EFFETTI PRO-AUTOFAGICI E PRO-APOPTOTICI INDOTTI DAL PARAQUAT IN COLTURE ASTROGLIALI UMANE

Mollace Vincenzo Università "Magna Graecia" di Catanzaro - Facoltà di Farmacia -ARPACAL

Evidence exists that herbicides, including paraquat (PQ), may be implied in the pathogenesis of Parkinson’s Disease, a common neurodegenerative disorder. In addition, it is well known that PQ causes severe neurodegenerative effects both in vitro and in vivo, though exact mechanisms are not firmly established. PQ produced a significant reduction of Lipari human cultured astroglial cells viability, an effect associated to early autophagic response followed by sustained apoptosis as shown by immunocytochemical analysis and by western blotting determinations. These effects have been also associated to significant reduction of activity and expression of astroglial glutamine synthase (GS), the enzyme which converts glutamate into non toxic glutamine. Furthermore PQ, microinfused into substantia nigra, induced severe behavioural and EEG alterations in treated rats, being both effects followed by increased rat mortality. Treatment of cells with a melatonin receptor MT3 ligand (MT3L), which is also an inhibitor of the quinone oxydoreductase 2 (QR2) enzyme, antagonised cell death and rats mortality, restored astroglial cell viability and GS activity and expression and also counteracted behavioural and electocorticogram effects induced by PQ in rats, thus confirming that oxidative stress may play a role in PQ-induced neurodegenerative disorders. In conclusion, the present experiments demonstrate that PQ is toxic when incubated with human astroglial cells and microinfused into substantia nigra of rats and that all these effects were counteracted by MT3L, thus suggesting a role for QR2 enzyme in PQ-related brain damage.