Inflammatory Regulators in Parkinson's Disease: iNOS, Lipocortin-1, and Cyclooxygenases-1 and -2

Knott, Christine; Stern, Gerald; Wilkin, Graham P.

doi:10.1006/mcne.2000.0914

Cited by 449 publications

(309 citation statements)

References 103 publications

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“…Recently, the involvement of neuroinflammation and microglial activation in the pathogenesis of PD (Table 1) has been emphasized (Mogi et al, 1994a,b;Mogi et al, 1995;Blum-Degen et al, 1995;Rowe et al, 1998;Langston et al, 1999;Mirza et al, 2000;Knott et al, 2000Knott et al, , 2002McGeer et al, 2001;McGeer et al, 2002;Imamura et al, 2003;Ouchi et al, 2005;Ishida et al, 2006;Kim and Joh, 2006). Results of neurotoxin models of PD, corroborating findings obtained in transgenic animal models and epidemiological studies, strongly Table 1 Evidence of inflammation in PD-Human data…”

Section: Inflammation In Parkinson's Diseasesupporting

confidence: 56%

Non-steroidal anti-inflammatory drugs in Parkinson's disease

Esposito

Matteo

Benigno

et al. 2007

Experimental Neurology

218

176

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Parkinson's disease (PD) is known to be a chronic and progressive neurodegenerative disease caused by a selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). A large body of experimental evidence indicates that the factors involved in the pathogenesis of this disease are several, occurring inside and outside the DAergic neuron. Recently, the role of the neuron-glia interaction and the inflammatory process, in particular, has been the object of intense study by the research community. It seems to represent a new therapeutic approach opportunity for this neurological disorder. Indeed, it has been demonstrated that the cyclooxygenase type 2 (COX-2) is upregulated in SNc DAergic neurons in both PD patients and animal models of PD and, furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) pre-treatment protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6 hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine degeneration. Moreover, recent epidemiological studies have revealed that the risk of developing PD is reduced in humans who make therapeutical use of NSAIDs. Consequently, it is hypothesized that they might delay or prevent the onset of PD. However, whether or not these common drugs may also be of benefit to those individuals who already have Parkinson's disease has not as yet been shown.In this paper, evidence relating to the protective effects of aspirin or other NSAIDs on DAergic neurons in animal models of Parkinson's disease will be discussed. In addition, the pharmacological mechanisms by which these molecules can exert their neuroprotective effects will be reviewed. Finally, epidemiological data exploring the effectiveness of NSAIDs in the prevention of PD and their possible use as adjuvants in the therapy of this neurodegenerative disease will also be examined.

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Section: Inflammation In Parkinson's Diseasesupporting

confidence: 56%

Non-steroidal anti-inflammatory drugs in Parkinson's disease

Esposito

Matteo

Benigno

et al. 2007

Experimental Neurology

218

176

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“…COX-2, although an inducible protein, is constitutively expressed in only a few tissues including the brain, particularly in neuronal soma, not in astrocytes, of different regions including cortex, amygdala, hippocampal formation, and the dorsal horn of the spinal cord (Yamagata et al, 1993;Breder et al, 1995). It becomes upregulated brieflyFafter 1-8 hFafter seizure, trauma, intracerebral hemorrhage, ischemia, or other neurodegenerative diseases (Yamagata et al, 1993;Beiche et al, 1996;Nogawa et al, 1998;Knott et al, 2000;Kim et al, 2001;Gong et al, 2001). Other types of brain cells, including microglia, astrocytes, and vascular cells, do not express significant levels of COX-2 normally, but its expression is also increased after cerebral insults (Laflamme et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Induction of Cyclooxygenase-2 Accounts for Restraint Stress-Induced Oxidative Status in Rat Brain

Madrigal

Moro

Lizasoaín

et al. 2003

Neuropsychopharmacol

136

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Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolism of arachidonic acid into prostanoids. Although it is constitutively expressed in brain neurons, the inducible isoform (COX-2) is also upregulated in pathological conditions such as seizures, ischemia or some degenerative diseases. To assess whether COX-2 is regulated after stress, we have used adult male Wistar rats, some of which were immobilized during 6 h. An increase in PGE 2 concentration occurs in brain cortex after 2-6 h of the onset of stress as well as an enhancement of COX-2 protein. Immunohistochemical studies indicate that COX-2 is expressed in the cortex and hippocampus after stress in cells with morphology of neurons. Administration of PDTC (150 mg/kg), an inhibitor of the transcription factor NF-kB or MK-801 (0.2 mg/kg), an N-methyl-D-aspartate receptor blocker, prevents both stress-induced increase in COX-2 activity and protein levels, suggesting an implication of these factors in the mechanism by which stress induces COX-2 in brain. To assess if COX-2 accounts for the oxidative status seen in brain after stress, a group of animals were i.p. injected with NS-398, a specific COX-2 inhibitor 1 h prior to the onset of stress. NS-398 (5 mg/kg) decreases stress-induced malondialdehyde accumulation in cortex as well as prevents the stressinduced oxidation of glutathione. Finally, NS-398 reduced Ca 2+ -independent inducible nitric oxide synthase (iNOS, NOS-2) activity and lowered the stress-induced accumulation of NO metabolite levels in cortex. These effects of NS-398 seem to be due to the specific inhibition of COX-2, since it has no effect on stress-induced corticosterone release, glutamate release, and NF-kB activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.

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“…Characteristic pathological features of the PD brain are a selective and progressive loss of dopamine neurons of the substantia nigra (SN) and focal accumulation of activated microglia in the SN (McGeer et al, 1988;Forno, 1996;Banati et al, 1998;Knott et al, 2000;Mirza et al, 2000). Activation of microglia also has been identified in the SN and/or striatum of the parkinsonian animal models, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian brain (O'Callaghan et al, 1990;Francis et al, 1995;Czlonkowska et al, 1996;Kohutnicka et al, 1998;Kurkowska-Jastrzebska et al, 1999) or medial forebrain bundle (MFB), which transmits axons from the nigral dopamine neurons to the striatum, axotomized rat brain (Brecknell et al, 1995;Revuelta et al, 1999;Sugama et al, 2003).…”

Section: Pathological Dynamics Of Activated Microglia In Pathogenesismentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

593

450

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Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

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Inflammatory Regulators in Parkinson's Disease: iNOS, Lipocortin-1, and Cyclooxygenases-1 and -2

Cited by 449 publications

References 103 publications

Non-steroidal anti-inflammatory drugs in Parkinson's disease

Non-steroidal anti-inflammatory drugs in Parkinson's disease

Induction of Cyclooxygenase-2 Accounts for Restraint Stress-Induced Oxidative Status in Rat Brain

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

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