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(1/642) Increased neurodegeneration during ageing in mice lacking high-affinity nicotine receptors.

We have examined neuroanatomical, biochemical and endocrine parameters and spatial learning in mice lacking the beta2 subunit of the nicotinic acetylcholine receptor (nAChR) during ageing. Aged beta2(-/-) mutant mice showed region-specific alterations in cortical regions, including neocortical hypotrophy, loss of hippocampal pyramidal neurons, astro- and microgliosis and elevation of serum corticosterone levels. Whereas adult mutant and control animals performed well in the Morris maze, 22- to 24-month-old beta2(-/-) mice were significantly impaired in spatial learning. These data show that beta2 subunit-containing nAChRs can contribute to both neuronal survival and maintenance of cognitive performance during ageing. beta2(-/-) mice may thus serve as one possible animal model for some of the cognitive deficits and degenerative processes which take place during physiological ageing and in Alzheimer's disease, particularly those associated with dysfunction of the cholinergic system.  (+info)

(2/642) Oligodendroglial vacuolar degeneration in the bilateral motor cortices and astrocytosis in epileptic beagle dogs.

We performed a pathologic examination of the brains of three dogs in an epileptic beagle colony. Histologically, all the cases had diffuse astrocytosis in the cerebral cortex and basal ganglia as well as the hippocampus, whereas they showed acute nerve cell change in the hippocampus and some other areas of the cerebrum. One of these animals showed laminar myelin pallor associated with the presence of many vacuoles in the IV to VI layers of the bilateral motor cortices. Most of the vacuoles contained fine granules stained with luxol-fast-blue stain. Ultrastructural examination revealed that some oligodendrocytes and perineuronal satellite oligodendrocytes in the bilateral cerebral motor cortices of the two affected dogs had many vacuoles surrounded by myelin-like lamellar structures. These findings suggest a possibility that astrocytosis in the cerebrum and vacuolar degeneration of oligodendrocytes in the cerebral motor cortex may be, at least in part, related to the occurrence or development of seizures.  (+info)

(3/642) Cyclo-oxygenase-2 mediates P2Y receptor-induced reactive astrogliosis.

Excessive cyclo-oxygenase-2 (COX-2) induction may play a role in chronic neurological diseases characterized by inflammation and astrogliosis. We have previously identified an astroglial receptor for extracellular nucleotides, a P2Y receptor, whose stimulation leads to arachidonic acid (AA) release, followed, 3 days later, by morphological changes resembling reactive astrogliosis. Since COX-2 may be upregulated by AA metabolites, we assessed a possible role for COX-2 in P2Y receptor-mediated astrogliosis. A brief challenge of rat astrocytes with the ATP analogue alpha,beta-methylene ATP (alpha,beta(me)ATP) resulted, 24 h later, in significantly increased COX-2 expression. The selective COX-2 inhibitor NS-398 completely abolished alpha,beta(me)ATP-induced astrocytic activation. Constitutive astroglial COX-1 or COX-2 did not play any role in purine-induced reactive astrogliosis. PGE2, a main metabolite of COX-2, also induced astrocytic activation. These data suggest that a P2Y receptor mediates reactive astrogliosis via induction of COX-2. Antagonists selective for this receptor may counteract excessive COX-2 activation in both acute and chronic neurological diseases.  (+info)

(4/642) Platelet activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity.

Platelet activating factor (PAF), an endogenous proinflammatory agent, mediates neuronal survival, glutamate release, and transcriptional activation following excitotoxin challenge. To determine whether PAF receptor (PAFR) expression is altered during excitotoxicity, changes in PAFR mRNA localization were compared with markers of neuronal apoptosis and reactive gliosis following systemic injection of kainic acid. Data from semi-quantitative RT-PCR, in situ hybridization, DNA fragmentation, cellular morphology analysis, and immunohistochemistry demonstrate that the localization of PAFR mRNA is altered during kainic acid-induced neurodegeneration. While PAFR mRNA is normally exhibited by neurons and microglia in rat hippocampus, expression becomes restricted to apoptotic neurons and to glia involved in phagocytosing apoptotic debris following treatment with excitotoxin. PAFR mRNA is rarely detected in surviving neurons. These data provide the first indication that PAFR-expressing neurons may be preferentially susceptible to excitotoxic challenge.  (+info)

(5/642) Multifocal meningioangiomatosis: a report of two cases.

We report the CT and MR findings in two patients with multifocal meningioangiomatosis, neither of whom had a family history or stigmata of neurofibromatosis. All lesions were located in the cortical and subcortical areas and had round dense calcifications with eccentric cysts. The masses were associated with surrounding edema and gliosis.  (+info)

