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

Inclusions containing ubiquitin-protein aggregates appear in neurons of patients with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The relationship between inclusion production and cell viability is not understood. To address this issue, we investigated the response of an established mouse neuronal cell line and of embryonic rat mesencephalic cultures to inhibition of the ubiquitin/proteasome pathway. Two proteasome inhibitors, a peptidyl aldehyde and an epoxy ketone, which cause accumulation of ubiquitinated proteins, were found to enhance expression of stress-inducible genes, including HSP70i and the polyubiquitin genes UbB and UbC. Under these conditions, mRNA and protein levels of the inducible form of cyclooxygenase (COX-2) were upregulated together with its product, PGE(2), a proinflammatory prostaglandin. Proteasomal inhibition also led to stabilization of COX-2 as ubiquitin conjugates, suggesting that the ubiquitin/proteasome pathway contributes to the regulation of COX-2 protein levels. Treatment with antioxidants known to inhibit NFkappaB and AP-1 transcriptional activation failed to abrogate COX-2 upregulation. Instead, these inhibitors exacerbated the stress response by potentiating HSP70i levels while eliciting a decrease in PGE(2) production. These findings suggest that the accumulation of ubiquitinated proteins resulting from proteasome inhibition in neuronal cells is associated with a proinflammatory response that may be an important contributor to neurodegeneration.
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PMID:Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). 1066 14

To study the possible role of the isoenzymes of cyclooxygenase COX-1 and COX-2 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease we used acetylsalicylic acid, a COX-1/COX-2 inhibitor, in comparison with meloxicam, a preferential COX-2 inhibitor. As markers of protection we determined the effects on MPTP-induced striatal dopamine depletion, locomotor activity, cell loss, and tyrosine hydroxylase immunoreactivity (TH-IR) in the substantia nigra pars compacta. Male C57BL/6 mice (n = 82) were treated with a single dose of acetylsalicylic acid (10, 50, 100 mg/kg i.p.) or meloxicam (2, 7.5, 50 mg/kg i.p.) immediately prior to administration of MPTP (30 mg/kg s.c.) or saline. After 7 days the mice were sacrificed to analyze striatal dopamine and metabolite levels. Nigral sections were processed for Nissl-staining and TH-IR. In the saline-treated MPTP control group striatal dopamine levels were reduced to 15.9% of control values. Dopamine depletion was significantly attenuated to values of 37.1 and 38.6% of saline control values by acetylsalicylic acid (50 and 100 mg/kg) and to values of 36 and 40% by meloxicam (7.5 and 50 mg/kg), respectively. MPTP-induced decrease of locomotor activity was significantly attenuated by acetylsalicylic acid and meloxicam. Remarkably, the MPTP-induced decrease of TH-IR as well as the loss of nigral neurons was nearly completely prevented by acetylsalicylic acid (100 mg/kg) and meloxicam (7.5 and 50 mg/kg). In conclusion, the inhibition of either COX-1/COX-2 by acetylsalicylic acid or preferentially COX-2 by meloxicam provided a clear neuroprotection against MPTP-toxicity on the striatal and nigral levels.
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PMID:Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease. 1118 May 4

Cyclooxygenases (COX), key enzymes in prostanoid biosynthesis, may represent important therapeutic targets in various neurodegenerative diseases. In the present study, we explored the role of COX in Parkinson's disease (PD) by using 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine (MPTP) as a tool to create a rodent Parkinsonian model. MPTP (20 mg/kg, subcutaneously) was injected daily into COX-1- and COX-2-deficient mice and wild-type (WT) controls for five consecutive days. Immunocytochemical analysis of tissues collected 7 days after the final MPTP treatment showed that MPTP significantly decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNc) of WT (40% decrease) and COX-1(-/-) (45% decrease) mutants. However, a much smaller loss of TH-ir neurons in COX-2(-/-) mutants (20% decrease) was observed. Furthermore, electrochemical analysis revealed a more than 70% decrease in the levels of dopamine and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the striatum of the WT control COX-1(-/-) and COX-2(-/-) mutant mice. These results indicate that loss of COX-2 activity reduces MPTP-induced damage to the dopaminergic neurons of the SNc, but does not alter the levels of dopamine and its metabolites in the striatum. Interestingly, MPTP caused the same degree of loss of dopaminergic neurons in both COX-2(+/-) and COX-2(-/-) mice (20% loss). The results of this study indicate an important role of COX-2 in MPTP-induced neuronal degeneration and suggest the possibility that manipulation of the COX-2 could be an important target for therapeutic interventions in PD.
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PMID:Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. 1218 47

