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neurotrophic effects to cell death in midbrain cultures: implications for
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Glutathione depletion switches nitric oxide neurotrophic effects to
cell death in midbrain cultures: implications for Parkinson's disease
S. Canals, M. J. Casarejos, S. de Bernardo, E. RodrõÂguez-MartõÂn and M.
A. Mena
J. Neurochem. (2001) 79, 1183±1195
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ABSTRACT
Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine
(DA) function in primary midbrain cultures. We investigate herein the role
of glutathione (GSH) homeostasis in the neurotrophic effects of NO. Fetal
midbrain cultures were pretreated with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine
(BSO), 24 h before the addition of NO donors (diethylamine/nitric oxide-complexed
sodium and S-nitroso-Nacetylpenicillamine) at doses tested previously as
neurotrophic. Under these conditions, the neurotrophic effects of NO
disappeared and turned on highly toxic. Reduction of GSH levels to 50% of
baseline induced cell death in response to neurotrophic doses of NO. Soluble
guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (PKG)
inhibitors protected from cell death for up to 10 h after NO addition; the
antioxidant ascorbic acid also protected from cell death but its ef®cacy
decreased when it was added after NO treatment (40% protection 2 h after NO
addition). The pattern of cell death was characterized by an increase in
chromatin condensed cells with no DNA fragmentation and with breakdown of
plasmatic membrane. The inhibition of RNA and protein synthesis and of
caspase activity also protected from
cell death. This study shows that alterations in GSH levels change the
neurotrophic effects of NO in midbrain cultures into neurotoxic. Under these
conditions, NO triggers a programmed cell death with markers of both
apoptosis and necrosis characterized by an early step of free radicals
production
followed by a late requirement for signalling on the sGC/cGMP/PKG pathway.
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