Preliminary ReportIndomethacin protects against neurodegeneration caused by MPTP intoxication in mice
Introduction
There is evidence that the use of anti-inflammatory medications is inversely associated with such neurodegenerative disorder as Alzheimer's disease (AD) and slows decline of patients with AD [1], [2], [3]. One of the possible mechanisms underlying their effectiveness is attenuation of inflammatory reaction associated with neurodegeneration. The inflammatory reaction consisting of accumulation of microglia, a local production of cytokines, acute phase proteins and activation of complement cascade may damage neurons and exacerbate the pathologic process underlying the disease. Indomethacin (IND), a nonsteroid anti-inflammatory agent was shown to be effective in treating patients with AD [1], [3].
IND inhibits cyclooxygenases (COX) 1 and 2 and decreases the production of PG in glial cells and neurons. IND activates also the peroxisome proliferator α and γ (PPAR α and γ) nuclear transcription factor controlling cytokine production, adhesion molecule expression and macrophages' function [4].
In this study, we investigated the effect of IND on neural survival and inflammation caused by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP damages dopaminergic neurons in the substantia nigra (SN) and causes the decrease of TH activity in the SN and the dopamine content in striatum. This injury produces glial activation with an increased expression of plenty of molecules (MHC classes I and II, cytokines, APP) and lymphocytic infiltration in the SN and striatum [5].
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Materials and methods
C57Bl/10 male mice, 8–10 months old, received MPTP–HCl (Sigma), in four i.p. injections of 10 mg/kg each, in 1-h intervals. Control animals were injected with 0.9% NaCl. Animals were sacrificed on the 3rd and 7th days following MPTP intoxication.
Indomethacin (Sigma) was dissolved in 0.9% NaCl (1 mg/ml). It was given in two doses of 1 and 2.5 mg/kg 1 day before MPTP treatment and every 2nd day to the end of the experiment. The effective dose of IND (1 mg/kg) was given also 24 h after MPTP in one
Nigrostriatal degeneration
The dopamine content in striatum was decreased following MPTP treatment by 32% (p<0.02) on the 3rd day and by 52% (p<0.004) on the 7th day after intoxication (Fig. 1). When IND was given 1 day before MPTP intoxication in the dose of 1 mg/kg, there was no decrease of dopamine on the 3rd day and the decrease on the 7th day was significantly lower compared to MPTP group (by 22%; p<0.02). This effect was not observed when IND 1 mg/kg was administered 24 h after MPTP intoxication and when IND was
Discussion
Our study showed that treatment with indomethacin protects against MPTP-induced neural damage of dopaminergic neurons. This effect is associated with diminished microglial activation and lymphocytic infiltration in the damaged areas.
The mechanism of the observed phenomenon may depend on an anti-inflammatory action of IND. There is a strong suggestion that the inflammation, which begins in answer to neuronal damage, may aggravate the injury. Many experimental studies showed that an inhibition of
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