Neuroinflammation and oxidative stress are believed to be contributing factors to neurodegeneration in normal aging, as well as in age-related neurological disorders. Reactive microglia are found in increased numbers in aging brain and are prominently associated with lesions in such age-related degenerative conditions as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In vitro, stimulated microglia or microglial-like cells secrete neurotoxic materials and are generators of free radicals through their respiratory burst system. Agents that suppress microglial activation are therefore candidates for neuroprotection. We have developed quantitative in vitro assays for measuring neurotoxicity of microglia or other mononuclear phagocytes. Neuronal like SH-SY5Y cells are cultured in supernatants from activated cells of the human monocytic THP-1 line and their survival is followed. Respiratory burst is directly measured on the activated cells. We tested inhibitors of the cyclooxygenase (COX) or the 5-lipoxygenase (5-LOX) pathways as possible neuroprotective agents. The COX pathway generates inflammatory prostaglandins, while the 5-LOX pathway generates inflammatory leukotrienes. We found that inhibitors of both these pathways suppressed neurotoxicity in a dose-dependent fashion. They included the COX-1 inhibitor indomethacin; the COX-2 inhibitor NS-398; the mixed COX-1/COX-2 inhibitor ibuprofen; the nitric oxide (NO) derivatives of indomethacin, ibuprofen and flurbiprofen; the 5-LOX inhibitor REV 5901; and the 5-LOX activating protein (FLAP) inhibitor MK-886. The FLAP inhibitor also reduced respiratory burst activity in a more potent manner than indomethacin. Combinations of COX and 5-LOX inhibitors were more effective than single inhibitors. The data suggest that both COX inhibitors and 5-LOX inhibitors may be neuroprotective in vivo by suppressing toxic actions of microglia/macrophages, and that combinations of the two might have greater therapeutic potential than single inhibitors of either class.
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PMID:Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. 1239 82

Supra-pontine lesions resulting from neurological disorders such as vascular disease, Parkinson's disease, or Alzheimer type senile dementia lead to an increase in bladder activity. This is due in part to the removal at the cortical inhibitory control of the micturition center in the brain stem - i.e. the pontine micturition center (PMC) - and in part to facilitation of excitatory control. These inhibitory or excitatory controls consist of several neurotransmitter systems, including glutamate, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine. Bladder overactivity caused by cerebral infarction is mediated by upregulation of N-methyl-D-aspartate (NMDA) glutamatergic and D2 dopaminergic excitatory mechanisms, and by downregulation of NMDA glutamatergic and Ml muscarinic inhibitory mechanisms in the brain. Bladder overactivity associated with Parkinson's disease is reportedly induced by a loss of input to the D1 dopaminergic receptor. Furthermore, bladder overactivity caused by Alzheimer type dementia is thought to be mediated by downregulation of M1 muscarinic inhibitory mechanisms. Development of bladder overactivity following cerebral infarction is mediated by activation of the NMDA receptor and accompanied by an increase in c-fos, zif268 and COX-2 mRNA expression in the dorsal pontine tegmentum.
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PMID:Overactive bladder--experimental aspects. 1247 19

We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM) showed no effect on *OH formation and diclofenac caused a reduction in *OH generation only at high doses (100 microM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100 nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin involvement in MPP(+) action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of *OH by SA and its ability to protect DA depletion in the striatum caused by MPP(+) indicates a direct involvement of *OH in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.
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PMID:Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. 1261 47

The primary lesion in Parkinson's disease is the death of dopaminergic neurons in the substantia nigra. The role of cyclooxygenase (COX)-2 in the etiology of Parkinson's disease was explored using COX-2 gene knockout mice. Mortality after injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP, a chemical known to cause parkinsonism in humans) in heterozygous COX-2-deficient mice was lower than that in wild-type mice. The number of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta of MPTP-treated wild-type mice declined to a greater extent than in heterozygous mice. Inhibition of COX-2 protein expression decreased the lesion caused by MPTP and protected the dopaminergic neurons in substantia nigra pars compacta. This result suggested that inhibition of COX-2 has potential therapeutic implications.
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PMID:COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice. 1456 22

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.
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PMID:JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. 1470 77

Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration.
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PMID:Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease. 1528 96

Many physiological functions of the body change during the aging process. Dysregulated immune and inflammatory responses have been well documented in both humans and animals. The investigation into the cellular and molecular mechanism underlying these disorders has provided compelling evidence that up-regulated cyclooxygenase (COX)-2 and its product, particularly prostaglandin (PG)E2, play a critical role in the age-associated dysregulation of the immune and inflammatory responses. In particular, several studies have shown that increased PGE2 production in old macrophages (Mphi) contributes to the suppression of T cell function with aging. Furthermore, interventions targeted at decreasing PGE2 production have been shown to enhance T cell-mediated function. COX-2 and its catalytic products are also suggested to play a key role in age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Administration of anti-inflammatory drugs which inhibit COX activity has been shown, by some investigators, to be beneficial in preventing and treating these diseases. It is, thus, important to understand the underlying mechanisms of age-related COX-2 up-regulation and to delineate the factors, which contribute to this age-related change. This review focuses on the regulation of PGE2 production in murine Mphi; the age-associated changes in COX-2 expression; and its implication for certain disorders observed in the aged immune system and brain. Increased PGE2 production has been shown to be mainly due to an increase in COX activity, which is, in turn, due to an increase in COX-2 protein and mRNA expression. Elevated COX-2 mRNA represents a higher transcription rate rather than an altered stability of COX-2 mRNA. Upon stimulation, Mphi from old mice generate more ceramide, a sphingolipid, than those from young mice. Ceramide has been shown to induce, by itself, and also augment, LPS-stimulated COX-2 expression and PGE2 production. Several lines of evidence indicate that the higher ceramide levels in old Mphi are an important contributor to the age-associated up-regulation of COX-2 in Mphi. Ceramide up-regulates COX-2 transcription by increasing activation of transcription factor NF-kappaB. Further understanding of molecular mechanisms involved in COX-2 up-regulation will help in delineating fundamental age-related changes, which lead to the development of immune and neurological disorders in the aged.
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PMID:Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. 1533 Nov 18


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