Neurodegeneration最新文献

There have been no reports of changes in free radical inactivating enzymes in the anterior horn of the spinal cord in ALS despite great interest in the possibility that free radicals might be important in the aetiology of the disease. In this study we have measured copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GSHPX) activities in anterior horn tissue obtained from patients with ALS and from controls. Total SOD activity was no different in the anterior horn of ALS cases compared to controls, but Cu/ZnSOD activity was reduced, and that of MnSOD increased, at thoracic cord level only. No detectable activity of GSHPX or cytochrome P₄₅₀(unpublished data) was found. These latter negative findings are important because they suggest that generation of free radicals from exogenous chemicals is not important in ALS and further that the neurone (as compared to other cell types) is poorly protected against the toxicity of hydrogen peroxide.

Aberrant neurofilament (NF) phosphorylation in the soma of the ventral horn neurons of neo-natal rat spinal cord is observed following exposure to cerebrospinal fluid (CSF) of patients suffering from Amyotrophic Lateral Sclerosis (ALS). CSF samples from ALS and non-ALS neurological patients were injected into the spinal subarachnoid space of 3 day old rat pups. After 48 h, sections of spinal cords were stained for the presence of phosphorylated NF epitopes with SMI-31 antibody. The number of neuronal soma staining with this antibody in the ventral and dorsal horns sides of the spinal cord was counted. There was a significant 3-fold increase in the number of soma stained with SMI-31 antibody in the ventral horns of rat spinal cords exposed to CSF of patients with ALS compared to cords from rats exposed to CSF of non-ALS patients and those which were not exposed to any CSF samples. Such an increase in staining of neuronal soma was not observed in the dorsal horns. Hyperphosphorylation of neuronal soma suggests an initial stage of degenerative changes occurring in the motor (ventral horn) neurons following exposure to circulating factor(s) in the CSF of patients with ALS.

Flupirtine belongs to the class of triaminopyridines and is successfully applied clinically as a non-opiate analgesic drug with additional muscle relaxant properties. Recently it was reported that flupirtine acts like an antagonist of the N-methyl-D-aspartate (NMDA) receptor complex in neuronal cells bothin vitroandin vivo. Here we have used primary cortical cells from rat embryos to demonstrate that this compound is also neuroprotective against the toxic effects caused by the prion agent PrP^Scand lead acetate (Pb). These two agents display pleiotropic effects on neurons, which include activation of the NMDA receptor complex. At concentrations above 30 μM the toxic-peptide fragment of PrP^Sccauses apoptotic fragmentation of DNA and is consequently neurotoxic. Pb is neurotoxic at concentrations above 10 μM. Co-administration of flupirtine (10 μM) with either of these agents resulted in reduced neurotoxicity. These data indicate that the cytoprotective effect of flupirtine is measurablein vitroagainst these noxious agents which show their effects, including modulation of the NMDA receptor complex, pleiotropically.

Levels of 10 trace elements were analysed in autopsied lumbar spinal cords of 38 motor neuron disease patients and 22 control subjects using instrumental neutron activation analysis. Statistically significant elevations of iron, selenium and zinc, and depletions of mercury and cesium were found in the spinal cords of motor neuron disease patients compared with control subjects. No significant correlations were found between disease duration, clinical severity or lumbar motor neuron counts and iron and selenium levels, suggesting that accumulation of these elements occur early as well as late in the disease process and therefore are not a consequence of end stage pathology. Increased iron in motor neuron disease spinal cord could act to enhance formation of reactive oxygen species. Our study supports the free readical hypothesis of neuron degeneration in motor neuron disease.

Apolipoprotein E (APO E) genotypes were determined in a UK population of neuropathologically confirmed control cases, and in cases of Lewy body dementia (SDLT) and late onset Alzheimer's disease (AD). APO E ϵ4 allele frequency was significantly elevated in both SDLT and AD groups with a concomitant reduction in the APO E ϵ3 allele frequency. The ϵ2 allele frequency in the AD group was only 25% of the control population, though because of the relatively small sample size this reduction was not significant; the ϵ2 allele frequency in the SDLT group was normal. No significant association was found between senile plaque density and neurofibrillary tangle density in the neocortex and APO E allele dose in either SDLT or AD. Although the possession of APO E ϵ4 is associated with an increased risk of developing SDLT and AD, actual APO E genotype does not appear to affect the burden of pathology.

