BDNF causes complex modifications of cortical neurotransmitter protein expression in the rat cortex after photothrombotic ischaemia

Functional reorganization of the cerebral cortex following cerebral ischemia is associated with structural remodeling reflected by changes in expression patterns of a battery of different proteins. Trophic substances, such as brain-derived neurotrophic factor (BDNF) and granulocyte-colony stimulating factor (G-CSF), have been shown to influence these processes and improve postischemic outcome. Since neurotranmitter receptors are major candidate molecules to be modified in the postischemic reorganization phase, we checked for alterations of postischemic protein expression patterns and potential modifications by BDNF or G-CSF treatment, respectively. Using a rat model of photothrombotic cortical ischemia, protein expression of NMDA receptor subunit 1 (NR1), AMPA receptor subunit GluR1 and GABA(A) receptor were analyzed, respectively. Thirty male Wistar rats were randomly assigned to (1) a sham group (sham operation without ischemia + 0.5ml saline i.v. 1h after sham operation), (2) a control group (ischemia + 0.5ml saline i.v. 1h after ischemia), (3) a G-CSF group (ischemia + 15µg G-CSF soluted in 0.5ml saline i.v. 1h after ischemia) or (4) a BDNF group (ischemia + 20µg BDNF soluted in 0.5ml saline i.v. 1h after ischemia). In addition, a group of rats was treated with either BNDF or G-CSF. Rats were sacrificed at 6 weeks after ischemia and their brains processed for immunohistochemistry. Immunoreactivity (IR) was semiquantitatively assessed in the immediate vicinity of the lesion (ischemic border zone), adjacent cortex, and corresponding contralateral cortex, respectively. Treatment with BDNF or G-CSF without ischemia caused no significant alterations of the various neurotransmitter receptor IR. In the various experimental ischemic groups, NR1 IR decreased slightly, but not significantly, in the ischemic border zone as well as in the ipsi- and contralateral cortex. Perilesional GluR1 IR decreased most pronounced in the BDNF group, while contralaterally lowered protein expression was observed in all experimental groups. IR for GABA(A) receptor increased in all experimental groups in the ischemic borderzone, but was lowered in the adjacent and contralateral cortex reaching significance only in the BDNF group.

In conclusion, while both BDNF and G-CSF have been demonstrated to improve postischemic neurological outcome, structural modifications of cortical neurotransmitter protein expression were more pronounced by BDNF treatment.