Parkinson Disease: Le W

Pan T, Kondo S, Le W, Jankovic J. · Parkinson's Disease Research Laboratory, Baylor College of Medicine, Houston, TX 77030, USA. · Brain. · Pubmed #18187492 links to  free full text

Abstract: The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of alpha-synuclein and the increase of intracellular concentrations of non-mutant alpha-synuclein have been associated with Parkinson's disease phenotype. The demonstration that alpha-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant alpha-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease. In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

Deng H, Le W, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Brain. · Pubmed #17353225 links to  free full text

Abstract: Essential tremor (ET), the cause of which remains poorly understood, is one of the most common neurological disorders. While environmental agents have been proposed to play a role, genetic factors are believed to contribute to its onset. Thus far, three gene loci (ETM1 on 3q13, ETM2 on 2p24.1 and a locus on 6p23) have been identified in patients and families with the disorder. In addition, a Ser9Gly variant in the dopamine D3 receptor gene on 3q13 has been suggested to be a risk factor. Moreover, genetically deficient animal models express a phenotype that overlaps with some clinical characteristics of the human form of the illness. Further analyses of these genetic abnormalities may lead to the identification of causative mutations and a better understanding of the molecular mechanisms in this common movement disorder.

Chen S, Le W. · Institute of Neurology, Ruijin Hospital, Shanghai 2nd Medical University, Shanghai, China. · Am J Ther. · Pubmed #16988541 No free full text.

Abstract: During the past decade, there has been a remarkable progress in our understanding of the biology of Parkinson disease (PD), which has been translated into searching for novel therapy for PD. Much focus is shifted from the development of drugs that only relieve PD symptoms to new generation of remedies that can potentially protect dopaminergic neurons and modify the disease course. Several novel therapeutic approaches have been tested in preclinical experiments and in clinical trials, including molecules targeting on genes involved in the pathogenesis of the disease, neurotrophic factors critical for dopaminergic neuron survival and function, new generation of dopamine receptor agonists that may possess neuroprotective effects, and agents of antioxidation, antiinflammation, and antiapoptosis. The results of these studies will shed new light to our hope that PD can be cured in the future.

Le W, Appel SH. · Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Curr Opin Pharmacol. · Pubmed #15018843 No free full text.

Abstract: Recent progress has documented the presence of at least 10 disease-related genes or loci linked to Parkinson's disease. Analysis of the genotypes and phenotypes of these mutant genes has revealed a broad spectrum of clinical and pathological presentations, many of which share a common feature of alteration in the ubiquitin proteasome system. Further understanding of the pathogenesis of these inherited cases of Parkinson's disease and development of transgenic animal models bearing these mutations should provide novel insight into the causes of nigral cell death and meaningful strategies for future therapy.

Pan T, Jankovic J, Le W. · Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. · Drugs Aging. · Pubmed #12875608 No free full text.

Abstract: Tea is one of the most frequently consumed beverages in the world. It is rich in polyphenols, a group of compounds that exhibit numerous biochemical activities. Green tea is not fermented and contains more catechins than black tea or oolong tea. Although clinical evidence is still limited, the circumstantial data from several recent studies suggest that green tea polyphenols may promote health and reduce disease occurrence, and possibly protect against Parkinson's disease and other neurodegenerative diseases.Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury. The biological properties of green tea polyphenols reported in the literature include antioxidant actions, free radical scavenging, iron-chelating properties, (3)H-dopamine and (3)H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyltransferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation. All of these biological effects may benefit patients with Parkinson's disease.Despite numerous studies in recent years, the understanding of the biological activities and health benefits of green tea polyphenols is still very limited. Further in-depth studies are needed to investigate the safety and efficacy of green tea in humans and to determine the different mechanisms of green tea in neuroprotection.

Guo Y, Jankovic J, Zhu S, Le W, Song Z, Xie W, Liao D, Yang H, Deng H. · Department of Medical Information, Xiangya School of Medicine, Central South University, Changsha, China. · Neurosci Lett. · Pubmed #19429085 No free full text.

