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)

alpha-Synuclein has been implicated in the pathogenesis of Parkinson disease (PD) and related neurodegenerative disorders. More recently, it has been suggested to be an important regulatory component of vesicle transport in neuronal cells. alpha-Synuclein is also highly expressed in platelets and is loosely associated with the membrane of the secretory alpha-granules. However, the functional significance of these observations is unknown. In this study, the possible function of alpha-synuclein in vesicle transport, with particular regard to alpha-granule release from the platelets, was investigated. The results showed that ionomycin- or thrombin-induced alpha-granule secretion was inhibited by exogenous alpha-synuclein addition in a dose-dependent manner. However, [(3)H]5-HT release from the dense granules and hexosaminidase release from the lysosomal granules were not affected. Two point mutants (A30P and A53T) found in some familial types of PD, in addition to beta-synuclein and alpha-synuclein112, effectively inhibited PF4 release from the alpha-granules. However, the deletion mutants, which completely lacked either the N-terminal region or the C-terminal tail, did not affect alpha-granule release. Interestingly, exogenously added alpha-synuclein appeared to enter the platelets but did not change the Ca(++) level in the platelets at the resting state and the increase in the Ca(++) level on stimulation. Electron microscopy also supported that alpha-synuclein inhibits alpha-granule release. These results suggest that alpha-synuclein may function as a specific negative regulator of alpha-granule release in platelets.
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PMID:Evidence that alpha-synuclein functions as a negative regulator of Ca(++)-dependent alpha-granule release from human platelets. 1223 63

Alpha-synuclein (alphaSN) has been implicated in Parkinson's Disease (PD) and alphaSN is a major component of Lewy bodies (LBs). This study explored platelets as a model system for study of alphaSN metabolism and platelet alphaSN as a diagnostic marker for PD. We used Western blot analysis to characterize and compare platelet and brain alpha-, beta- and gammaSN; and to quantitate alphaSN levels in platelets from PD and age-matched controls. We found that platelets contain full-length alphaSN and 6 and 12 kDa fragments, and gammaSN-like protein. alphaSN and gammaSN were not secreted by thrombin-activated platelets. Furthermore, we also found that the alphaSN and gammaSN levels in sporadic PD patients and age-matched normal controls were not significantly different. This indicates that platelet alphaSN or gammaSN is not a suitable peripheral diagnostic marker for PD. Platelets may be used for study of alphaSN and gammaSN metabolism, and may give some broad insight into the normal functions of alphaSN and gammaSN.
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PMID:Platelet alpha- and gamma-synucleins in Parkinson's disease and normal control subjects. 1244 33

The present study examined whether thrombin-induced microglial activation could contribute to death of dopaminergic neurons in the rat substantia nigra (SN) in vivo. Seven days after thrombin injection into the SN, tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by immunohistochemical staining using antibodies against the complement receptor type 3 (OX-42) and the major histocompatibility complex class II antigens were also observed in the SN, where degeneration of nigral neurons was found. Reverse transcription PCR at various time points demonstrated that activated microglia in vivo exhibited an early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several proinflammatory cytokines, including interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor alpha. Western blot analysis and double-label immunohistochemistry showed an increase in the expression of iNOS and COX-2 and the colocalization of these proteins within microglia. The thrombin-induced loss of SN dopaminergic neurons was partially inhibited by NG-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were activated in the SN as early as 30 min after thrombin injection, and that these kinases were localized within microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA expression and rescued dopaminergic neurons in the SN. The present results strongly suggest that microglial activation triggered by endogenous compound(s) such as thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
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PMID:Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. 1284 92

