Huntington’s disease (HD), even when its administration was delayed until
the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with
creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive
neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP
model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2
transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine
may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine,
however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine
increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical
trials for the treatment of Parkinson’s disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement
in Unified Parkinson’s Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in
a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine
in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the
CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases. 相似文献
9.
Environmental toxins and α-synuclein in Parkinson’s disease 总被引:3,自引:0,他引:3
In recent years, environmental influences have been thought to play an important role in Parkinson’s disease (PD). Evidence
from epidemiological investigations suggests that environmental factors might take part in the disease process. Intriguingly,
most of environmental toxins share the common mechanism of causing mitochondria dysfunction by inhibiting complex I and promoting
α-synuclein aggregation, a key factor in PD. Therefore, understanding the mechanism of interactions between α-synuclein and
environmental factors could lead to new therapeutic approaches to PD. 相似文献
10.
11.
α-Synuclein plays a key role in the pathological neurodegeneration in Parkinson’s disease. Although its contribution to normal
physiology remains elusive, the selective degeneration of α-synuclein-containing dopaminergic neurons in Parkinson’s disease
may be linked to abnormal α-synuclein induced toxicity. In the present study, a complex of α-synuclein and vesicular monoamine
transporter-2 was identified by GST-Pull Down experiment. In wild-type α-synuclein stably transfected SH-SY5Y cell lines,
the activity of vesicular monoamine transporter-2 decreased by 31% as determined by [3H] dopamine uptake, and its expression also decreased in both protein and mRNA levels using western and northern blot analysis.
Overexpression of wild-type α-synuclein did not induce cell death or apoptosis, but significantly enhanced the intracellular
reactive oxygen species level as assayed by flow cytometry. These data suggest that Up-regulated α-synuclein expression inhibits
the activity of vesicular monoamine transporter-2, thereby interrupting dopamine homeostasis and resulting in dopaminergic
neuron injury in Parkinson’s disease. 相似文献
12.
3-Nitropropionic acid (3-NP)-induced neurotoxicity can be used as a model for the genetic neurodegenerative disorder Huntington’s
disease (HD). A metabolic profiling strategy was adopted to explore the biochemical consequences of 3-NP administered to rats
in specific brain regions. 1H NMR spectroscopy was used to characterize the metabolite composition of several brain regions following 3-NP-intoxication.
Dose-dependent increases in succinate levels were observed in all neuroanatomical regions, resulting from the 3-NP-induced
inhibition of succinate dehydrogenase. Global decreases in taurine and GABA were observed in the majority of brain regions,
whereas altered lipid profiles were observed only in the globus pallidus and dorsal striatum. Depleted phosphatidylcholine
and elevated glycerol levels, which are indicative of apoptosis, were also observed in the frontal cortex of the 3-NP model.
Many of the metabolic anomalies are consistent with those reported in HD. The 3-NP-induced model of HD provides a means of
monitoring potential mechanisms of pathology and therapeutic response for drug interventions, which can be efficiently assessed
using metabolic profiling strategies. 相似文献
13.
Takuya Oshikawa Hayato Kuroiwa Ryohei Yano Hironori Yokoyama Naoto Kadoguchi Hiroyuki Kato Tsutomu Araki 《Cellular and molecular neurobiology》2009,29(5):769-777
Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons.
Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-l-γ-t-butyl-l-glutamyl-l-alanyl-l-leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations
of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid)
and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease
in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at
a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial
fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose
of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP
treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum
and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP
neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation
of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson’s disease.
Takuya Oshikawa and Hayato Kuroiwa contributed equally to this work. 相似文献
14.
Yu WH Matsuoka Y Sziráki I Hashim A Lafrancois J Sershen H Duff KE 《Neurochemical research》2008,33(5):902-911
Familial Parkinson’s disease (PD) has been linked to point mutations and duplication of the α-synuclein gene and mutant α-synuclein
expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine
and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T
α-synuclein (α-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if
mutant human α-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single,
sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the α-syn tg and ntg mice. In the olfactory
bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the α-syn tg mice. In addition, we identified
a significant increase in dopamine metabolism in the α-syn transgenic, but not ntg mice. Finally, MPTP treatment of α-syn
tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with α-synuclein.
Cumulatively, the data support the hypothesis that mutant α-synuclein sensitizes dopaminergic neurons to neurotoxic insults
and is associated with greater oxidative stress. The α-syn tg line is therefore useful to study the genetic and environmental
inter-relationship in PD. 相似文献
15.
Norepinephrine and dopamine have important role in movement disorders but their role in movement disorders associated with
Japanese encephalitis (JE) has not been evaluated. Therefore, in the present study, cerebrospinal fluid (CSF) catecholamine
levels and its metabolites in JE patients with movement disorders were compared with those without JE. CSF was collected by
lumbar puncture and analyzed by HPLC-ED. Norepinephrine, dopamine and homovanillic acid concentrations were significantly
(P<0.005) lower in JE patients compared to control groups. Low levels of catecholamines in JE associated movement disorders
compared to idiopathic Parkinson’s disease and other extrapyramidal symptoms may be due to severe structural damage to thalamus,
basal ganglia and brainstem in JE patients as revealed by MRI findings. 相似文献
16.
