Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroprotective effects of estrogen and estrogen-like chemicals on neurodegenerative diseases, especially Parkinson's disease, have been well established. In the present study, we compared the effects of Bak Foong Pill (BFP), a well-known gynaecological tonic in China, and 17beta-estradiol, on dopamine transporter (DAT) and tyrosine hydroxylase (TH) gene expression patterns in ovariectomized, 1-methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-induced Parkinson's disease (PD) model mice, using multiplex reverse transcription-polymerase chain reaction (RT-PCR). MPTP, a specific dopaminergic neurotoxin, significantly decreased DAT and TH mRNA levels in the striatum, midbrain and cerebellum, but not the cortex, of C57BL/6 mice. However, MPTP-challenge with BFP pretreatment demonstrated reduced neurotoxicity, with DAT and TH mRNA levels either not affected by MPTP or affected to a significantly lesser extent in the midbrain and striatum as compared to the MPTP treated controls. 17beta-estradiol treatment prevented MPTP-induced reduction of DAT expression in striatum and midbrain, but failed to alter TH expression. These results suggest that BFP is able to protect dopaminergic neurons against MPTP-induced neuronal damage in a mechanism that is different from the protective effect of estrogen.
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PMID:Neuroprotective effects of Bak Foong Pill in 1-methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-induced Parkinson's disease model mice. 1530 30

Apoptosis may be initiated in neurons via mitochondrial release of the respiratory protein, cytochrome c. The mechanism of cytochrome c release has been studied extensively, but little is known about its dynamics. It has been claimed that release is all-or-none, however, this is not consistent with accumulating evidence of cytosolic mechanisms for 'buffering' cytochrome c. This study has attempted to model an underlying disease pathology, rather than inducing apoptosis directly. The model adopted was diminished activity of the mitochondrial respiratory chain complex I, a recognized feature of Parkinson's disease. Titration of rat brain mitochondrial respiratory function, with the specific complex I inhibitor rotenone, caused proportional release of cytochrome c from isolated synaptic and non-synaptic mitochondria. The mechanism of release was mediated, at least in part, by the mitochondrial outer membrane component Bak and voltage-dependent anion channel rather than non-specific membrane rupture. Furthermore, preliminary data were obtained demonstrating that in primary cortical neurons, titration with rotenone induced cytochrome c release that was subthreshold for the induction of apoptosis. Implications for the therapy of neurodegenerative diseases are discussed.
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PMID:Cytochrome c release from rat brain mitochondria is proportional to the mitochondrial functional deficit: implications for apoptosis and neurodegenerative disease. 1568 86

Bak Foong Pills (BFP), a traditional Chinese medicine used for centuries for the enhancement of women's health, was shown to display neuro-protective activity in the 1-methyl-4-phenyl-1,2,4,6,-tetrahydro-pyridine (MPTP)-induced mouse model in a previous study. In order to elucidate its mechanism of action, we investigated the anti-apoptotic properties of Bak Foong Pills and its main ingredients, including Panax ginseng, Angelica sinensis, Glycyrrhiza uralensis, and Ligusticum chuanxiong, in the 6-hydroxydopamine (6-OHDA)-treated PC12 cell model. The addition of the neurotoxin could cause significant cell death and reduction of cell proliferation, as shown in the results determined by MTT assay, nitric oxide (NO) measurement and flow cytometric propidium iodine (PI) staining analysis, while pre-treatment of PC12 cell with either BFP or its main ingredients prevented the toxicity to some degree. In addition, the neurotoxin caused an elevated activation of caspase-3, the key enzyme for activation of the cellular apoptotic cascade, whereas BFP or its main ingredients inhibited the activation of caspase-3. These results strongly indicate that BFP and its main ingredients may provide a useful therapeutic strategy for the treatment of neurodegenerative diseases, such as Parkinson's disease.
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PMID:Anti-apoptotic activity of Bak Foong Pills and its ingredients on 6-hydroxydopamine-induced neurotoxicity in PC12 cells. 1615 79