Abstract: Parkinson disease (PD) is one of the most common neurodegenerative disorders with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. At least thirteen gene loci responsible for PD or parkinsonism have been found and nine causative genes have been identified. Recently, Asn56Ser or Asn457Thr mutations in the Grb10-Interacting GYF Protein-2 gene (GIGYF2) were found to occur in about 2.4% familial PD Italian and French patients. We conducted genetic examination of Asn56Ser or Asn457Thr mutations, but none was found in 310 PD patients from North America. We did identify a non-disease-associated polymorphism Pro460Thr. Our results suggest that the GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population.

Du Y, Yang D, Li L, Luo G, Li T, Fan X, Wang Q, Zhang X, Wang Y, Le W. · Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. · Autophagy. · Pubmed #19337030 No free full text.

Abstract: The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important components of cellular mechanisms for protein degradation. In the present study we investigated the functional relationship of the two systems and the interactional role of p53 in vitro. Our study showed that the proteasome inhibitor lactacystin induced an increase in p53 level and autophagy activity, whereas inhibition of p53 by pifithrin-alpha or small interference RNA (siRNA) of p53 attenuated the autophagy induction and increased protein aggregation. Furthermore, we found that pretreatment with the autophagy inhibitor 3-methyladenine or beclin 1 siRNA further activated p53 and its downstream apoptotic pathways, while the autophagy inducer rapamycin showed the opposite effects. Moreover, we demonstrated that rapamycin pretreatment increased tyrosine hydroxylase (TH) protein level in dopamine (DA) neurons, which was associated with its induction of autophagy to degrade aggregated proteins. Our results suggest that p53 can mediate proteasomal inhibition-induced autophagy enhancement which in turn can partially block p53 or its downstream mitochondria-dependent apoptotic pathways. Further autophagy induction with rapamycin protects DA neurons from lactacystin-mediated cell death by downregulating p53 and its related apoptotic pathways and by inducing autophagy to degrade aggregated proteins. Therefore, rapamycin may be a promising drug for protection against neuronal injury relevant to Parkinson disease (PD). Our studies thus provide a mechanistic insight into the functional link between the two protein degradation systems.

Fan X, Luo G, Ming M, Pu P, Li L, Yang D, Le W. · Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China. · Neuroimmunomodulation. · Pubmed #19246938 No free full text.

Abstract: OBJECTIVE: Nurr1, a transcription factor essential for the differentiation and maturation of central dopaminergic cells, is primarily expressed in neurons of the central nervous system. In this study, we intend to determine the expression and modulation of Nurr1 in cultured microglia. METHODS: Nurr1 expression in cultured primary mouse microglia was measured by reverse transcription polymerase chain reaction, Western blot and immunofluorescent staining. Lipopolysaccharide (LPS) was used to activate microglia. Specific inhibitors were used to investigate whether the mitogen- activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), MAPK/Jun N-terminal kinase (JNK), P38 MAPK and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways were involved in the modulation of Nurr1 expression. RESULTS: Nurr1 was found to be located at both the cytoplasm and the nucleus of the microglia. After LPS stimulation, the expression of Nurr1 was significantly increased, which could be partially blocked by inhibitors of ERK, JNK and PI3K/Akt, but not by the P38 MAPK inhibitor; the ERK inhibitor can partially block the translocation of Nurr1 from the cytoplasm to the nucleus. CONCLUSION: Nurr1 is found to be expressed in cultured mouse microglia. The expression of Nurr1 is increased and the protein is translocated from the cytoplasm to the nucleus after activation by LPS, which could be modulated by the ERK, JNK and PI3K/Akt pathways.

Li X, Du Y, Fan X, Yang D, Luo G, Le W. · Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. · J Neuropathol Exp Neurol. · Pubmed #18800014 No free full text.

