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-(nitrooxy)butyl ester], HCT1026 (30 mg kg-1 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 [3H]dopamine 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.
Highlights
Current 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
In 2-3 month-old mice fed with flurbiprofen or HCT1026 diets and treated with saline, DA uptake levels were not different compared to saline-treated mice fed with the control diet
Mice exposed to higher (15 and 30 mg kg-1 day-1) MPTP doses and fed with control or flurbiprofen diets exhibited far greater (p < 0.05) decreases of striatal DA uptake compared with mice fed with HCT1026 (Figure 1B)
Summary
Current 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. Elevated expression of macrophage-antigen complex 1 (Mac-1), a b2-integrin family member expressed exclusively in microglia, and NADPH oxidase (PHOX), one of the major sources for production of ROS or related reactive nitric species (RNS) in activated microglia, have been reported in PD animal models [8,11,13,14,15,16,22,23,24,25,26,27,28,29,30,31,32,33,34,35] In keeping with these findings, genetic or pharmacological inhibition of most inflammatory factors, including iNOS, PHOX, Mac-1 and COX-2-derived mediators, significantly attenuated DAergic degeneration in experimental models of PD [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. Blocking the action of endogenous anti-inflammatory molecules, such as glucocorticoid hormones in transgenic mice expressing a glucocorticoid receptor (GR) antisense RNA, sharply increases microglial activation in response to MPTP, resulting in increased DAergic neuron vulnerability [8,10,11]
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