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-omega-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.