Bak Foong pill (BFP) is a well-known traditional Chinese medicine used for treatment of various gynaecological disorders. In addition, it exerts beneficial effects on other functional systems including the central nervous system. In the present study, we have investigated the possible neuroprotective action of BFP upon the nigrostriatal dopaminergic system by examining its effect on the expression patterns of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the 1-methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. MPTP significantly decreased TH and DAT mRNA levels in the striatum and midbrain of both female and male C57BL/6 mice. However, with BFP pre-treatment mice showed a reduced neurotoxicity, with TH and DAT mRNA levels either not affected by MPTP or affected to a lesser extent in the midbrain and striatum when compared to vehicle treated animals. Possible anti-apoptotic activity of BFP was further studied in a dopamine-secreting neuroendocrine cell line, PC12. In this assay, MPTP elevated the expression of a pro-apoptotic gene, Bax, while this expression was reduced by BFP pre-treatment. Flow cytometry results also revealed that the effect of MPTP-induced apoptosis in PC12 cell lines was significantly reduced by BFP. The present results suggest that BFP is able to protect dopaminergic neurons from neurotoxin-induced neuronal injury with anti-apoptotic activity being one of the possible mechanisms.
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PMID:Bak Foong protects dopaminergic neurons against MPTP-induced neurotoxicity by its anti-apoptotic activity. 1792 Sep 44

Paraquat (PQ) causes selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, reproducing an important pathological feature of Parkinson disease. Oxidative stress, c-Jun N-terminal kinase activation, and alpha-synuclein aggregation are each induced by PQ, but details of the cell death mechanisms involved remain unclear. We have identified a Bak-dependent cell death mechanism that is required for PQ-induced neurotoxicity. PQ induced morphological and biochemical features that were consistent with apoptosis, including dose-dependent cytochrome c release, with subsequent caspase-3 and poly(ADP-ribose) polymerase cleavage. Changes in nuclear morphology and loss of viability were blocked by cycloheximide, caspase inhibitor, and Bcl-2 overexpression. Evaluation of Bcl-2 family members showed that PQ induced high levels of Bak, Bid, BNip3, and Noxa. Small interfering RNA-mediated knockdown of BNip3, Noxa, and Bak each protected cells from PQ, but Bax knockdown did not. Finally, we tested the sensitivity of Bak-deficient mice and found them to be resistant to PQ treatments that depleted tyrosine hydroxylase immuno-positive neurons in the substantia nigra pars compacta of wild-type mice.
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PMID:Paraquat neurotoxicity is mediated by a Bak-dependent mechanism. 1805 1

An important feature of Parkinson's disease is the degeneration of dopaminergic neurons in the Substantia Nigra pars compacta. Paraquat (PQ) and MPTP cause the selective degeneration of these neurons in vivo, and combining PQ with maneb exacerbates that pathology. Elucidation of the cell death mechanisms involved is important to understand how multiple environmental toxins may contribute to sporadic Parkinson's disease. We recently reported that PQ induces neuronal apoptosis through Bak activation, in contrast to MPP(+), the toxic metabolite of MPTP, which relies on Bax and p53. Here we show that individually PQ and maneb activate Bak, but together they trigger Bax-dependent cell death. Focusing on mechanisms responsible for this synergy, we found that maneb+PQ increased the expression of three strong Bak inhibitors, Bfl-1, Bcl-xL and Mcl-1, and also induced Bax activators that included Bik and Bim. Those responses favor Bax-dependent MOMP and apoptosis. SiRNA knockdown of Bax and Bak confirmed that individually PQ and maneb induce Bak-dependent cell death, but together they block the Bak pathway and activate apoptosis through Bax.
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PMID:Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members. 1826 26

Parkinson's disease (PD) results from the death of specific neuronal populations in the CNS. Potential causative factors include environmental toxins and gene mutations that can combine to dysregulate the processing and degradation of alpha-synuclein. Oxidative stress induced by the neurotoxins MPTP, paraquat, maneb, and rotenone causes lipid peroxidation and protein misfolding that affects cell death through members of the Bcl-2 family. Sufficient activation of Bax and Bak facilitates mitochondrial outer-membrane permeabilization, which releases death-inducing factors that cause apoptotic and nonapoptotic programmed cell death. The formation of alpha-synuclein aggregates is a defining pathologic feature of PD and is induced by these neurotoxins as well as several Parkinson-linked familial mutations. Of the familial mutations identified thus far, two of the loci encode proteins associated with ubiquitin-proteasome degradation of misfolded proteins (Parkin and Uch-L1), and two encode proteins associated with mitochondria and oxidative stress (DJ-1 and PINK1). Both gene and toxin findings indicate that dopaminergic neuron losses in PD are the result of oxidative stress affecting mitochondria function and ubiquitin-proteasome activity. Here we describe how related cell death mechanisms are involved in the pathophysiology of Parkinson's disease.
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PMID:Parkinson-linked genes and toxins that affect neuronal cell death through the Bcl-2 family. 1871 46

