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The Journal of Neuroscience, February 1, 1998, 18(3):1038-1046
Free Radical Scavenging and Inhibition of Nitric Oxide Synthase
Potentiates the Neurotrophic Effects of Brain-Derived Neurotrophic
Factor on Axotomized Retinal Ganglion Cells In Vivo
Nikolaj
Klöcker1,
Alessandro
Cellerino2, and
Mathias
Bähr1
Departments of 1 Neurology and
2 Ophthalmology, University of Tübingen, 72076 Tübingen, Germany
Brain-derived neurotrophic factor (BDNF) partially promotes the
survival of axotomized retinal ganglion cells (RGCs). In analogy with
in vitro experiments (; ), we tested whether neuroprotection by BDNF is limited by adverse effects as a consequence of excessive free radical formation. First, we
investigated whether BDNF and the free radical scavenger N-tert-butyl-(2-sulfophenyl)-nitrone
(S-PBN) cooperate in protecting RGCs from axotomy-induced death.
Although systemic S-PBN treatment alone did not influence RGC survival
after axotomy, it potentiated the neuroprotective effects of BDNF
significantly. Single BDNF treatment rescued 27% of the RGCs, which
otherwise would have died 14 d after optic nerve transection,
whereas a combined treatment of BDNF and S-PBN improved this rescue
rate up to 68%. We then investigated whether the adverse effects of
BDNF could be ascribed to activation of nitric oxide synthase (NOS). We
found colocalization of NOS and the BDNF receptor TrkB in the retina.
NADPH-diaphorase reactivity, a reliable marker for NOS in the rat
retina, increased after chronic BDNF treatment in vivo.
Systemic application of the NOS-inhibitor
N- -nitro-L-arginine-methylester
(L-NAME) potentiated the neuroprotective action of
BDNF (55% rescue rate). We conclude that activation of NOS is a
pathological consequence of BDNF application, which reduces its
neuroprotective potential. The observation that this adverse effect can
be antagonized by systemic application of free radical scavengers could
be of relevance for clinical applications of neurotrophins in human
neurodegenerative diseases.
Key words:
BDNF; S-PBN; apoptosis; excitotoxicity; free radical
scavenger; nitric oxide; retina; axotomy; neurodegeneration
Copyright © 1998 Society for Neuroscience 0270-6474/98/1831038-09$05.00/0
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