Dopaminergic activity is expected to be altered in patients with Huntington’s disease (HD) and be related to factors like
duration and severity of illness or patients’ specific symptomatology like dementia, depression, or psychotic features. We
assessed plasma homovanillic acid (pHVA) and plasma prolactin (pPRL), two correlates of dopaminergic activity, in 116 subjects
with CAG repeats expansion in the HD gene, 26 presymptomatic (18 females) and 90 with overt symptomatology (43 females). Patients
were evaluated using the Unified HD Rating Scale and the Total Functional Capacity Scale. Presence of dementia, depression,
and psychotic features were also assessed. The age range of the patients was 22–83 years, duration of illness from 0.5 to
27 years, and CAG repeat number from 34 to 66. A group of 60 age and sex matched healthy subjects served as control group.
Plasma PRL in subjects at risk and in neuroleptic-free patients, evaluated separately for males and females, did not differ
from controls. Plasma HVA levels did not differ from controls in the group of presymptomatic subjects, but were significantly
higher in the patients group. This increase was positively associated mainly with severity of illness and functional capacity
of the patients, and not with presence of depression or dementia. Plasma HVA levels may be proven to be a peripheral index
of disease progression. Reducing dopaminergic activity may have not only symptomatic, but also neuroprotective effects in
HD. 相似文献
17.
Several lines of evidence support the neuroprotective action of cyclooxygenase-2 (COX-2) inhibitors in various models of Parkinson’s
disease (PD). In the current study, we investigated the neuroprotective properties of several COX inhibitors against 1-methyl-4-phenylpyridinium
(MPP+) in neuroblastoma Neuro 2A (N-2A) cells in vitro and the protection against degeneration of substantia nigra pars compacta
(SNc) dopaminergic (DA) neurons after the administration of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) in C57/BL6
male mice. The data obtained demonstrate a lack of protective effects observed by COX 1-2 inhibitors ibuprofen and acetylsalicylic
acid against MPP+ toxicity in N-2A, where piroxicam was protective in a dose dependent manner (MPP+ control: 15 ± 2% MPP+
piroxicam: 5 mM 89 ± 4%). The data also indicate a drop in mitochondrial oxygen (O2) consumption and ATP during MPP+ toxicity with no restoration of mitochondrial function concurrent to a heightened concentration
of somatic ATP during piroxicam rescue. These findings indicate that the neuroprotective effects of COX inhibitors against
MPP+ are not consistent, but that piroxicam may work through an unique mechanism to propel anaerobic energy metabolism. On
the other hand, using mice, piroxicam (20 mg/kg) was effective against MPTP-induced dopaminergic degeneration in the (SNc)
and loss of locomotive function in mice. Administering a 3 day pre-treatment of piroxicam (20 mg/kg) was effective in antagonizing
the losses in SNc tyrosine hydroxylase protein expression, SNc DA concentration and associated anomaly in ambulatory locomotor
activity. It was concluded from these findings that piroxicam is unique among COX inhibitors in providing very significant
neuroprotection against MPP+ in vitro and in vivo. 相似文献
18.
Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia
possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus,
and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The
experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with
simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility
during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects.
In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration
of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It
was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or
stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor
of adenosine A2A receptors, as an anti-Parkinson drug. 相似文献
19.
Salsolinol, an endogenous neurotoxin, is known to be involved in the pathogenesis of Parkinson’s disease (PD). In the present
study, we have investigated the effects of salsolinol on the activation of two different signaling pathways that involve c-Jun
N-terminal kinase (JNK), and nuclear factor-κB, (NF-κB) in human dopaminergic neuroblastoma SH-SY5Y cells. Salsolinol treatment
caused upregulation in the levels of c-Jun and phosphorylated c-Jun. It also caused degradation of IκBα and translocated the
active NF-κB into the nucleus. The binding activity of NF-κB to DNA was enhanced by salsolinol in a concentration dependent
manner. Furthermore, salsolinol decreased the levels of the anti-apoptotic protein Bcl-2, and increased pro-apoptotic protein
Bax, while enhancing the release of cytochrome-c from mitochondria. Mitochondrial complex-I activity was significantly decreased and reactive oxygen species (ROS) were increased
in salsolinol treated cells. These results partly suggest that salsolinol-induced JNK and NF-κB signaling pathways may be
involved in induction of apoptosis in human dopaminergic neurons, as seen in Parkinson’s disease. 相似文献
20.
In China, it has been estimated that there are more than 2.0 million people suffering from Parkinson’s disease, which is currently
becoming one of the most common chronic neurodegenerative disorders during recent years. For many years, scientists have struggled
to find new therapeutic approaches for this disease. Since 1994, our research group led by Drs. Ji-Sheng Han and Xiao-Min
Wang of Neuroscience Research Institute, Peking University has developed several prospective treatment strategies for the
disease. These studies cover the traditional Chinese medicine—herbal formula or acupuncture, and modern technologies such
as gene therapy or stem cell replacement therapy, and have achieved some original results. It hopes that these data may be
beneficial for the research development and for the future clinical utility for treatment of Parkinson’s disease.
Special issue article in honor of Dr. Ji-Sheng Han. 相似文献