[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that inflammation plays an important role in the progression of Parkinson's disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase (COX), specifically the inducible isoform, COX-2, is believed to be a critical enzyme in the inflammatory response. Induction of COX-2 is also found in an experimental model of PD produced by administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
COX-2-deficient mice or C57BL/6 mice were treated with MPTP to investigate the effects of COX-2 deficiency or by using various doses of valdecoxib, a specific COX-2 inhibitor, which induces inhibition of COX-2 on dopaminergic neuronal toxicity and locomotor activity impairment. Immunohistochemistry, stereological cell counts, immunoblotting, an automated spontaneous locomotor activity recorder and rotarod behavioral testing apparatus were used to assess microglial activation, cell loss, and behavioral impairments.
MPTP reduced tyrosine hydroxylase (TH)-positive cell counts in the substantia nigra pars compacta (SNpc); total distance traveled, vertical activity, and coordination on a rotarod; and increased microglia activation. Valdecoxib alleviated the microglial activation, the loss of TH-positive cells and the decrease in open field and vertical activity. COX-2 deficiency attenuated MPTP-induced microglial activation, degeneration of TH-positive cells, and loss of coordination.
These results indicate that reducing COX-2 activity can mitigate the secondary and progressive loss of dopaminergic neurons as well as the motor deficits induced by MPTP, possibly by suppression of microglial activation in the SNpc.
Journal of Neuroinflammation 02/2006; 3:6. DOI:10.1186/1742-2094-3-6 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dynorphins, endogenous kappa-opioid agonists widely expressed in the central nervous system, have been reported to increase following diverse pathophysiological processes, including excitotoxicity, chronic inflammation, and traumatic injury. These peptides have been implicated in cognitive impairment, especially that associated with aging. To determine whether absence of dynorphin confers any beneficial effect on spatial learning and memory, knockout mice lacking the coding exons of the gene encoding its precursor prodynorphin (Pdyn) were tested in a water maze task. Learning and memory assessment using a 3-day water maze protocol demonstrated that aged Pdyn knockout mice (13-17 months) perform comparatively better than similarly aged wild-type (WT) mice, based on acquisition and retention probe trial indices. There was no genotype effect on performance in the cued version of the swim task nor on average swim speed, suggesting the observed genotype effects are likely attributable to differences in cognitive rather than motor function. Young (3-6 months) mice performed significantly better than aged mice, but in young mice, no genotype difference was observed. To investigate the relationship between aging and brain dynorphin expression in mice, we examined dynorphin peptide levels at varying ages in hippocampus and frontal cortex of WT 129SvEv mice. Quantitative radioimmunoassay demonstrated that dynorphin A levels in frontal cortex, but not hippocampus, of 12- and 24-month mice were significantly elevated compared to 3-month mice. Although the underlying mechanisms have yet to be elucidated, the results suggest that chronic increases in endogenous dynorphin expression with age, especially in frontal cortex, may adversely affect learning and memory.
Behavioural Brain Research 07/2005; 161(2):254-62. DOI:10.1016/j.bbr.2005.02.010 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelination of axons is important for central nervous system function, but oligodendrocytes, which constitute CNS myelin, are vulnerable to excitotoxic injury and death. Although mature oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) and kainate-type glutamate receptors, the relative roles of these subtypes in excitotoxicity are not well understood. Using recently developed selective antagonists for subtypes of ionotropic non-NMDA receptors, we addressed this issue. By examining the pharmacological, biochemical, and morphologic features of kainite-induced excitotoxic death, we also determined whether it occurs by apoptosis, necrosis, or both. We conclude that when mature oligodendrocytes die after exposure to kainate: (1) AMPA receptors are the most important mediators, (2) kainate receptors play a smaller role, and (3) death occurs predominantly by necrosis, not apoptosis.
Neurobiology of Disease 01/2004; 14(3):336-48. DOI:10.1016/j.nbd.2003.07.004 · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that inflammation plays an important role in the progression ofParkinson's disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase(COX), especially the inducible isoform, COX-2, is believed to be the critical enzyme in theinflammatory response. Induction of COX-2 is also found in an experimental model of PD producedby administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To investigate whetherinhibition of COX-2 by valdecoxib or deficiency in COX-2 could prevent dopaminergic neuronaltoxicity and locomotor activity impairment, we injected MPTP into valdecoxib-treated C57BL/6N miceand COX-2 deficient mice, respectively. Both automated total distance and vertical activitymeasurements of the open-field test were significantly reduced in the vehicle-treated mice at two weekspost-MPTP injection. In contrast, valdecoxib treatment significantly attenuated these deficits.Similarly, COX-2 deficiency attenuated MPTP-induced loss of coordination on a rotarod assay.Valdecoxib or deficiency of COX-2 reduced microglial activation while preventing loss of tyrosinehydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc). The total number ofactivated microglia in the SNpc had a strong positive correlation with the level of COX-2 anddopaminergic neurodegeneration. The results of this study indicate that reducing the activity of COX-2can mitigate the progressive loss of dopaminergic neurons as well as the motor deficits caused byMPTP neurotoxicity, possibly by suppressing the activation of microglia in the SNpc.