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UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
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Neuroprotection studies in in vivo models of neurodegeneration
Prof Laura Della Corte (guest of Prof. G. Di Giovanni)
Department of Pharmacology, University of Florence
+39 3290179291
+39 055410778
[email protected]
7th February 2011
Abstract
Our work was aimed to establish in vivo models, using rat brain microdialysis, to
evaluate neuroprotection against neurotoxic stimuli.
Excitotoxicity may contribute to oxidative stress and neuronal death occurring in
many neurodegenerative disorders of the basal ganglia, such as Parkinson’s
disease. A model was set up where a microdialysis probe was implanted into the rat
striatum and the locally applied glutamatergic non-NMDA agonist, kaininc acid (KA),
was used as the excitotoxic stimulus. Striatal neurotransmitter release and ex vivo
striatal apoptotic signal were monitored. In this model, pre-treatment with PF9601N a MAO B inhibitor, more potent and selective than l-deprenyl, was shown to prevent
apoptotic degeneration & astrocyte activation, reducing the KA-evoked release of
excitatory amino acids while increasing that of taurine, thus showing the validity of
this model for neuroprotection studies.
A novel method to detect highly reactive oxygen species (hROS) formation,
simultaneously to amino acid release, was developed using the new indicator
terephthalic acid (TA2-). The formation of the fluorescent 2-hydroxyterephthalate
(OH-TA) was shown to be quantitatively-related to the excitotoxic stimulus. The
dihydropyridine derivative of taurine, tauropyrone (TRP), and JAK-D, a potent
inhibitor of thyroid releasing hormone-degrading enzyme (TRH-DE) were tested as
possible protectans against KA-induced hROS production. Pre-treatment with TRP
or JAK-D significantly reduced the KA-evoked OH-TA formation, thus indicating that
in this model the terephthalic method provides a valid approach for assessing the
relative importance of OH· in neurodegeneration and neuroprotection.
Finally, using a rat model of “Binge Drinking” (BD), where microdialysis samples
were collected from the ventral hippocampus (vHIP), the BD regimen (2g/kg or
3g/kg EtOH, 3 wk by gavage: 3xday, 2 days/wk) was shown to enhance glutamate
(Glu) basal levels and microglial activation, detected by ex vivo brain
immunohistochemistry.