Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of parkinson’s disease

Parkinson’s disease (PD) is characterized by a progressive loss of substantia nigra pars compacta (SNc) neurons. The onset of clinical symptoms only occurs after the degeneration has exceeded a certain threshold. In most of the current 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nonhuman primate models, nigrostriatal lesions and the onset of PD symptoms are the result of an immediate neuronal degeneration in the SNc caused by acute injection of the toxin. In order to develop a model that more closely mimics the degeneration pattern of human PD, we eventually established a protocol that produces a progressive parkinsonian state by treating monkeys repeatedly with MPTP for 15 ± 2 d. Mean onset of parkinsonian symptoms occurred after 13.2 d of treatment. At this time, 56.8 ± 6.3% of tyrosine hydroxylase immunoreactive neurons and 75.2 ± 6.2% of Nissl-stained cells remained in the SNc. Striatal dopamine transporter (DAT) binding and dopamine (DA) content decreased to 19.7 ± 4.9% and 18.2 ± 5.6% of untreated monkeys. Parallel ¹²³I-PEI single-photon emission computed tomography (SPECT) imaging in living animals showed a similar decrease in striatal DAT binding. In this article, we examine how this and other chronic MPTP models fit with human pathology.     

Remarkable substituent effect: beta-aminosquamocin, a potent dual inhibitor of mitochondrial complexes I and III

The introduction of a primary amine function on the terminal alpha,beta-unsaturated lactone of squamocin 1, a common structural hallmark of annonaceous acetogenins, shifted this specific inhibitor of mitochondrial complex I into a potent dual inhibitor of complexes I and III. The mechanism of action of beta-aminosquamocin 2, against these two respiratory targets, is studied and discussed in view of current structure-activity relationship knowledge in the acetogenin series.     

Roles for T and NK cells in the innate immune response to Shigella flexneri

Shigella flexneri, an enteroinvasive Gram-negative bacterium, is responsible for the worldwide endemic form of bacillary dysentery. The host response to primary infection is characterized by the induction of an acute inflammation, which is accompanied by polymorphonuclear cell (PMN) infiltration, resulting in massive destruction of the colonic mucosa. However, PMN play a major role in the recovery from primary infection, by restricting the bacterial infection at the intestinal mucosa. In this study, we assessed the roles for T and NK cells in the control of primary S. flexneri infection, using an alymphoid mouse strain (Rag null gamma(c) null) devoid of B, T, and NK cells. Using the mouse pulmonary model of Shigella infection, we showed that alymphoid Rag null gamma(c) null mice were highly susceptible to S. flexneri infection in comparison with wild-type (wt) mice. Whereas PMN recruitment upon infection was similar, macrophage recruitment and production of proinflammatory cytokines were significantly decreased in Rag null gamma(c) null mice compared with wt mice. Upon selective engraftment of Rag null gamma(c) null mice with polyclonal alphabeta T cells, but not with alphabeta T cells from IFN-gamma null , S. flexneri infection could be subsequently controlled. Rag null mice devoid of B and T cells but harboring NK cells could control infection. Local IFN-gamma production by T and NK cells recruited to the lung was demonstrated in S. flexneri-infected wt mice. These data demonstrate that both alphabeta T cells and NK cells contribute to the early control of S. flexneri infection through amplification of an inflammatory response. This cellular lymphocyte redundancy assures IFN-gamma production, which is central to innate immunity against Shigella infection.     

Investigating the receptor-independent neuroprotective mechanisms of nicotine in mitochondria

Although nicotine has been associated with a decreased risk of developing Parkinson disease, the underlying mechanisms are still unclear. By using isolated brain mitochondria, we found that nicotine inhibited N-methyl-4-phenylpyridine (MPP(+)) and calcium-induced mitochondria high amplitude swelling and cytochrome c release from intact mitochondria. Intra-mitochondria redox state was also maintained by nicotine, which could be attributed to an attenuation of mitochondria permeability transition. Further investigation revealed that nicotine did not prevent MPP(+)- or calcium-induced mitochondria membrane potential loss, but instead decreased the electron leak at the site of respiratory chain complex I. In the presence of mecamylamine hydrochloride, a nonselective nicotinic acetylcholine receptor inhibitor, nicotine significantly postponed mitochondria swelling and cytochrome c release induced by a mixture of neurotoxins (MPP(+) and 6-hydroxydopamine) in SH-SY5Y cells, suggesting that there is a receptor-independent nicotine-mediated neuroprotective effect of nicotine. These results show that interaction of nicotine with mitochondria respiratory chain together with its antioxidant effects should be considered in the neuroprotective effects of nicotine.     

The effect of compact formulations on the environmental profile of Northern European granular laundry detergents Part II: Life Cycle assessment

The environmental profile of laundry detergents at three time points (1988, 1992, and 1998) were compared on the basis of two distinct, complementary approaches: Environmental Risk Assessment (ERA) and Life-Cycle Assessment (LCA). The results are presented in this paper and its accompanying paper in this issue (Part I: Product Environmental Risk Assessment). Life-Cycle Inventory (LCI) data from The Netherlands and Sweden were used for this retrospective analysis. The chosen time period studied (1988 - 1998) spans significant, multiple formulation and process change in laundry detergents, including the introduction of compact, then super-compact, granular detergents. Cradle-to-Gate LCAs based on 1 kg of finished product (from raw material supply to packaged finished product leaving the suppliers site) revealed no significant differences between the products themselves, as manufactured between 1988, 1992 and 1998. Cradle-to-Grave LCAs based on 1000 wash cycles (from raw material supply to disposal of used product) indicated that the consumption of raw materials and energy, as well as environmental emissions (air, water and solid waste), decreased after the introduction of compact detergents in 1988. The LCAs revealed that a number of category indicator values decreased (for acidification, aquatic toxicity greenhouse effects, eutrophication, toxicity, ozone depletion and smog). Furthermore, the results of the LCAs support the conclusion that the differences between The Netherlands and Sweden are due to (1) differences in electrical generation between the countries, (2) differences in energy consumption during consumer use, (3) differences in detergent dosage per wash and (4) differences in the wastewater treatment infrastructure.     

In vitro tumoricidal activity of peritoneal macrophages and splenic lymphocytes of rats under diet with or without fish

Rats were fed with or without a diet supplemented with fish meal over a 4-week period. The moderate fish fatty acids intake had no influence on the tumoricidal activity of peritoneal and splenic lymphocytes.     

An evaluation ofmer-specified reduction of ionic mercury as a remedial tool of a mercury-contaminated freshwater pond

Summary The potential former-mediated reduction/volatilization of ionic mercury as a tool in the decontamination of a freshwater pond was evaluated using laboratory incubations and a microcosm simulation. In flask assays inoculations with ionic mercury-resistant bacteria (10⁵–10⁷ cells ml^–1) isolated from the pond, significantly increased the rate of mercury loss (MANOVA,P0.05) relative to uninoculated controls. The effects of cell density, mercuric mercury concentration, addition of nutrients and supplementation with the sulfhydryl reagent -mercaptoethanol on the rate of mercury loss, were investigated. Inoculation (by 10⁵ cells ml^–1) of a flow-through microcosm that simulated the cycling of mercury in the contaminated pond, stimulated by more than 4-fold the formation of volatile elemental mercury. Thus, biological formation of volatile mercury may hold a promise as a remedial tool of contaminated natural waters.Publication no. 906 of the US Environmental Research Laboratory, Gulf Breeze, FL 32561, USA.Mention of trade names or commercial products does not constitute endorsement on recommendation for use.     

Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson’s Disease Models

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