579466 research-article2015
ANP0010.1177/0004867415579466ANZJP CorrespondenceANZJP Correspondence
Commentary Australian & New Zealand Journal of Psychiatry 1–2
Commentary
© The Royal Australian and New Zealand College of Psychiatrists 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav anp.sagepub.com
Tropisetron for postoperative cognitive decline Chun Yang, Qian Ren, Ji-Chun Zhang and Kenji Hashimoto Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Corresponding author: Kenji Hashimoto, Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan. Email: [email protected] DOI: 10.1177/0004867415579466
Postoperative cognitive decline (POCD) is a sometimes permanent or transient cognitive dysfunction seen after surgery, lasting several months or longer. Patients undergoing general anesthesia and surgery, particularly the elderly, may develop POCD, which is characterized by hypomnesia, mental derangement and an impaired ability to study. At postoperative discharge, approximately 41% of the elderly patients suffer from POCD. Additionally, POCD also has a negative effect on patients’ quality of life and contributes greatly to healthcare costs. However, the mechanisms underlying this disorder are not clearly understood, and no beneficial treatment strategy has yet emerged. Tropisetron (Navoban®), a 5-hydroxytryptamine (5-HT)3 receptor antagonist, is an antiemetic and is widely used in patients receiving chemotherapy and general anesthesia outside the United States.
Postoperative nausea and vomiting is a common surgical problem, and this has led to the use of tropisetron and other 5-HT3 receptor antagonists in the treatment and prevention of these conditions. In addition to its antiemetic effect, mediated through 5-HT3 receptors, tropisetron is also a potent partial agonist at α7 nicotinic acetylcholine receptors (α7 nAChRs) (Hashimoto, 2015). Previously, we reported that tropisetron, but not ondansetron (a selective 5-HT3 antagonist), improved cognitive deficits in rodents, after the repeated administration of phencyclidine (Hashimoto et al., 2006). A subsequent study showed that tropisetron significantly increased the ratio of soluble amyloid precursor protein (sAPPα)/β-amyloid (Aβ)1-42, suggesting a beneficial effect in ameliorating the Alzheimer’s disease (AD) phenotype (Spilman et al., 2014). In vivo studies showed that tropisetron (0.5 mg/kg/day for 28 days) improved the sAPPα/Aβ1-42 ratio associated with spatial and working memory in an animal model of AD (Spilman et al., 2014). Moreover, tropisetron protected against Aβ-induced neurotoxicity in vivo, by inhibiting both 5-HT3 receptor-dependent and -independent pathways (Spilman et al., 2014). AD is characterized by the excessive accumulation of extracellular Aβ and intracellular hyperphosphorylated tau. Both POCD and AD are defined by cognitive decline and, more importantly, share identical mechanisms leading to the excessive accumulation of these molecules. In addition to occurring in elderly post-surgical patients, POCD is also associated
with the inappropriate use of anticholinergic agents for inhibiting glandular secretions, resulting in cholinergic receptor dysfunction. Considering these data, we hypothesize that tropisetron has the potential to treat POCD via activation of α7 nAChRs and antagonism of 5-HT3 receptors. Multiple lines of evidence suggest that the pathogenesis of POCD is similar to that of AD. Both disorders are characterized by excessive accumulation of extracellular Aβ and intracellular hyperphosphorylated tau, resulting in neurotoxicity. Ondansetron is reported to protect or improve cognitive decline in patients undergoing surgery with general anesthesia. Additionally, indirect stimulation of α7 nAChRs by ondansetron can improve auditory sensory gating deficits in DBA/2 mice, suggesting a therapeutic benefit for cognitive impairment in schizophrenia patients (Wildeboer et al., 2009). Taken together, 5-HT3 receptor antagonists, such as ondansetron, may have potential to treat the cognitive decline seen in POCD and AD. Tropisetron and ondansetron share the same pharmacological effect of preventing emesis. Besides binding to 5-HT3 receptors, tropisetron also stimulates α7 nAChRs to improve cognitive decline (Hashimoto, 2015). Terrando et al. (2014) reported that stimulating the cholinergic anti-inflammatory pathway could prevent the onset of postoperative complications, including cognitive decline. Considering all the data, we propose that tropisetron may offer therapeutic help in POCD, via mechanisms related to the activation of α7 nAChRs and 5-HT3 receptor antagonism.