(6/642) Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized clinically by motor and psychiatric disturbances and pathologically by neuronal loss and gliosis (reactive astrocytosis) particularly in the striatum and cerebral cortex. We have recently created HD full-length cDNA transgenic mouse models that may serve as a paradigm for HD. A more detailed characterization of these models is presented here. The transgene encoding normal huntingtin consists of 9417 bp of the huntingtin coding sequences including 16 tandem CAGs coding for polyglutamines as part of exon 1. The transgene is driven by a heterologous cytomegalovirus promoter. Five independent transgenic mouse lines were obtained using this construct. An additional six transgenic lines were obtained using full-length HD constructs that have been modified to include either 48 or 89 CAG repeat expansions. Southern blot and densitometric analyses indicated unique integration sites for the transgene in each of the lines with a copy number ranging from two to 22 copies. Widespread expression of the transgene in brain, heart, spleen, kidney, lung, liver and gonads from each line was determined by Western blot analyses. In the brain, transgene expression was found in cerebral cortex, striatum, hippocampus and cerebellum. Expression of the transgene was as much as five times the endogenous mouse huntingtin level. Phenotypically, only mice expressing 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction. Early behavioural abnormalities were characterized by trunk curling and clasping of both fore- and hindlimbs when the animals were suspended by their tails. Subsequently, these mice exhibited hyperkinetic movements, including heightened exploratory activities, unidirectional rotational behaviour, backflipping and excessive grooming that lasted for several weeks. Eventually, the animals progressed to a hypokinetic phase consisting of slowed movements and lack of response to sensory stimuli. Urine retention or incontinence was also a prominent feature of the hypokinetic phase. At the end stage of the disease process, HD48(B,D) and HD89(A-C) mice became akinetic just prior to death. Neuropathological examination of mice at various stages indicated that it was only during the hypokinetic phase and thereafter when selective neuronal loss was most apparent. Regions of neurodegeneration and loss included the striatum, cerebral cortex, thalamus and hippocampus. TUNEL staining indicated an apoptotic mode of cell death in these brain regions. Comparative neuronal counts after Nissl staining showed as much as 20% loss of small and medium neurons in the striatum in mice at the hypokinetic and akinetic stages. Reactive astrocytosis accompanied the areas of neurodegeneration and loss. Polyglutamine aggregates in the form of neuronal intranuclear inclusions and diffuse nuclear and perinuclear aggregations were found in a small percentage of neurons, including those in brain regions that are typically spared in HD. This observation suggests that polyglutamine aggregates may not be sufficient to cause neuronal loss in HD. In both behavioural and neuropathological analyses, wild-type and transgenic animals with 16 CAG repeats were indistinguishable from each other and do not exhibit the changes observed for mice carrying the 48 and 89 CAG repeat mutations. Thus, animals expressing the CAG repeat expansions appear to represent clinically analogous models for HD pathogenesis, and may also provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.  (+info)

(7/642) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy.

BACKGROUND AND PURPOSE: The mechanisms behind the demyelination that is characteristic of multiple sclerosis (MS) are still poorly understood. The purpose of this study was to compare immunopathologic findings in demyelinating lesions of three patients with in vivo assessments obtained by quantitative proton MR spectroscopy (MRS). METHODS: Between four and seven stereotactic needle brain biopsies were performed in three young adults with diagnostically equivocal findings for MS. Axonal density, gliosis, blood brain-barrier breakdown, and demyelinating activity of lesions were determined. Combined MR/MRS studies were performed (T1-weighted fast low-angle shot and single-voxel stimulated-echo acquisition mode), and absolute metabolite levels were obtained with a user-independent fitting routine. Metabolite control values were obtained from a group of age-matched healthy volunteers (n = 40, age range, 20-25 years old). Alterations of metabolite levels of control subjects were considered significant when exceeding two standard deviations. RESULTS: There were parallel decreases of N-acetylaspartate (21%-82%) and reductions of axonal density (44%-74%) in demyelinating plaques. Concomitant increases of choline (75%-152%) and myo-inositol (84%-160%) corresponded to glial proliferation. Elevated lactate was associated with inflammation. CONCLUSION: The present data suggest that in vivo MRS indicates key pathologic features of demyelinating lesions.  (+info)

(8/642) Differential diagnosis between organic and inorganic mercury poisoning in human cases--the pathologic point of view.

Differences in pathology were found between acute and chronic exposure to methylmercury, mercury vapor, and inorganic mercury. Characteristic pathologic changes produced by organic mercury in the brain have previously been described in patients with Minamata disease. The brains of patients who presented with acute onset of symptoms and died within 2-mo showed loss of neurons with reactive proliferation of glial cells, microcavitation, vascular congestion, petechial hemorrhage, and edema in the cerebral cortices, predominantly in the calcarine, pre- and postcentral, and transverse temporal cortices and in the cerebellar cortex. The neuropathologic changes in the patients with acute onset of symptoms who survived for a long period (>10 yr) were also included neuronal loss with reactive proliferation of glial cells in similar anatomic locations. The neuropathologic changes in patients with inorganic mercury poisoning are quite different. Autopsies performed on 3 individuals with fatal cases of acute inorganic mercury poisoning who were exposed to mercury vapor for about 2 wk revealed diffuse organized pneumonia, renal cortical necrosis, disseminated intravascular coagulopathy, and infarctions in the brain and kidneys. In 2 other patients who worked in mercury mines for about 10 yr and who suffered from chronic inorganic poisoning, no specific lesions were demonstrated in the brain. However, the assay and the histochemistry of mercury revealed that inorganic mercury was present in the brain in all 3 groups irrespective of the brain lesions and the duration of clinical signs.  (+info)