Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice.

Parkinson's disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-ß-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.

Stereological approaches to dementia research using human brain tissue.

The relationship between the clinical features of dementia disorders and the resultant changes in underlying neuropathological mechanisms has long been of interest to researchers working in the field of neurodegenerative disorders. The majority of neuropathological research in dementia has utilized semi-quantitative analysis of protein inclusions, which have defined the hallmark histological features of the conditions. However, the advent of three-dimensional stereological techniques has enabled unbiased and fully quantitative assessment of brain tissue. The present review focuses on studies that have used these techniques to elucidate important relationships between neuropathological changes and clinical features and, in doing so, revealed important mechanistic insights into the pathophysiology of dementia disorders.

Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias.

BACKGROUND: Optimal vascular function is vital for prevention of dementia. We hypothesized that elderly post-stroke survivors who preserve cognitive function show unperturbed cerebral microvasculature compared with those who develop dementia. METHODS: Using stereological spherical probe software, we compared the length density (Lv, cumulative vessel length per unit tissue volume) of hippocampal microvessels in post mortem brain tissue from post-stroke survivors, Alzheimer's disease (AD), vascular dementia (VaD) and normal ageing control subjects. We also assessed microvessel diameters in the same subjects. Microvessels were identified by markers of endothelial cells (glucose transporter 1; GLUT1), basement membrane (collagen IV; COL4) and smooth muscle cell α-actin (SMA). RESULTS: We found increased Lv of both GLUT1 and COL4 immunostained microvessels (P < 0.05) in the hippocampal CA1 region of post-stroke demented (PSD) and AD cases compared with post-stroke nondemented (PSND), control and VaD subjects. However, no changes were apparent in the CA2 region. We also noted significant increase in Lv in the entorhinal cortex of AD compared with PSND and PSD subjects. The mean diameter of microvessels was decreased in PSD, compared with PSND, as well as in AD and VaD compared with controls. Cumulative frequency analysis showed PSND subjects to have significantly greater proportion of microvessels with diameters, ranging from 7 to 12 µm. CONCLUSIONS: An increase in microvascular Lv in AD and PSD suggests either an increase in angiogenesis or the formation of newer microvessel loops in response to cerebral hypoperfusion. The decreased vessel diameters found in AD and VaD suggests increased vasoconstriction in dementia.

Biphasic change in BDNF gene expression following antidepressant drug treatment explained by differential transcript regulation.

Brain-derived neurotrophic factor (BDNF) has been suggested as a possible target for the treatment of depression. The effect by antidepressant drugs on BDNF mRNA expression is, however, strictly dependent on both treatment duration and time after the last administration. The rat BDNF gene itself is complex and expresses four different mRNA isoforms which can be regulated by different signaling cascades. The aim of the present study was to test the hypothesis that the previously shown biphasic action by the antidepressant drugs on total BDNF expression is explained by differential BDNF transcript regulation. For this purpose, we used in situ hybridization with exon-specific oligo nucleotides for exon V (total BDNF mRNA), exon I (protein synthesis-dependent transcripts), exon III and exon IV (immediate early-gene like-transcripts). Following an acute injection, all three drugs tested: fluoxetine, desipramine and TCP decreased total BDNF mRNA (exon V) as well as exon IV mRNA, while no significant effect was recorded for exons I and III mRNAs. In contrast chronic administration of all three drugs resulted in increased expression of exon V- and exon I-containing transcripts (fluoxetine and TCP only) but no significant changes were recorded for exon III and IV mRNAs. Electroconvulsive shock administration showed up-regulation of all four BDNF mRNAs following a single shock, but after repeated administration increases were restricted to exons I- and V-containing transcripts. In summary, this study shows clear evidence of differential BDNF transcript regulation following acute and chronic antidepressant drug treatment.