Abstract: Parkinson disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been proposed that dysfunction of the ubiquitin proteasome system plays an important role in the pathogenesis of Parkinson disease, but the mechanisms underlying ubiquitin proteasome system-related neuron degeneration are unknown. Here, we demonstrate that the proteasome inhibitor lactacystin induces phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, the release of cytochrome c, activation of both caspase-9 and caspase-3, and sequential apoptosis of dopaminergic neurons in vitro. Most of these effects can be attenuated by the JNK inhibitor SP600125. Furthermore, infusion of lactacystin in rats in vivo also leads to phosphorylation of JNK before nigral neuron loss; chronic administration of SP600125 also blocks this loss. These results indicate that JNK is involved in proteasome inhibition-induced dopaminergic neuron degeneration through caspase-3-mediated apoptotic pathways, suggesting that this kinase may be a therapeutic target for the prevention of substantia nigra pars compacta degeneration in Parkinson disease patients.

Le W, Pan T, Huang M, Xu P, Xie W, Zhu W, Zhang X, Deng H, Jankovic J. · Parkinson Disease Research Laboratory, USA. · J Neurol Sci. · Pubmed #18684475 No free full text.

Abstract: NURR1 is a transcription factor essential for the development, survival, and functional maintenance of midbrain dopaminergic (DAergic) neurons and NURR1 is a potential susceptibility gene for Parkinson's disease (PD). To determine whether NURR1 gene expression is altered in patients with PD, we measured its expression in human peripheral blood lymphocytes (PBL) in 278 patients with PD, 166 healthy controls (HC), and 256 neurological disease controls (NDC) by quantitative real-time PCR. NURR1 gene expression was significantly decreased in patients with PD (particularly those with family history of PD) as compared with HC (p<0.01) and also as compared with NDC (p<0.05). There was no significant difference in NURR1 gene expression among PD patients with or without anti-PD medications. When adjusted for gender, age, and ethnicity, lower levels of NURR1 gene expression were associated with significantly increased risk for PD in women, in patients 60 years old or older, and in patients of Caucasian origin. The observed reduction in PBL NURR1 gene expression indicates possible systemic involvement in PD, and the finding may help identify individuals with PD and other disorders associated with impaired central DAergic system.

Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W. · Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Neurobiol Dis. · Pubmed #18640276 No free full text.

Abstract: The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important cellular mechanisms for protein degradation. To investigate the role of autophagy in reversing neuronal injury, the proteasome inhibitor lactacystin was used to cause UPS dysfunction in differentiated PC12 cells and in C57BL/6 mice and rapamycin was used as an autophagy enhancer. The results showed that rapamycin pre-treatment attenuated lactacystin-induced apoptosis and reduced lactacystin-induced ubiquitinated protein aggregation in differentiated PC12 cells. The observed protection was partially blocked by the autophagy inhibitor 3-methyladenine. Furthermore, post-treatment of mice with rapamycin significantly attenuated lactacystin-induced loss of nigral DA neurons and the reduction of striatal DA levels. The lactacystin-induced high molecular ubiquitinated proteins were also attenuated by rapamycin treatment in vivo. In addition, as a chemical compound, rapamycin caused an increase of bcl2 protein level and blocked the release of cytochrome c from mitochondria to cytosal. We concluded that the neuroprotective effect of rapamycin is partially mediated by autophagy enhancement through enhanced degradation of misfolded proteins and autophagy enhancement may be considered to be a promising strategy to prevent diseases associated with misfolded/aggregated proteins, such as Parkinson's disease.