Australian & New Zealand Journal of Psychiatry Downloaded from anp.sagepub.com at Umea University Library on April 4, 2015
2 Future studies are needed to investigate whether tropisetron is beneficial in the treatment of POCD and to determine whether this action is mediated by α7 nAChR activation. If our hypothesis is correct, it may provide the basis for a novel target and strategy in the prevention and treatment of POCD. Declaration of interest Prof. Kenji Hashimoto holds a patent for the use of tropisetron in neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease. In addition, he has served as a scientific consultant to Astellas, Dainippon-Sumitomo and Taisho, and he has also received research support from Abbvie, Dainippon-Sumitomo, Mochida,
ANZJP Correspondence Otsuka and Taisho. Other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Funding Dr Chun Yang was supported by the Uehara Memorial Foundation (Tokyo, Japan). Dr Qian Ren was supported by the Otsuka Toshimi Scholarship Foundation (Osaka, Japan). This study was supported by Smoking Research Foundation, Tokyo, Japan (to Prof. Kenji Hashimoto).
References Hashimoto K (2015) Tropisetron and its targets in Alzheimer’s disease. Expert Opinion on Therapeutic Targets 19: 1–5.
Hashimoto K, Fujita Y, Ishima T, et al. (2006) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors. European Journal of Pharmacology 553: 191–195. Spilman P, Descampus O, Gorostiza O, et al. (2014) The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer’s model. Brain Research 1551: 25–44. Terrando N, Yang T, Ryu JK, et al. (2014) Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Molecular Medicine 20: 667–675. Wildeboer KM, Zheng L, Choo KS, et al. (2009) Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism. Brain Research 1300: 41–50.
Australian & New Zealand Journal of Psychiatry Downloaded from anp.sagepub.com at Umea University Library on April 4, 2015
ANP0010.1177/0004867415579466ANZJP CorrespondenceANZJP Correspondence
Commentary Australian & New Zealand Journal of Psychiatry 1–2
Commentary
© The Royal Australian and New Zealand College of Psychiatrists 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav anp.sagepub.com
Tropisetron for postoperative cognitive decline Chun Yang, Qian Ren, Ji-Chun Zhang and Kenji Hashimoto Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Corresponding author: Kenji Hashimoto, Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan. Email: [email protected] DOI: 10.1177/0004867415579466
Postoperative cognitive decline (POCD) is a sometimes permanent or transient cognitive dysfunction seen after surgery, lasting several months or longer. Patients undergoing general anesthesia and surgery, particularly the elderly, may develop POCD, which is characterized by hypomnesia, mental derangement and an impaired ability to study. At postoperative discharge, approximately 41% of the elderly patients suffer from POCD. Additionally, POCD also has a negative effect on patients’ quality of life and contributes greatly to healthcare costs. However, the mechanisms underlying this disorder are not clearly understood, and no beneficial treatment strategy has yet emerged. Tropisetron (Navoban®), a 5-hydroxytryptamine (5-HT)3 receptor antagonist, is an antiemetic and is widely used in patients receiving chemotherapy and general anesthesia outside the United States.
