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| Anna Fiedorowicz |
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Laboratory of Neurochemistry, Nencki Institute of Experimental Biology,Pasteur 3 St., 02-093 Warsaw, Poland
e-mail: afiedro@nencki.gov.pl |
Poster Presentation: |
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| DIFFERENTIAL VULNERABILITY OF MURINE HIPPOCAMPAL NEURONS TO TRIMETHYLTIN INTOXICATION: A MODEL SYSTEM FOR STUDIES A DIFFERENTIAL RESPONSE OF HUMAN BRAIN STRUCTURES TO PATHOGENIC STIMULI. |
| Fiedorowicz A., Figiel I., Zaremba M. Oderfeld-Nowak B. | |
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- Nencki Institute of Experimental Biology, Warsaw; Schliebs R. - Paul Flechsig Insitute for Brain Research, Leipzig |
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| Animal models of diseases have been used in experiments to study the
pathology of a disease and to compare the efficacy of proposed therapeutic
interventions to existing clinical treatment. Differential vulnerability of
different brain structures and various neuronal classes to pathogenic stimuli
is well recognized, however the mechanisms responsible for this phenomenon
are still not clear. In the hippocampus, the pyramidal neurons are destroyed
in Alzheimer disease, ischemia and some types of epilepsy, while dentate
gyrus granule cells are resistant to majority of pathological stimuli. We have
elaborated the model of selective degeneration of murine hippocampal
granule neurons caused by neurotoxin - trimethyltin (TMT). The
neuropathological findings, that trimethyltin causes the hippocampal damage
have raised the possibility that there is a link between trimethyltin
neurotoxicity and degenerative events in human brain. In our studies one
month-old BalbC mice were administered a single dose of TMT (2.5 mg/kg
body weight). Neurodegeneration of the granule cells bears the apoptotic
features, as manifested by chromatin condensation and oligonucleosomal
fragmentation of DNA and was detected as early as 1 day after toxin
injection. The neurodegeneration of granule cells was accompanied by
strong accumulation of reactive microglia, 3 days after toxin exposure and
was practically restricted to the region of neurodegeneration. In the same
time a strong induction of IL-1beta, the proinflammatory cytokine, was
detected immunocytochemically in these cells. Simultaneous studies using
Ribonuclease Protection Assay (RPA) showed the increase of IL-1beta mRNA
in the hippocampus. Sequential analysis of appearance of degenerating
granule cells and accumulation of IL-1beta-positive microglia cells, suggests
that inflammation processes may contribute to the neurodegeneration. On
the other hand, astroglia activated by intoxication were observed
practically in the whole hippocampus, 3 days after TMT injection, and were
associated with the induction of nerve growth factor (NGF). In addition, we
observed the increased immunoreactivity of brain derived neurotrophic
factor (BDNF) in astrocytes surrounding injured dentate gyrus, 3 days after
exposure to TMT. These neurotrophins may have an important prosurviving
influence on neighboring neurons. An immunoreactivity augmentation of NGF
was also observed in pyramidal cells of CA3/CA4 layers as early as 1 day
following exposure to TMT. Particularly interesting appears the possibility
that NGF may protect the CA3/CA4 cells, which do not degenerate, in spite
of direct connections with the injured dentate gyrus. We have also proved,
by using RPA, the induction of IL-1 receptor antagonist (IL-1ra) mRNA,
another neuroprotective cytokine. Its regional and cellular localization is
presently examined and it appears that its augmentation may contribute to
neuroprotection of these granule cells, which survive the damaging action
of trimethyltin. |
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