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Vol. 62, Issue 5, 1043-1052, November 2002
Institut National de la Santé et de la Recherche
Médicale U289, Experimental Neurology and Therapeutics,
Hôpital de la Salpêtrière, Paris (J.-D.T., S.M.,
T.D., M.R., P.P.M.); Centre de Recherche Pierre Fabre, Castres, France
(M.M., F.C., P.P.M.)
We have shown previously that low concentrations of noradrenaline (NA)
confer long-term but partial protection to tyrosine hydroxylase
(TH+) dopaminergic neurons by reducing spontaneously
occurring oxidative stress. We demonstrate here that the effect of NA
is strongly enhanced by cAMP-elevating agents, in particular forskolin
(FK), through a mechanism that does not involve activation of
adrenoceptors. FK also enhanced the neuroprotective action of
antioxidants that mimic the trophic effects of NA, such as trolox and
pyrocatechol, but was totally ineffective by itself, suggesting that
inhibition of oxidative stress was a required step to reveal the
cAMP-dependent mechanism. Neuroprotection afforded by FK was rapidly
reversible, optimal when the treatment was initiated in the early phase
of the culture and exquisitely specific to dopaminergic neurons. FK
stimulated the phosphorylation of extracellular signal-activated kinases (ERK)1/2 in a subpopulation of dopaminergic
neurons, suggesting that the mitogen-activated protein kinase (MAPK)
pathway was involved in the effects of cAMP-elevating agents.
Accordingly, inhibition of the upstream kinases of ERK1/2
by 2'-amino-3'-methoxyflavone (PD98059) not only suppressed MAPK
activation caused by FK but also abolished the survival promoting
activity that this compound exerts on TH+ neurons. PD98059
did not reduce, however, the trophic effects provided by NA alone.
Surprisingly, the archetypal cAMP-dependent protein kinase was
apparently not responsible for ERK1/2 activation. The data
suggest that the MAPK signaling pathway plays a key role in the trophic
effects that cAMP elevating agents and NA cooperatively exert on
TH+ neurons.
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