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Selective inhibition of cyclooxygenase-2 exacerbates methamphetamine-induced dopamine depletion in the striatum in rats.

Abstract：

:Neuroinflammatory processes associated with induction of cyclooxygenase (COX) have been implicated in the deleterious events resulting in neurodegeneration. The present study was designed to investigate the impact of acute methamphetamine (MA) administration on COX expression and prostaglandin E2 (PGE(2)) production, and to evaluate the effect of selective COX-2 inhibition using celecoxib in MA-induced degeneration of dopaminergic terminal and cell apoptosis in the striatum. Male Sprague-Dawley rats were treated with either a neurotoxic regimen of methamphetamine hydrochloride (5 mg/kg, i.p., every 2 h for four injections) with or without celecoxib (7.5 mg/kg) or vehicle. COX-1 expression was not affected by MA, while both COX-2 protein expression and number of COX-2 positive cells in striatum were significantly reduced 24 h after MA treatment. However, after 72 h, a significant upregulation of COX-2 protein was detected. PGE(2) production was correlated with altered COX-2 levels. NFkappa-B (NFkappa B), a key regulator of COX-2 expression, was activated 72 h after MA administration, and was accompanied by increased Ikappa B (Ikappa B) phosphorylation. Animals receiving MA exhibited an increase in apoptotic cells and notable reductions in dopamine (DA) content (63.9%) in immunoreactivity of tyrosine hydroxylase (TH) and neuron specific microtubule-associated protein 2 (MAP2) in striatum. Administration of celecoxib exacerbated MA-induced DA depletion, and did not affect MA-induced MAP2 damage, apoptosis or proliferation of glial cells. Our findings suggest that COX-2 containing cells are targets of the damage during earlier stages of MA-related neurotoxicity, and that the selective inhibition of COX-2 enzyme is harmful rather than protective. The COX-2 induction appears during the recovery period, and NFkappa B activation may be an important mechanism.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Zhang X,Dong F,Mayer GE,Bruch DC,Ren J,Culver B

doi

10.1016/j.neuroscience.2007.09.059

subject

Has Abstract

pub_date

2007-12-19 00:00:00

pages

950-8

issue

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(07)01224-9

journal_volume

150

pub_type

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Selective inhibition of cyclooxygenase-2 exacerbates methamphetamine-induced dopamine depletion in the striatum in rats.