Irina A. Kiprianova
Diplom Biologin
Neuroprotective Effects of Exogenous Brain-Derived Neurotrophic Factor after
Transient Forebrain Ischemia in Rats
Geboren am 14.01.1961 in Novosibirsk, Russland
Reifeprüfung am 20.06.1978 in Novosibirsk, Russland
Studiengang der Fachrichtung Biologie vom 01.09.1978 bis 24.06.1983
Vordiplom am 10.10.1981 an der Universität von St.-Petersburg, Russland
Diplom am 24.06.1983 an der Staatliche Universität von Tomsk, Russland
Promotionsfach: Neurologie
Doktorvater: Priv.-Doz. Dr. med. M. Spranger
We investigated the effect of brain derived neurotrophic factor (BDNF) on neuronal
degeneration, hippocampal long-term potentiation (LTP) and cognitive functions after global
cerebral ischemia in the rat. After four-vessel occlusion, BDNF was continuously
administered intracerebroventricularly via an osmotic minipump. For histological analyses,
rats were sacrificed up to 7 days after ischemia and neuronal degeneration was estimated by
TUNEL staining. Additionally, the glial reaction was investigated immunohistochemically
and by measuring the activation of immunological nitric oxide synthase (iNOS) protein
expression. Post-ischemic intracerebroventricular infusion of BDNF prevented neuronal death
in the vulnerable CA1 region of the hippocampus. BDNF was demonstrated to inhibit the
iNOS expression in hippocampus and prevented the activation of astroglia and macrophage
infiltration associated with neuronal death.
The BDNF action on cognitive functions was analyzed repeatedly with a passive avoidance
test, a hole-board test, and an activity center on the same animal. Transient forebrain ischemia
resulted in a significant decrease in spatial discrimination performance but not of associative
memory. The ratios for working memory (WM) and reference memory (RM) 15 days after
ischemia were lower in the ischemic rats than in the sham operated control animals (WM = 22
± 6 vs. 72 ± 7; RM = 30 ± 7 vs. 72 ± 5). Post-ischemic intracerebroventricular BDNF infusion
increased both WM (63 ± 4) and RM (58 ± 5). The spontaneous locomotor activity did not
differ significantly in all three groups.
Electrophysiological experiments were performed 14 days after cerebral ischemia. Test
stimuli and tetanization were delivered to the Shaffer collaterals of the hippocampus and field
excitatory post-synaptic potentials (fEPSP) were recorded in the CA1 region. In sham
operated animals LTP was consistently induced after delivering a tetanus (increase of initial
fEPSP slopes to 174 ± 11% of baseline). After transient forebrain ischemia LTP could not be
induced (115 ± 8% of baseline). In ischemic animals treated with BDNF, LTP could be
induced (165 ± 15% of baseline).
These data indicate a protective effect of BDNF on neuron degeneration, synaptic
transmission and cognitive functions after transient forebrain ischemia and suggest a
therapeutic potential of BDNF in cerebral lesions.