Experimental lesions using the retrogradely transported toxic lectin, volkensin, were used in conjunction with quantitative autoradiography to investigate the cellular localization of nicotinic and adenosine A₁receptors. Lesions were produced by unilateral intrastriatal injection of volkensin, ricin (another toxic lectin but not transported in the central nervous system), quinolinate, and unilateral intrathalamic injection of ibotenate. Volkensin injection significantly reduced the number and mean cell size of large, infragranular pyramidal neurones in cortical areas Fr1/Fr2 (close to the midline) and more laterally in Par1/Par2. Selective destruction of these cells was accompanied by significant increases in the binding of [³H] nicotine in cortical areas contralateral to the lesion. A small but significant reduction in the binding of [³H] 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) to adenosine A₁receptors was observed only in deep layers of Fr1/Fr2 on the side ipsilateral to the lesion. No other toxin consistently changed the binding of either ligand in control animal groups with the exception of [³H] nicotine where small reductions were observed in the middle layers of one thalamic injection group. These data indicate differential plasticity of nicotinic receptors compared with other receptors studied previously using this paradigm. In the light of these findings, nicotinic receptors are discussed as targets for pharmacological manipulation of the activity of pyramidal neurones.

Calbindin-D_28kis a calcium-binding protein that protects nerve cells from degeneration. It is located in the midbrain dopaminergic neurons that are relatively invulnerable to degeneration in Parkinson's disease. Because the hypothalamic dopaminergic neurons do not degenerate in Parkinson's disease, the present study sought to determine whether these neurons also contain calbindin-D_28k. Using immunocytochemical staining with antibodies against calbindin-D_28kand tyrosine hydroxylase, and computer imaging techniques, the distributions of calbindin-D_28kand tyrosine hydroxylase-containing neurons were mapped. Both neuronal populations were present throughout the rostral-caudal extent of the hypothalamus. However, only in the periventricular region, at the preoptic and anterior hypothalamic levels, was there an overlap in the two cellular distributions. Using the presence of neuromelanin pigment as a marker for dopaminergic neurons, approximately 30% of the dopaminergic neurons contain calbindin-D_28kin the periventricular region. These data indicate that a sub-population of hypothalamic dopaminergic neurons contain calbindin-D_28k. This finding is discussed in terms of why hypothalamic dopaminergic neurons are resistant to degeneration in Parkinson's disease.

Adult mice and rats were sacrificed by perfusion between 2 and 90 days after right pyramidotomy to study the microglial and astroglial response in the brain and spinal cord. The microglia were detected immunohistochemically with OX-42, OX-18 and OX-6 to assess respectively the expression of complement type 3 receptor, and major histocompatibility class I and class II antigens. Cell counting was also carried out in some animals to determine the possible proliferation of glial cells in the corticospinal tract and around layer V neurons in the cerebral cortex. Some operated animals were given rhodamine B isothiocyanate injection to investigate whether macrophages/monocytes could have migrated from the blood stream to the reactive area. The glial response around the cell bodies of layer V neurons in the ipsilateral cerebral cortex did not display any noticeable difference compared with that of the contralateral side and of the cerebral cortex of the sham-operated and normal control animals. In the cervical and lumbar cord segments of the operated animals, reactive microglial cells in the contralateral corticospinal tract appeared as early as 2 days post pyramidotomy (PP) in rats and 4 days PP in mice. Activation of microglial cells lasted up till 35 days PP, showing gradual increase in immunoreactive staining and hypertrophy. After that, the microglial immunoreactivity subsided and the cells assumed normal appearance by 90 days PP. Quantitative analysis showed a marked increase in the number of microglial cells in the contralateral CST up till 60 days PP. In mice, at 6 days PP, astroglial cells were hypertrophic and more intensely stained but showed no increase in number. No noticeable changes were noted in the astroglia of the rats throughout the period studied. Rhodamine-labelled cells were found at the lesion site, but not in layer V of the cerebral cortex, nor in the corticospinal tract. Though different glial reactions in the degenerating corticospinal tract were noted in mice and rats, there was the same apparent lack of glial reaction around the cell bodies of layer V neurons in the two animal species. Such lack of significant glial response is different from the vigorous glial response around the cell bodies of peripherally projecting neurons demonstrated in previous work. The possible mechanisms for such difference and the implication of the difference in axonal regeneration were discussed.

We have previously shown that the brains of patients with Alzheimer's disease (AD) express transforming growth factor (TGF)-β2 in neurofibrillary tangle (NFT) -bearing neurons and reactive astrocytes. The present study was undertaken to determine whether other neurodegenerative diseases were also associated with an alteration of the TGF-β's. The immunohistochemical expression of TGF-β1, -2 and -3 was assessed in the brains of patients with progressive supranuclear palsy (n=2), amyotrophic lateral sclerosis (n=3), Lewy body disease (n=5), Parkinson's disease (n=1), Shy-Drager syndrome (n=1), Pick's disease (n=3), lobar atrophy (n=1), and corticobasal degeneration (n=2). Our results were compared to norms for controls (n=8). We found expression of TGF-β2 in both NFT bearing neurons and tangle-bearing glial cells in progressive supranuclear palsy and in neurons with age-related NFT formation. Widespread staining of reactive astrocytes for TGF-β2 was observed in all degenerative diseases. TGF-β1 and -3 staining was not selectively altered in these diseases. We conclude that induction of TGF-β2 may be an intrinsic part of the processes that underlie NFT formation and reactive gliosis in a variety of neurodegenerative diseases.