Low-dose thrombin given several days before lesioning is neuroprotective in ischemic and hemorrhagic models of stroke, an effect termed thrombin preconditioning (TPC). Here, the ability of TPC to provide protection in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD) was evaluated. All animals received 10 microg 6-OHDA into the right medial forebrain bundle. Three days prior to 6-OHDA, the animals received either 1 U rat thrombin (n=17) or saline (n=14) 1 mm above the site of neurotoxin delivery. The animals were then evaluated for neurobehavioral deficits until 21 days post-injection. TPC animals performed significantly better on both a vibrissae-elicited forelimb placing test and a forelimb-use asymmetry test than the saline controls. The animals were then sacrificed for either catecholamine determination by HPLC with electrochemical detection or for histopathology to determine lateral ventricular volume or striatal tyrosine hydroxylase immunoreactivity. Although TPC did not protect against the dopamine depletion associated with this severe model, it did reduce dopaminergic terminal loss and ventricular enlargement as compared to saline-treated animals. This report presents the new finding that preconditioning (and TPC in particular) provides protection in a 6-OHDA PD model. Understanding the mechanisms involved in TPC-mediated protection may stimulate innovative therapeutic regimens.
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PMID:Thrombin preconditioning provides protection in a 6-hydroxydopamine Parkinson's disease model. 1561 41

This study evaluated the role of thrombin-activated microglia in the neurodegeneration of mesencephalic cultures. Immunocytochemical and biochemical evidence indicated that in co-cultures consisting of rat cortical microglia and mesencephalic neurons, thrombin led to nonselective loss of mesencephalic neurons. Accompanying neurodegeneration, microglial activation was obvious, evidenced by expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and by increasing production of TNF-alpha and nitric oxide (NO). In mesencephalic neurons treated with conditioned media (CM) taken from thrombin-activated microglia, the number of dopaminergic neurons was significantly attenuated. The neurotoxicity of the CM was diminished when it was derived from microglia co-treated with thrombin and either an extracellular signal-regulated kinase 1/2 (ERK1/2) pathway inhibitor (PD98059) or a p38-mitogen-activated protein kinase (p38-MAPK) inhibitor (SB203580). Moreover, jun N-terminal kinase (JNK) and p38-MAPK were activated in mesencephalic neurons treated with CM of thrombin-activated microglia. Inhibition of JNK and p38-MAPK rescued the dopaminergic neurons. Collectively, these results indicate that thrombin-activated microglia induce neurodegeneration in cultured mesencephalic neurons and that the MAPKs actively participate in both microglial activation and neurodegeneration. The present data carefully suggest that microglial activation triggered by thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
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PMID:Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. 1578 35

In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.
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PMID:Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. 1641 Jul 50

The etiology of Parkinson's disease remains poorly understood, and current treatment options do not slow disease progression. Recently, chemical (thrombin) preconditioning (TPC) was found to be protective in a 6-hydroxydopamine (6-OHDA) model of the disease. It is important to understand the mechanisms behind these thrombin-induced protective effects. The current study was conducted in the rat to determine whether the protective effects of TPC are mediated via activation of protease-activated receptors (PARs). Preconditioning with specific local infusion of agonist peptides for PAR-1 and PAR-4 3 days before unilateral 6-OHDA administration (10 microg into the medial forebrain bundle) was tested. In addition, co-administration of a PAR-1 antagonist with TPC was examined. In a neurobehavioral assessment battery, PAR-1 agonist preconditioning provided protection in a vibrissae-elicited forelimb placing test, a forelimb-use asymmetry test, and a corner turn test. In addition, inclusion of a PAR-1 antagonist prevented the protective effects elicited by TPC. In contrast to the effects of the PAR-1 agonist, PAR-4 agonist preconditioning afforded no such protection. Indeed, in a lower-dose model of 6-OHDA (5 microg), PAR-4 preconditioning significantly increased behavioral deficits. These results indicate that the protective effects of TPC in this model are mediated through PAR-1 activation. Neither the effects of PAR-1 nor TPC on later 6-OHDA-induced behavioral deficits appeared to be mediated through (DA) content sparing. Further mechanistic studies on the actions of PAR-1 and PAR-4 as detrimental in experimental models of Parkinson's disease are warranted.
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PMID:Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease. 1693 79

