Cesar Carpio

 Introduction: At the time of discharge it is reported that 41.4% of patients 60 years or older are subjected to Postoperative Cognitive Dysfunction (POCD) after noncardiac surgery.¹ Clinical findings of POCD include disturbance of learning, memory, and processing of information even years post-surgery/anesthesia.² Although rodent models seem to indicate that hippocampal inflammation is a major contributor of pathogenesis, the actual mechanism remains unclear.³ Initial studies have demonstrated that microglia can drive neuroinflammation post-surgery and have hypothesized that this innate response in the hippocampus can manifest in POCD symptomatology.³ It was found that microglial depletion reduced surgically induced hippocampal neuroinflammation.³ Minocycline has been shown to decrease microglial activation in models of Parkinson’s Disease and Multiple Sclerosis.¹ Minocycline’s inhibitory effects towards neuroinflammation and microglial activation has made it a prime candidate for the treatment of POCD.¹ Methods: In the first experiment, aged mice were divided into six groups with some groups receiving appendectomies. After surgery, the Morris water maze was used to test spatial memory and cognition. After the maze, hippocampal tissues were derived from the mice and subjected to western blot, antibody, and immunofluorescence analysis for the presence of pro and anti-inflammatory cytokines and a microglial activation marker, Iba-1.¹ In the second study, rats were placed in the following groups: control, surgery alone, and minocycline injection prior to surgery. Cytokine mRNA levels in the hippocampus and microglial activation were quantified post-surgery via PCR and immunohistochemistry; Morris water maze testing was also performed.⁴ Results: While the methods are similar in both studies, the results are contradictory. Wang et al found that Minocycline treated mice performed better in maze testing as well as showed decreased expression of pro-inflammatory cytokines. Anti-inflammatory cytokines were found in increased levels in Minocycline treated groups.¹ Li et al found that Minocycline prevented post-operative upregulation of IL-1beta and TNF alpha, but they became elevated 7 days post-surgery. It was also found that Minocycline did not improve the rats’ performance in the Morris water maze and in fact increased latency.⁴ Conclusion: These studies posited limitations such as the use of only one dosing strategy⁴ as well as not taking into consideration the state of microglial activation¹. Further study of dosing strategies, routes of administration, and possible clinical trials is required before indicated therapeutic use of minocycline is recommended for the treatment of POCD.

1.  Wang HL, Liu H, Liao QW, Fang H. Minocycline attenuates post‐operative cognitive impairment in aged mice by inhibiting microglia activation. Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.12854. Published April 6, 2016.
2.  C. D. Hanning, Postoperative cognitive dysfunction, BJA: British Journal of Anaesthesia, Volume 95, Issue 1, July 2005, Pages 82–87, https://doi.org/10.1093/bja/aei062
3.  Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI insight. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374063/. Published April 6, 2017.
4.  Li W, Chai Q, Zhang H, et al. High doses of minocycline may induce delayed activation of microglia in aged rats and thus cannot prevent postoperative cognitive dysfunction – Wenyao Li, Qing Chai, Hongwei Zhang, Jing Ma, Chengfen Xu, Jifu Dong, Xianghua Wei, Zhiyi Wang, Kexian Zhang, 2018. SAGE Journals. https://journals.sagepub.com/doi/abs/10 .1177/0300060517754032.