Amantadine Alleviates Postoperative Cognitive Dysfunction Possibly by Preserving Neurotrophic Factor Expression and Dendritic Arborization in the Hippocampus of Old Rodents.

Jing Zhong,Cheng Ni,Zhiyi Zuo,Jun Li

doi:10.3389/fnagi.2020.605330

Abstract

ObjectivesAmantadine has been shown to attenuate postoperative learning and memory dysfunction in young adult rats. However, postoperative cognitive dysfunction often occurs in elderly patients. We aimed to determine whether amantadine attenuated postoperative learning and memory dysfunction and whether these effects were associated with improved dendritic arborization in old rodents.MethodsEighteen-month old male C57BL/6J mice or Fischer 344 rats were subjected to right carotid artery exposure (surgery) under isoflurane anesthesia. This age represents an early old stage in rodents. Carotid artery exposure was used to simulate commonly performed carotid endarterectomy in elderly patients. Amantadine was injected intraperitoneally at 25 μg/g once a day for 3 days with the first dose at 15 min before surgery. The animals were tested by Barnes maze and fear conditioning starting one week after the surgery. Hippocampus was harvested for Western blotting and Golgi staining.ResultsSurgery and anesthesia impaired the learning and memory in old mice and rats. Surgery reduced the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), dendritic arborization and spine density in the hippocampus of old rats. These effects were attenuated by amantadine. The effects of amantadine were blocked by intracerebroventricular injection of anti-BDNF antibody or anti-GDNF antibody.ConclusionSurgery and anesthesia impaired learning, memory and dendritic arborization in old rodents that are age relevant to postoperative cognitive dysfunction. These effects may be attenuated by amantadine via preserving the expression of neurotrophic factors.

Highlights

Postoperative cognitive dysfunction (POCD) affects millions of patients annually and is associated with increased hospital stay length and 1-year mortality (Newman et al, 2001; Monk et al, 2008)
These results suggest that surgery induces learning and memory dysfunction, which is attenuated by amantadine
Rats receiving surgery plus amantadine plus anti-glial cell line-derived neurotrophic factor (GDNF) antibody had reduced context-related freezing behavior and this effect disappeared in rats receiving surgery plus amantadine plus heat denatured anti-GDNF antibody (Figure 3C). These results suggest that anti-Brain-derived neurotrophic factor (BDNF) antibody and anti-GDNF antibody blocked the protective effects of amantadine on learning and memory after surgery in old rats

Summary

Introduction

Postoperative cognitive dysfunction (POCD) affects millions of patients annually and is associated with increased hospital stay length and 1-year mortality (Newman et al, 2001; Monk et al, 2008). The use of amantadine at more than 6 months after brain trauma did not improve the cognition of these patients (Hammond et al, 2018), possibly because it was too late after the injury for any beneficial effect to occur. Our study has shown that amantadine attenuates POCD in young adult rats possibly via maintaining GDNF levels (Rocha et al, 2012; Zhang et al, 2014) and sepsis-induced cognitive dysfunction via inhibiting neuroinflammation in young mice (Xing et al, 2018). The effects of amantadine on old animals after surgery have not been reported

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