Recent results in animal models suggest that thrombin may modulate brain injury in Parkinson's disease (PD). High doses of thrombin ( approximately 20U) can damage dopaminergic neurons, while we have found that low dose thrombin (1U), given several days before a brain insult (thrombin preconditioning), is protective in models of PD and stroke. However, the effects of such low levels of thrombin at the time of, or after, exposure to the dopamine neurotoxin 6-hydroxydopamine (6-OHDA) have not been examined and are the focus of this study. In the first set of experiments, rats received co-administration of thrombin (1U) or saline and 6-OHDA (5microg) into the medial forebrain bundle. 6-OHDA+thrombin resulted in striking increases in behavioral deficits, compared to 6-OHDA+saline. Similarly, co-administration of an agonist to protease-activated receptor (PAR)-1, a thrombin receptor, also resulted in significantly greater behavioral deficits. In a second set of experiments, thrombin (1U) or saline was administered 1 or 7 days after 6-OHDA to determine the effects of thrombin after 6-OHDA. Surprisingly, the rats that received saline had strikingly increased behavioral and neurochemical deficits resulting from the 6-OHDA lesion, while delayed thrombin administration prevented this effect. The results indicate that thrombin has differential effects in the 6-OHDA model, dependent on the time of administration. The ability of a second cannula insertion with saline infusion to increase dramatically deficits raises questions as to what role physical injury to already susceptible cells might play in the pathogenesis of some cases of PD.
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PMID:The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing. 1762 81

Protease-activated receptors (PARs) are G protein-coupled receptors that regulate the cellular response to extracellular serine proteases, like thrombin, trypsin, and tryptase. The PAR family consists of four members: PAR-1, -3, and -4 as thrombin receptors and PAR-2 as the trypsin/tryptase receptor, which are abundantly expressed in the brain throughout development. Recent evidence has supported the direct involvement of PARs in brain development and function. The expression of PARs in the brain is differentially upregulated or downregulated under pathological conditions in neurodegenerative disorders, like Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, and human immunodeficiency virus-associated dementia. Activation of PARs mediates cell death or cell survival in the brain, depending on the amplitude and the duration of agonist stimulation. Interference or potentiation of PAR activation is beneficial in animal models of neurodegenerative diseases. Therefore, PARs mediate either neurodegeneration or neuroprotection in neurodegenerative diseases and represent attractive therapeutic targets for treatment of brain injuries. Here, we review the abnormal expression of PARs in the brain under pathological conditions, the functions of PARs in neurodegenerative disorders, and the molecular mechanisms involved.
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PMID:Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. 1791 33

Several serine proteases including thrombin, tissue-type plasminogen activator and urokinase-type plasminogen activator have been well characterized in the brain. In this article, we review the brain-related trypsin and trypsin-like serine proteases. Accumulating evidence demonstrates that trypsin and trypsin-like serine proteases play very important roles in neural development, plasticity, neurodegeneration and neuroregeneration in the brain. Neuropsin is able to hydrolyze the extracellular matrix components by its active site serine, and regulates learning and memory in normal brain. The mutant neurotrypsin contributes to mental retardation in children. Neurosin seems to be involved in the pathogenesis of neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease or multiple sclerosis. Although mesotrypsin/trypsin IV is also implicated in neurodegeneration, its functional significance still remains largely unknown. Particularly, mesotrypsin/trypsin IV, P22 and neurosin exert their physiological and pathological functions through activation of certain protease-activated receptors (PARs). In the brain, the presence of serpins controls the activity of serine proteases. Therefore, understanding the interaction among brain trypsin, serpins and PARs will provide invaluable tools for regulating normal brain functions and for the clinical treatment of neural disorders.
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PMID:Trypsin and trypsin-like proteases in the brain: proteolysis and cellular functions. 1796 32


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