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 Parkinson's disease

Background 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. 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. Methods Ageing 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. Results HCT1026 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. Conclusions Oral 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

A Monte Carlo Method for the Auto-Evaluation of the Uncertainties in the Analog-to-Digital Conversion-Based Measurements

This paper concerns with the measurement uncertainty estimation in the analog-to-digital conversion-based instruments. By using an ad hoc developed software tool, the Monte Carlo method is applied in order to assess the uncertainties associated with the measurement results, overcoming the possible inapplicability of the pure theoretical approach prescribed in the ISO - "Guide to the Expression of Uncertainty in Measurement". By implementing the software tool in the measurement instruments, the proposed approach can be utilized in order to make the instrument itself able to auto-estimate the measurement uncertainties

A chirp-z transform-based synchronizer for power system measurements

In the last few years increased interest in power and voltage quality has forced international working groups to standardize testing and meas-urement techniques. IEC 61000-4-30, which defines the characteristics of instrumentation for the measurement of power quality, refers to IEC 61000-4-7 for the evaluation of harmonics and interharmonics. This standard, revised in 2002, requires a synchronous sampling of volt-age or current signal, in order to limit errors and to ensure reproducible results even in the presence of non-stationary signals. Therefore an accurate estimation of the fundamental frequency is required, even in the presence of disturbances. In this paper an algorithm to detect the fundamental frequency is proposed; it is based on the Chirp Z Transform (CZT) spectral analysis and is able to observe all standards in force because of its accuracy and working characteristics. Theoretical aspects are discussed and various experimental tests are reported, comparing the proposed method with a similar well-known one based on interpolated Fast Fourier Transform analysis. Finally, a complete characterization of the proposed system was performed and its accuracy was evaluated by means of a calibrato