Du Y, Li X, Yang D, Zhang X, Chen S, Huang K, Le W. · Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China. · Exp Biol Med (Maywood). · Pubmed #18445767 links to  free full text

Abstract: The impairment of ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors promoting the growth and survival of mesencephalic dopamine (DA) neurons. To investigate whether GDNF has neuroprotective effects in a PD model induced by UPS impairment we administered GDNF by osmotic pump in C57BL/6 mice after nigrostriatal lesions with stereotactic injection of proteasome inhibitor lactacystin in the middle forebrain bundle. We found that lactacystin injection severely injured the nigral DA neurons and reduced the striatal levels of DA and its metabolites, while prolonged administration of GDNF at a sustained moderate dose for two weeks can significantly attenuate the lactacystin-induced loss of nigral DA neurons and striatal DA levels by 31% and 40%, respectively. We also investigated the molecular mechanisms for the neuroprotective effects of GDNF showing that lactacystin administration can cause the phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK (p38), and the c-Jun N-terminal kinase (JNK), whereas GDNF treatment can further enhance the phosphorylation of ERK and Akt but reduce the levels of JNK and p38. These results indicate that prolonged treatment with GDNF can protect the nigral DA neurons from the UPS impairment-induced degeneration. Several signaling path-ways including p38, JNK, Akt and ERK molecules seem to play an important role in this neuroprotection by GDNF.

Chen S, Zhang X, Yang D, Du Y, Li L, Li X, Ming M, Le W. · Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China. · FEBS Lett. · Pubmed #18242171 No free full text.

Abstract: Ropinirole, a D2/D3 receptor agonist has been reported to have neuroprotective effects. We showed that ropinirole can prevent rotenone-induced apoptosis in dopaminergic cell line SH-SY5Y through D3 receptor. We found that ropinirole can block the rotenone-induced phosphorylation of JNK, P38 and p-c-Jun, but promote the phosphorylation of ERK1/2. Furthermore, we demonstrated that ropinirole can reduce the rotenone-induced cleavages of caspase 9, caspase 3 and PARP and elevate the expression of anti-apoptotic proteins of p-Akt and bcl-2. These results provide a basis for neuroprotection by this drug for the treatment of Parkinson disease.

Deng H, Le W, Shahed J, Xie W, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Neurosci Lett. · Pubmed #18068301 No free full text.

Abstract: Mutations in the parkin gene and the PTEN-induced putative kinase 1 gene (PINK1) have been identified as the most common causes of autosomal recessive early-onset Parkinson disease (EOPD). To investigate the presence of the parkin and PINK1 gene mutation(s) and to explore genotype-phenotype correlations in American Caucasian families with EOPD from North American, we screened these two genes in probands of six families by direct sequencing, semi-quantitative PCR and RT-PCR. No PINK1 gene mutation was found in any of the probands, but compound heterozygous mutations (EX 3 del and EX 3_4 del) in the parkin gene were identified in one family. Extended analysis of the parkin-positive family showed the phenotype of patients was that of classic autosomal recessive EOPD, characterized by early age at onset, slow progression, beneficial response to levodopa, and levodopa-related motor complications. Three heterozygous mutation carriers (EX 3 del or EX 3_4 del) were free of any neurological symptoms. None of 62 healthy controls harbored EX 3 del or EX 3_4 del mutation. Our data suggest that compound heterozygous mutations (EX 3 and EX 3_4 del) in the parkin gene were the cause of EOPD in one of six Caucasian families; heterozygous EX 3 del and heterozygous EX 3_4 del forms were insufficient to cause this disorder, consistent with a loss-of-function mechanism of the parkin mutations. The results may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

Li X, Peng C, Li L, Ming M, Yang D, Le W. · Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. · J Gerontol A Biol Sci Med Sci. · Pubmed #17895431 No free full text.

Abstract: Evidence has shown that ubiquitin proteasome system (UPS) impairment plays an important role in the dopamine (DA) neurodegeneration in Parkinson's disease (PD). It has been reported that application of proteasomal inhibitor lactacystin in ventral mesencephalon (VM) cultures can cause DA neurodegeneration, although the underlying mechanisms are not clear. Herein, we used the lactacystin-induced DA cell degeneration model to study the neuroprotection of glial cell-derived neurotrophic factor (GDNF) in VM cultures. We measured the expression of endoplasmic reticulum stress (ERS)-related genes, and determined the caspase-3 activation, apoptotic cell death, as well as alpha-synuclein-positive inclusions in DA neurons. We found that GDNF treatment significantly suppressed the expression of ERS-related genes and inhibited the activation of caspase-3 and apoptotic cell death without affecting alpha-synuclein-positive inclusions in DA neurons. Our study suggests that the protection of GDNF against DA neurodegeneration in the UPS impairment model is associated with ERS and caspase-3 suppression.

