Background and Goal of Study: Postoperative cognitive dysfunction is a clinical entity that is associated with poor outcome. We determined the effectiveness of amantadine in reducing surgery-induced cognitive impairment and the role of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in this effect.
Materials and Methods: In the first experiment, eighteen-month old male C57BL/6J mice were randomly assigned to: 1) control group (not being exposed to surgery or any drugs), 2) surgery group (right carotid artery exposure + isoflurane for 2 h), and 3) surgery plus amantadine group. One week later, these mice were started to be tested in Barnes maze and then fear conditioning. These mice were sacrificed after fear conditioning and their brains were used for Golgi staining. Amantadine was injected intraperitoneally at 25 μg/g/day for three days with the first dose at 15 min before surgery. In the secondary experiment, eighteen-month old male Fischer 344 rats were assigned to: 1) control group, 2) surgery plus amantadine and anti-GDNF group, 3) surgery plus amantadine and anti-BDNF group, 4) surgery plus amantadine and heat-denatured anti-GDNF group. Two micrograms of rabbit polyclonal anti-GDNF, anti-BDNF or heat-denatured anti-GDNF antibody was injected intracerebro-ventricularly immediately at the end of the surgery. One week later, some rats were started to be tested in Barnes maze and fear conditioning and the others were used to harvest the right hippocampus immediately for Western blotting. After fear conditioning, these rats were sacrificed and the hippocampus was used for Golgi stain. 
Conclusions: Our results suggest that amantadine attenuates surgery-induced learning and memory impairment. This effect may be mediated by BDNF and GDNF (Fig.1). Intracerebro-ventricular injection of an anti-BDNF antibody and anti-GDNF antibody blocked the effects of amantadine on cognition (Fig.2). Furthermore, BDNF may promote the ramification of basal branches of CA1 hippocampal neurons (Fig.3).



07 / Amantadine alleviates postoperative cognitive dysfunction possibly by increasing both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in mice and rats