Delivery of DTPA through Liposomes as a Good Strategy for Enhancing Plutonium Decorporation Regardless of Treatment Regimen.

In this study, we assessed the efficacy of unilamellar 110-nm liposomes encapsulating the chelating agent diethylenetriaminepentaacetic acid (DTPA) in plutonium-exposed rats. Rats were contaminated by intravenous administration of the soluble citrate form of plutonium. The comparative effects of liposomal and free DTPA at similar doses were examined in terms of limitation of alpha activity burden in rats receiving various treatment regimens. Liposomal DTPA given at 1 h after contamination more significantly prevented the accumulation of plutonium in tissues than did free DTPA. Also, when compared to free DTPA, liposome-entrapped DTPA was more efficient when given at late times for mobilization of deposited plutonium. In addition, repeated injections of liposomal DTPA further improved the removal of plutonium compared to single injection. Various possible mechanisms of action for DTPA delivered through liposomes are discussed. The advantage of liposomal DTPA over free DTPA was undoubtedly directly and indirectly due to the better cell penetration of DTPA when loaded within liposomes, mainly in the tissues of the mononuclear phagocytic system. The decorporation induced by liposomal DTPA may result first from intracellular chelation of plutonium deposited in soft tissues, predominantly in the liver. Afterwards, the slow release of free DTPA molecules from these same tissues may enable a sustained action of DTPA, probably mainly by extracellular chelation of plutonium available on bone surfaces. In conclusion, decorporation of plutonium can be significantly improved by liposomal encapsulation of DTPA regardless of the treatment regimen applied.

Effects of Human Alpha-Synuclein A53T-A30P Mutations on SVZ and Local Olfactory Bulb Cell Proliferation in a Transgenic Rat Model of Parkinson Disease.

A transgenic Sprague Dawley rat bearing the A30P and A53T α-synuclein (α-syn) human mutations under the control of the tyrosine hydroxylase promoter was generated in order to get a better understanding of the role of the human α-syn mutations on the neuropathological events involved in the progression of the Parkinson's disease (PD). This rat displayed olfactory deficits in the absence of motor impairments as observed in most early PD cases. In order to investigate the role of the mutated α-syn on cell proliferation, we focused on the subventricular zone (SVZ) and the olfactory bulbs (OB) as a change of the proliferation could affect OB function. The effect on OB dopaminergic innervation was investigated. The human α-syn co-localized in TH-positive OB neurons. No human α-syn was visualized in the SVZ. A significant increase in resident cell proliferation in the glomerular but not in the granular layers of the OB and in the SVZ was observed. TH innervation was significantly increased within the glomerular layer without an increase in the size of the glomeruli. Our rat could be a good model to investigate the role of human mutated α-syn on the development of olfactory deficits.

Kinetics of microglial activation and degeneration of dopamine-containing neurons in a rat model of Parkinson disease induced by 6-hydroxydopamine.

In both Parkinson disease and in animal models of Parkinson disease, there is a microglial reaction in addition to the loss of dopaminergic neurons in the ventral midbrain. To determine the pathological role of this microglial reaction, we analyzed the kinetics of microglial activation and dopaminergic cell death induced in rats with the neurotoxin 6-hydroxydopamine. As early as Day 1 after the injection, there was a decline in the motor performance of the 6-hydroxydopamine-lesioned rats that correlated with a reduction of dopaminergic innervation of the contralateral striatum. Loss of dopaminergic neurons in the ventral midbrain developed a few days later and seemed to follow a specific temporospatial pattern. Degenerating neurons and activated microglia were seen only in areas in which dopaminergic cells were no longer observed, suggesting that the loss of the dopaminergic phenotype preceded the degenerative process. In sham-lesioned rats, there was a transient activation of microglia in the vicinity of the needle tract without any cell degeneration. This chronology of events supports the hypothesis that microglial activation is a secondary rather than primary phenomenon in dopaminergic cell degeneration induced by 6-hydroxydopamine.