Deng H, Le W, Huang M, Xie W, Pan T, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Neurosci Lett. · Pubmed #17482357 No free full text.

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified both in familial and sporadic cases of PD. Recently, a P755L variant in the LRRK2 gene has been found to be responsible for 2% of Chinese patients with sporadic PD. To evaluate the frequency of the LRRK2 P755L variant in North American Caucasian patients with PD, we screened 426 PD patients and 37 additional patients with the combination of PD and essential tremor (ET) from our Parkinson Disease Center and Movement Clinic at Baylor College of Medicine. No P755L variant was found in our PD cohort. Therefore, we conclude that LRKK2 P755L variant is a rare cause of Caucasian PD and has no diagnostic utility in genetic testing of this population of patients.

Deng H, Le W, Guo Y, Hunter CB, Xie W, Huang M, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · J Neurol Sci. · Pubmed #17097110 No free full text.

Abstract: In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype-phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

Deng H, Le W, Davidson AL, Xie W, Jankovic J. · Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. · Neurosci Lett. · Pubmed #16939701 No free full text.

Abstract: Several mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified both in familial and sporadic cases of Parkinson's disease (PD). G2019S, located at a kinase (MAPKKK) domain, is the most common mutation in the LRRK2 gene in PD, Two adjacent mutations (I2012T and I2020T) were mapped to the same domain suggesting shared pathogenic mechanism of these mutations. Since phenotypes of PD overlap with essential tremor (ET), we investigated LRRK2 G2019S, I2012T, and I2020T mutations in a cohort of 272 patients with ET. No mutations were found in our ET cohort and, therefore, we conclude that LRKK2 I2012T, G2019S and I2020T variants are rare causes of Caucasian ET.

Deng H, Xie W, Guo Y, Le W, Jankovic J. · No affiliation provided · Mov Disord. · Pubmed #16552756 No free full text.

This publication has no abstract.

Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH. · Department of Neurological Science, Rush University Medical Center, Chicago, Illinois 60612, USA. · J Comp Neurol. · Pubmed #16320253 links to  free full text

Abstract: In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organism's lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson's disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing alpha-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.

Pan T, Li X, Xie W, Jankovic J, Le W. · Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · FEBS Lett. · Pubmed #16313906 No free full text.

Abstract: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, has been reported to exert neuroprotection against a variety of insults. We now show that VPA attenuates rotenone (a potent complex I inhibitor)-induced apoptosis through the induction of heat shock protein 70, which may interact with apoptotic-protease-activating factor 1. Activation of p-Akt, p-Bcl-2, as well as p-Erk1/2 by VPA may be co-contributors to the protection.

Pan T, Xie W, Jankovic J, Le W. · Department of Neurology, Parkinson Disease Research Laboratory, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. · Neurosci Lett. · Pubmed #15740846 No free full text.

Abstract: Pramipexole (PRX) is a non-ergot dopamine (DA) D2/D3 receptor agonist. Experimental studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT density in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to determine whether PRX has direct biological effects on DAergic neuron-associated genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 microM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, didn't show this effect. Our findings that PRX has biological regulatory effects on DAergic neuron-associated genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.

Jiang C, Wan X, He Y, Pan T, Jankovic J, Le W. · Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Exp Neurol. · Pubmed #15589522 No free full text.

