On 2015 Feb 09, Andrey Petrenko commented:

Dr. Junfeng Zhang and colleagues have demonstrated that postoperative deterioration of rat cognitive performance in the Barnes maze could be prevented by amantadine. Amantadine also increased GDNF production in hippocampus and pretreatment with anti-GDNF antibody could abolish cognitive improvement attained by this drug. Since both amantadine and GDNF also inhibited interleukin 1β production, the authors concluded that the observed beneficial effect of amantadine on cognition is essentially an anti-neuroinflammatory effect mediated through GDNF. These are novel and interesting findings suggesting possible therapeutic potential of amantadine in treating postoperative cognitive dysfunction in humans. While we do not doubt the overall authors’ conclusion, we believe that there may be another mechanism underlying the reported cognition-preserving effect of amantadine. It is based on the fact that amantadine is a noncompetitive NMDA receptor antagonist (Blanpied TA, 1997; Blanpied TA, 2005) that may have analgesic properties. Although Dr. Zhang and colleagues believe that by performing learning and memory tests one week after surgery they have avoided the influence of pain on their results, this might not be the case. Actual pain levels in operated animals were not assessed in this study, and it is possible that rats given amantadine could have experienced significantly less pain compared to those operated but not receiving the drug. Such a possibility is further supported by the regimen of amantadine administration chosen by the authors, which was similar to preventive analgesia (first dose of analgesic being administered before surgery) often employed to alleviate postoperative pain. In elderly patients postoperative pain can confound performance on cognitive tests (Heyer EJ, 2000) and also predicts decline in their mental status (Duggleby W, 1994). In aged rats postoperative pain impairs cognitive function and preventive administration of analgesics (including those with no anti-inflammatory effect) can prevent this cognitive decline　(Chi H, 2013; Kawano T, 2014). The extent of postoperative cognitive decline positively correlates with the level of expression of the NMDA receptor GluN2 subunits in rat hippocampus (Chi H, 2013), further supporting the notion that the NMDA receptor inhibiting properties of amantadine should have not be discarded when interpreting the results of the study in question. In adult spinal nerve ligated rats preventive administration of memantine (a derivate of amantadine and also a noncompetitive NMDA receptor antagonist) inhibits the phosphorylation of the NMDA receptor GluN2 subunits in the spinal cord and hippocampus, causes antinociception and, as a consequence, preserves their cognitive function (Morel V, 2013).<br> Finally, several reports indicate the involvement of NMDA receptors in brain expression of neurotrophic factors (including GDNF) (Al-Amin H, 2011; Ranju V, 2015) and in the mechanisms of neuroinflammation (Liu CH, 2011; Yan J, 2014) with documented beneficial effects of NMDA receptor antagonists. Thus, there is a possibility that the NMDA receptor-inhibiting properties of amantadine could also have contributed to its beneficial effect on neuroinflammation observed by Dr. Zhang and colleagues.

On 2015 Feb 09, Andrey Petrenko commented:

Dr. Junfeng Zhang and colleagues have demonstrated that postoperative deterioration of rat cognitive performance in the Barnes maze could be prevented by amantadine. Amantadine also increased GDNF production in hippocampus and pretreatment with anti-GDNF antibody could abolish cognitive improvement attained by this drug. Since both amantadine and GDNF also inhibited interleukin 1β production, the authors concluded that the observed beneficial effect of amantadine on cognition is essentially an anti-neuroinflammatory effect mediated through GDNF. These are novel and interesting findings suggesting possible therapeutic potential of amantadine in treating postoperative cognitive dysfunction in humans. While we do not doubt the overall authors’ conclusion, we believe that there may be another mechanism underlying the reported cognition-preserving effect of amantadine. It is based on the fact that amantadine is a noncompetitive NMDA receptor antagonist (Blanpied TA, 1997; Blanpied TA, 2005) that may have analgesic properties. Although Dr. Zhang and colleagues believe that by performing learning and memory tests one week after surgery they have avoided the influence of pain on their results, this might not be the case. Actual pain levels in operated animals were not assessed in this study, and it is possible that rats given amantadine could have experienced significantly less pain compared to those operated but not receiving the drug. Such a possibility is further supported by the regimen of amantadine administration chosen by the authors, which was similar to preventive analgesia (first dose of analgesic being administered before surgery) often employed to alleviate postoperative pain. In elderly patients postoperative pain can confound performance on cognitive tests (Heyer EJ, 2000) and also predicts decline in their mental status (Duggleby W, 1994). In aged rats postoperative pain impairs cognitive function and preventive administration of analgesics (including those with no anti-inflammatory effect) can prevent this cognitive decline　(Chi H, 2013; Kawano T, 2014). The extent of postoperative cognitive decline positively correlates with the level of expression of the NMDA receptor GluN2 subunits in rat hippocampus (Chi H, 2013), further supporting the notion that the NMDA receptor inhibiting properties of amantadine should have not be discarded when interpreting the results of the study in question. In adult spinal nerve ligated rats preventive administration of memantine (a derivate of amantadine and also a noncompetitive NMDA receptor antagonist) inhibits the phosphorylation of the NMDA receptor GluN2 subunits in the spinal cord and hippocampus, causes antinociception and, as a consequence, preserves their cognitive function (Morel V, 2013).<br> Finally, several reports indicate the involvement of NMDA receptors in brain expression of neurotrophic factors (including GDNF) (Al-Amin H, 2011; Ranju V, 2015) and in the mechanisms of neuroinflammation (Liu CH, 2011; Yan J, 2014) with documented beneficial effects of NMDA receptor antagonists. Thus, there is a possibility that the NMDA receptor-inhibiting properties of amantadine could also have contributed to its beneficial effect on neuroinflammation observed by Dr. Zhang and colleagues.