Hydrogen peroxide (H2O2) is a major Reactive Oxygen Species (ROS), which has been implicated in many neurodegenerative conditions including Parkinson's disease (PD). Rosmarinus officinalis (R. officinalis) has been reported to have various pharmacological properties including anti-oxidant activity. In this study, we investigated the neuroprotective effects of R. officinalis extract on H2O2-induced apoptosis in human dopaminergic cells, SH-SY5Y. Our results showed that H2O2-induced cytotoxicity in SH-SY5Y cells was suppressed by treatment with R. officinalis. Moreover, R. officinalis was very effective in attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H2O2. R. officinalis extract effectively suppressed the up-regulation of Bax, Bak, Caspase-3 and -9, and down-regulation of Bcl-2. Pretreatment with R. officinalis significantly attenuated the down-regulation of tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC) gene in SH-SY5Y cells. These findings indicate that R. officinalis is able to protect the neuronal cells against H2O2-induced injury and suggest that R. officinalis might potentially serve as an agent for prevention of several human neurodegenerative diseases caused by oxidative stress and apoptosis.
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PMID:Neuroprotective effect of Rosmarinus officinalis extract on human dopaminergic cell line, SH-SY5Y. 2056 2

Talipexole is a non-ergot dopamine (DA) agonist that has been used in the treatment of Parkinson's disease. In the present study, we examined the effect of talipexole on paraquat (PQ)-induced N27 cell death and the intracellular pathways involved in this effect. Pretreatment of N27 cells with talipexole (1mM) resulted in significant protection against paraquat-induced cell death. In N27 cells, talipexole inhibited paraquat-induced apoptotic hallmarks such as cytochrome c release, caspase-3 activation, chromatin condensation and externalization of phosphatidilserine. Talipexole pretreatment prevents the reduction in the anti-apoptotic Bcl-x(L) protein and increases in the pro-apoptotic form of Bak and p-Bad, both induced by PQ. Finally, we also observed that talipexole abrogates the activation of cell death pathways JNK1/2 and p38 produced by PQ, and increases the phosphorylated (active) forms of the pro-survival pathways ERK1/2 and Akt. These results reveal that talipexole exerts a neuroprotective effect in a mesencephalic cell line exposed to the neurotoxin PQ, which is related to the etiology of Parkinson's disease.
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PMID:The neuroprotective effect of talipexole from paraquat-induced cell death in dopaminergic neuronal cells. 2067 35

Autophagy is an evolutionarily conserved process that mediates the degradation of abnormal proteins and the removal of dysfunctional organelles. Recently, accumulating evidence has implicated the dysregulation of autophagy as underlying the pathophysiology of several neurodegenerative diseases. Using culture models of Parkinson's disease, we have investigated whether and how prototypic autophagic events occur upon exposure to N-methyl-4-phenylpyridinium, a dopaminergic neurotoxin, or nigericin, a K(+)/H(+) ionophore. From these independent studies, we have found that these drugs equally induce morphological and biochemical changes typical of autophagy, including accumulation of autophagic vacuoles, appearance of LC3-II forms, and alteration in the expression and distribution of p62. Further investigation has indicated that drug-induced autophagic phenomena are largely the consequences of an impaired autophagic flux. In these cell death paradigms, we have intriguingly found that Bak, a prototypic proapoptotic protein of the Bcl-2 family, exerts a protective role via reduction of the area occupied by swollen vacuoles and appearance of the LC3-II form, whereas silencing of Bak aggravates these phenomena. Further study has indicated that a protective role for Bak is primarily ascribed to its regulatory effect on the maintenance of autophagic flux and vacuole homeostasis. In this regard, a regulatory role for calcium has been proposed.
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PMID:Impaired autophagic flux is critically involved in drug-induced dopaminergic neuronal death. 2426 72


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