Abstract: The Nurr1 gene, which codes for a transcriptional factor in the nuclear receptor superfamily, plays an important role in the development of the mesencephalic dopaminergic (DAergic) system. To study the age-dependent effects of Nurr1 expression in maintaining mature nigrostriatal DAergic neuronal function, we examined motor behaviors, determined nigrostriatal dopamine (DA) levels and the number of nigral DAergic neurons, and measured the expression of several DAergic neuron-associated genes in heterozygous Nurr1-deficient (Nurr1+/-) and wild-type mice of different ages. In contrast to the same-aged, wild-type mice, old Nurr1+/- mice (>15 months) had a significant decrease in both rotarod performance and locomotor activities, suggesting a motor impairment that is analogous to parkinsonian deficit. Furthermore, the abnormal motor behaviors in old Nurr1+/- mice were associated with decreased DA levels in the striatum, decreased number of DAergic neurons in the nigra, and reduced expression of Nurr1 and DA transporter in the nigra. Our data indicate that Nurr1 plays an important role in the functional maintenance and survival of nigral DAergic neurons and suggest that the Nurr1+/- mouse is a useful animal model to study the pathogenesis of Parkinson disease (PD) and to explore disease-modifying strategies.

Jiang C, Wan X, Jankovic J, Christian ST, Pristupa ZB, Niznik HB, Sundsmo JS, Le W. · Parkinson Disease Research Lab, Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Clin Neuropharmacol. · Pubmed #15252266 No free full text.

Abstract: With a view toward improving the neural bioavailability of administered dopaminergic compounds, including dopamine, synthetic efforts have been directed toward enhancing the brain bioavailability of these compounds by accessing cellular sugar transport systems with stereoselective dopaminergic drugs. While synthesis and chemistry of the resultant class of compounds has recently been described in US Patent No. 6,548,484, the associated biologic properties have not previously been reported. One member of this new class, IPX-750, is a pro-drug dopamine-gluconamine designed to retain stereospecificity of binding at: glucose transporters (GLUT 1/GLUT 3 and intestinal Na/glucose co-transporters SGLT1), dopamine transporter (DAT); and, dopaminergic receptors of the D1/D2 families. Designed to be cleavable by tissue amidases, results reported here show that intact IPX-750 pro-drug retains dopaminergic agonist binding and biologic activities both in vitro and in vivo. IPX-750, like dopamine, exhibited predominant D5/D1 binding specificity with lower binding activity at D2. As expected, binding was highly stereo-specific, ie, IPX-760, a benzamide differing in just a hydrogen atom and keto oxygen from IPX-750, bound with 6-fold lower activity at D5. In cell culture, activation resulted from binding of IPX-750 at D1 or D5 in transfected cells was measured by increased intracellular cAMP. Interestingly, considering prior reported in vitro toxicity of dopamine oxidized and metabolic product dopamine, no evidence of in vitro toxicity was observed at up to 72 hrs in cell cultures at the EC50 of IPX-750 for increasing intracellular cAMP. IPX-750 was evaluated in the Parkinson's disease animal models, including MPTP mouse model, the 6-hydroxydopamine (6-OHDA) rat model and the Nurr1(+/-) knockout mouse model. In MPTP-lesioned and Nurr1+/- knockout mice, IPX-750 significantly increased Rota-rod time. In 6-OHDA-lesioned rats, IPX-750 significantly decreased apomorphine (APO)-induced rotation. Worthy of note, after cessation of IPX-750 treatments the anti-parkinsonian activity in MPTP-lesioned and Nurr1+/- mice required about 2 weeks to washout, suggesting a possible biologic reservoir of drug. In addition, after eight weeks of twice daily administration of 20 mg/kg IPX-750, mice did not show statistical difference in the total number of TH-positive neurons in substantia nigra (SN). These combined results suggest (i) that stereo-specific glycoconjugation may be an effective method to improve penetrability of drugs through the blood brain barrier; (ii) treatment with bioavailable IPX-750 in vitro did not show evidence for neurotoxicity; and, (iii) IPX-750 possesses dopaminergic properties and exerts anti-parkinsonian effects in three different PD rodent models, suggesting therapeutic potential for this new class of drugs in treating dopamine deficiency diseases.

Pan T, Le W, Jankovic J. · No affiliation provided · Neurology. · Pubmed #14750218 No free full text.

This publication has no abstract.