Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsons diseaseReportar como inadecuado




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Journal of Neuroinflammation

, 7:83

First Online: 23 November 2010Received: 10 September 2010Accepted: 23 November 2010

Abstract

BackgroundCurrent evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson-s disease PD and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs NSAIDs mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide NO-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, 2-fluoro-α-methyl 1,1-biphenyl-4-acetic-4-nitrooxybutyl ester, HCT1026 30 mg kg daily in rodent chow in mice exposed to the parkinsonian neurotoxin MPTP.

MethodsAgeing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomial dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase TH- and dopamine transporter DAT fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP.

ResultsHCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal Hdopamine uptake, TH- and DAT-stained fibers in striatum and TH neuron loss in subtantia nigra pars compacta SNpc, as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 Mac-1-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase PHOX, and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons.

ConclusionsOral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic DAergic neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.

List of abbreviations3-NT3-nitrotyrosine

COX-2Cyclooxygenase-2

DADopamine

DATDopamine transporter

EAEExperimental Allergic Encephalomyelitis

GRGlucocorticoid receptor

HCT10262-fluoro-α-methyl1,1-biphenyl-4-acetic-4-nitrooxybutyl ester

HRPHorseradish peroxidase

IFImmunofluorescence

iNOSInducible-nitric oxide synthase

LPSLipopolysaccharide

Mac-1Macrophage antigen-1

MAO-BMonoamine oxidase B

MOG35-55Myelin oligodendrocyte peptide

MPP1-methyl-4-phenylpyrdinium ion

MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NONitric oxide

NSAIDsNonsteroidal anti-inflammatory drugs

ONOOPeroxynitrite

PDParkinson-s disease

PGsProstaglandins

PHOXNADPH oxidase

PJ2Prostaglandin J2

PPAR-γPeroxisome proliferator-activated receptor-γ

RNSReactive nitrogen species

ROSReactive oxygen species

SNpcSubtantia nigra pars compacta

THTyrosine hydroxylase

VMVentral midbrain

WBWestern blot.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-7-83 contains supplementary material, which is available to authorized users.

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