Postoperative nausea and vomiting is a common surgical problem, and this has led to the use of tropisetron and other 5-HT3 receptor antagonists in the treatment and prevention of these conditions. In addition to its antiemetic effect, mediated through 5-HT3 receptors, tropisetron is also a potent partial agonist at α7 nicotinic acetylcholine receptors (α7 nAChRs) (Hashimoto, 2015). Previously, we reported that tropisetron, but not ondansetron (a selective 5-HT3 antagonist), improved cognitive deficits in rodents, after the repeated administration of phencyclidine (Hashimoto et al., 2006). A subsequent study showed that tropisetron significantly increased the ratio of soluble amyloid precursor protein (sAPPα)/β-amyloid (Aβ)1-42, suggesting a beneficial effect in ameliorating the Alzheimer’s disease (AD) phenotype (Spilman et al., 2014). In vivo studies showed that tropisetron (0.5 mg/kg/day for 28 days) improved the sAPPα/Aβ1-42 ratio associated with spatial and working memory in an animal model of AD (Spilman et al., 2014). Moreover, tropisetron protected against Aβ-induced neurotoxicity in vivo, by inhibiting both 5-HT3 receptor-dependent and -independent pathways (Spilman et al., 2014). AD is characterized by the excessive accumulation of extracellular Aβ and intracellular hyperphosphorylated tau. Both POCD and AD are defined by cognitive decline and, more importantly, share identical mechanisms leading to the excessive accumulation of these molecules. In addition to occurring in elderly post-surgical patients, POCD is also associated
with the inappropriate use of anticholinergic agents for inhibiting glandular secretions, resulting in cholinergic receptor dysfunction. Considering these data, we hypothesize that tropisetron has the potential to treat POCD via activation of α7 nAChRs and antagonism of 5-HT3 receptors. Multiple lines of evidence suggest that the pathogenesis of POCD is similar to that of AD. Both disorders are characterized by excessive accumulation of extracellular Aβ and intracellular hyperphosphorylated tau, resulting in neurotoxicity. Ondansetron is reported to protect or improve cognitive decline in patients undergoing surgery with general anesthesia. Additionally, indirect stimulation of α7 nAChRs by ondansetron can improve auditory sensory gating deficits in DBA/2 mice, suggesting a therapeutic benefit for cognitive impairment in schizophrenia patients (Wildeboer et al., 2009). Taken together, 5-HT3 receptor antagonists, such as ondansetron, may have potential to treat the cognitive decline seen in POCD and AD. Tropisetron and ondansetron share the same pharmacological effect of preventing emesis. Besides binding to 5-HT3 receptors, tropisetron also stimulates α7 nAChRs to improve cognitive decline (Hashimoto, 2015). Terrando et al. (2014) reported that stimulating the cholinergic anti-inflammatory pathway could prevent the onset of postoperative complications, including cognitive decline. Considering all the data, we propose that tropisetron may offer therapeutic help in POCD, via mechanisms related to the activation of α7 nAChRs and 5-HT3 receptor antagonism.
Australian & New Zealand Journal of Psychiatry Downloaded from anp.sagepub.com at Umea University Library on April 4, 2015
2 Future studies are needed to investigate whether tropisetron is beneficial in the treatment of POCD and to determine whether this action is mediated by α7 nAChR activation. If our hypothesis is correct, it may provide the basis for a novel target and strategy in the prevention and treatment of POCD. Declaration of interest Prof. Kenji Hashimoto holds a patent for the use of tropisetron in neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease. In addition, he has served as a scientific consultant to Astellas, Dainippon-Sumitomo and Taisho, and he has also received research support from Abbvie, Dainippon-Sumitomo, Mochida,
ANZJP Correspondence Otsuka and Taisho. Other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Funding Dr Chun Yang was supported by the Uehara Memorial Foundation (Tokyo, Japan). Dr Qian Ren was supported by the Otsuka Toshimi Scholarship Foundation (Osaka, Japan). This study was supported by Smoking Research Foundation, Tokyo, Japan (to Prof. Kenji Hashimoto).
References Hashimoto K (2015) Tropisetron and its targets in Alzheimer’s disease. Expert Opinion on Therapeutic Targets 19: 1–5.
Hashimoto K, Fujita Y, Ishima T, et al. (2006) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors. European Journal of Pharmacology 553: 191–195. Spilman P, Descampus O, Gorostiza O, et al. (2014) The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer’s model. Brain Research 1551: 25–44. Terrando N, Yang T, Ryu JK, et al. (2014) Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Molecular Medicine 20: 667–675. Wildeboer KM, Zheng L, Choo KS, et al. (2009) Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism. Brain Research 1300: 41–50.
Australian & New Zealand Journal of Psychiatry Downloaded from anp.sagepub.com at Umea University Library on April 4, 2015
