Nicotine administration reduces striatal MPP+ levels in mice

Nicotine administration has previously been shown to attenuate nigrostriatal damage in animal models of Parkinson's disease, including the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. The present experiments were done to determine whether nicotine may be exerting its effects by altering striatal levels of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of MPTP. Mice were injected with nicotine (0.33-1 mg/kg i.p.) 10 min prior to MPTP (30 mg/kg s.c.) followed by three subsequent doses of nicotine at 15-min intervals according to a dose schedule previously shown to be neuroprotective. The mice were sacrificed 1.5, 4 and 8 h after MPTP administration and striatal MPP+ levels measured. Nicotine administration (0.33-1.0 mg/kg) resulted in a time-dependent decline in striatal MPP+ levels that was significantly enhanced over that in saline injected animals. Experiments done to examine the effect of age showed that the decrease was observed in older (8-10 months) but not young (6-8 weeks) mice, a finding which may explain some of the variability in the effect of nicotine in the MPTP-induced model of nigrostriatal degeneration. In summary, these results suggest that nicotine may exert its neuroprotective action against nigrostriatal degeneration, at least in part, by decreasing striatal MPP+ levels.     

The formation and function of the neutrophil phagosome

Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.