Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration最新文献

The present study examined the effect of chronic intrastriatal infusion of the dopamine receptor agonist lisuride on apomorphine-induced rotational behaviour and on D2-dopamine receptors in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. The completeness of the lesion of the right ascending nigrostriatal dopaminergic pathway was confirmed by apomorphine-induced rotation and [3H]-mazindol autoradiography. The intrastriatal infusion of lisuride (0.5 microgram/h) into the lesioned striatum for 2 weeks induced an immediate but temporary spontaneous contralateral rotation and a reduction of apomorphine-induced rotation of 47.2% relative to pre-lisuride infusion. The density of D2-receptors in the lisuride-infused striatum was significantly decreased by 40% relative to vehicle-infused 6-OHDA lesioned rats. The level of D2-dopamine receptors returned to normal levels 3 weeks after the termination of lisuride infusion. These results show that the intrastriatal infusion of lisuride reverses the behavioural and D2-dopamine receptor changes present in the 6-OHDA lesion rat model of Parkinson's disease.

Increased free radical production may occur in Alzheimer's disease (AD). In view of the central role of iron in free radical reactions we have investigated the distribution of non-haem iron in the hippocampal formation in normal control individuals and in patients with AD. In controls, non-haem iron was principally associated with glial elements and the neuropil, with highest levels in the stratum radiatum/lacunosum, fimbria, alveus and oriens layers. Except for the subiculum, the pyramidal cell layers and the granule cell layer showed little or no non-haem iron staining. Intensity of staining was in the order of subiculum >> CA2 and adjacent regions of CA3 > CA4 > the remainder of CA3 > CA1. In the hippocampus in AD, iron was associated with cells containing neurofibrillary tangles (NFT) and was present in glial cells and neurites of senile plaques (SP). These findings were most pronounced in CA1 pyramidal cell layer and subicular complex although not all NFT or SP were stained. Since the NFT and SP staining for non-haem iron appears to be associated with glial cells, the association of non-haem iron with the pathological stigmata of AD may be a secondary response of glial cells, in particular microglia, to neuronal damage.

Raised tissue iron levels in the substantia nigra in Parkinson's disease (PD) suggests that altered iron homeostasis may underly the disorder. We have therefore investigated the distribution of non-haem iron in the normal and PD substantia nigra, using a sensitive histochemical procedure, to assess the pathogenic potential of this metal. In control cases non-haem iron staining was highest in the substantia nigra zona reticulata (SNr) and associated with the neuropil, oligodendrocytes, astrocytes and non-pigmented neurones. The substantia nigra zona compacta (SNc) showed lower non-haem iron staining than the SNr, with generalized impregnation of the neuropil and occasional non-haem iron-positive oligodendrocytes and astrocytes. The pigmented dopaminergic neurones were unstained, often present in areas of neuropil with low iron reactivity. In PD the SNc showed increased iron staining of the neuropil with many iron-positive microglial cells associated with extracellular melanin. The remaining dopaminergic neurones were unstained, though many of the non-pigmented neurones of the SNr were iron-positive.

In order that better therapeutic approaches to disorders in man characterized by aluminium (Al) overload might be developed it is essential to have an appropriate animal model. Chronic oral administration of Al citrate to male Wistar rats leads to an Al overload in a relatively short period of time when compared to previous published animal models. Liver and brain Al levels are increased by 25 and 30-fold respectively compared to control rats after 6 months of loading. Al tissue content was significantly greater when the Al citrate was administered in an iron-free diet. The distribution of Al in brain was similar to that in the Al encephalopathy of patients with chronic renal failure or Alzheimer's disease and is in accord with observations that areas of brain that accumulate greatest amounts of Al have highest concentrations of transferrin receptors. In the brain, the toxic effect of Al at the cellular level was characterized by an extensive cytoplasmic vacuolation in astrocytes (especially) and neurones. These changes are reminiscent of those observed in certain human neurodegenerative diseases.

We have produced by gene targeting a mouse line with an inactive PrP gene. In animals heterozygous for this mutation, PrP mRNA is reduced by approximately 50% throughout the brain compared with wild type mice. The steady-state level of PrPc is also significantly reduced in heterozygotes compared to wild type mice. PrP mRNA and protein are not detected in brains of mice homozygous for the mutation. We have infected wild type mice and mice heterozygous and homozygous for the mutation with the ME7 strain of scrapie. A gene dosage effect can be seen in time of disease onset and period over which the disease symptoms develop. In heterozygotes disease onset occurs around 220 days and terminal stages are reached by 280 days. In wild type mice disease onset occurs around 130 days and the terminal stages by 160 days. The PrP-/- mice are resistant to disease up to 475 days. PrP deposition in heterozygous mice starts in the same brain area as wild type mice and can be detected as early as 50 days. The pattern of PrP deposition in the brain of heterozygotes follows an identical course to that observed in wild type mice and by terminal stages of disease the amount deposited is equivalent to wild type mice. Vacuolation is detected later than PrP deposition and distribution and degree in the terminal stages of disease is similar in wild type and heterozygous mice. These results show that signs of disease, vacuolation and PrP deposition are dependent upon PrPc in a rate dependent manner.