26 May 2014: Hypothesis
Leptin: New hope for the treatment of post-operative cognitive dysfunction?
Fei Hua AEF , Chun Yang AE , Bin Zhu ABCDEF
DOI: 10.12659/MSM.890878
Med Sci Monit 2014; 20:866-868
Abstract
ABSTRACT: Leptin plays a critical role in neuronal development and also promotes structural and functional activities in the central nervous system. Recent studies have demonstrated that leptin could produce therapeutic effects for cognitive impairments of patients with Alzheimer’s disease (AD). Post-operative cognitive dysfunction (POCD), defined as a significant dysfunction in cognitive performance for several weeks after surgery, probably has a pathogenesis similar to that of AD. Specifically, they are both characterized by cognitive impairment. In this regard, we hypothesized that leptin probably has a therapeutic benefit of alleviating symptoms of patients with POCD, and the leptin signaling pathway may be involved in the pathogenesis of POCD.
Keywords: Cognition Disorders - etiology, Leptin - therapeutic use, Postoperative Complications - etiology
Background
Cognitive dysfunction is a disturbing event. Elderly individuals are at a greater risk for cognitive dysfunction following surgery [1]. This manifestation, widely known as post-operative cognitive dysfunction (POCD), is characterized by disordered thinking and impaired consciousness with later onset and fluctuating course [2–4]. POCD, as mentioned above, is common in elderly patients, and probably has a pathogenesis similar to that of AD and may even evolve into AD [5]. Unfortunately, it has been demonstrated that 41.4% of aged patients have POCD at hospital discharge [6,7]. The underlying mechanisms of POCD, however, have not been fully elucidated.
Leptin is synthesized and secreted by adipocytes, and has been recognized as having an important role in coordinating the peripheral and central signals, ultimately regulating food intake and body weight [8–11]. Although the biological effects of leptin are thought to regulate eating behavior and energy expenditure [12], a prospective clinical study with 785 participants showed that higher circulating levels of leptin contribute to reduce AD incidence [13]. A preclinical study has shown that leptin can reduce pathology and improve memory in a transgenic mouse model of AD. Collectively, these findings indicate that leptin has unique therapeutic effects on cognitive dysfunction, which is the primary pathological feature of AD. In addition to POCD, it is also characterized by cognitive dysfunction and shares similar pathogenesis with AD. Consequently, we hypothesized that leptin may have therapeutic effects on POCD.
Hypothesis
We hypothesized that leptin has prophylactic and therapeutic effects on POCD, and that the leptin signaling pathway may be involved in the pathogenesis of POCD. A previous study by Doherty et al. [14] indicated that leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid-β (Aβ). A study by Marwarha et al. [15] has shown that leptin treatment reversed the 27-hydroxycholesterol-induced increase in Aβ and tau phosphorylation (p-tau). AD, a progressive neurodegenerative disease, is characterized by the accumulation of Aβ peptide-containing neuritic plaques and neurofibrillary tangles composed of p-tau [16]. In this regard, POCD is also characterized by abnormal deposition of Aβ and p-tau. These findings strongly support the hypothesis that leptin may have beneficial effects for the treatment of POCD by down-regulation of Aβ and dephosphorylation of p-tau.
AMP-activated protein kinase (AMPK), a Ser/Thr kinase, has a critical role in the maintenance of energy metabolism at cellular and body levels [17,18]. Thornton et al. [19] verified that the activation of AMPK suppresses tau binding to microtubules. Furthermore, leptin is capable of decreasing the levels of tau phosphorylation by activation of AMPK in rat cortical neurons [20]. It is widely known that POCD and AD are both aging-related diseases, and slowing the aging process may have therapeutic effects. AMPK is a major regulator, which can activate the autophagic pathway, while activation of AMPK inhibits mTOR, an inducer of autophagy [21,22]. Our recent study proposed a hypothesis that inhibiting mTOR activates the autophagic pathway, thereby leading to therapeutic effects for POCD [23]. Leptin probably has prophylactic and therapeutic effects in POCD, and the leptin signaling pathway may be involved in the pathogenesis of POCD.
Conclusions
Further investigations are needed to determine whether leptin has unique effects in the treatment of POCD, and to make certain whether leptin signaling pathway is involved in the pathogenesis of POCD. If our hypothesis is correct, leptin may be a promising treatment for POCD.
References
1. Bryson GL, Wyand A, Evidence-based clinical update: general anesthesia and the risk of delirium and postoperative cognitive dysfunction: Can J Anaesth, 2006; 53(7); 669-77, pmid: 16803914
2. Wei H, Xie Z, Anesthesia, calcium homeostasis and Alzheimer’s disease: Curr Alzheimer Res, 2009; 6(1); 30-35, pmid: 19199872
3. Arora SS, Gooch JL, García PS, Postoperative cognitive dysfunction, Alzheimer’s disease, and anesthesia: Int J Neurosci, 2014; 124(4); 236-42, pmid: 23931049
4. Vlisides P, Xie Z, Neurotoxicity of general anesthetics: an update: Curr Pharm Des, 2012; 18(38); 6232-40, pmid: 22762477
5. Wang Y, He H, Li D, The role of the TLR4 signaling pathway in cognitive deficits following surgery in aged rats: Mol Med Rep, 2013; 7(4); 1137-42, pmid: 23426570
6. Li SY, Xia LX, Zhao YL, Minocycline mitigates isoflurane-induced cognitive impairment in aged rats: Brain Res, 2013; 1496; 84-93, pmid: 23270609
7. Hovens IB, Schoemaker RG, van der Zee EA, Thinking through postoperative cognitive dysfunction: how to bridge the gap between clinical and pre-clinical perspectives: Brain Behav Immun, 2012; 26(7); 1169-79, pmid: 22728316
8. Schwartz MW, Woods SC, Porte D, Central nervous system control of food intake: Nature, 2000; 404(6778); 661-71, pmid: 10766253
9. Castellano Filho DS, do Amaral Correa JO, Dos Santos Ramos P, Body weight gain and serum leptin levels of non-overweight andoverweight/obese pregnant women: Med Sci Monit, 2013; 19; 1043-49, pmid: 24264432
10. Cilekar M, Uysal O, Bal C, Leptin increases mitotic index and regeneration ratio in hepatectomized rats: Med Sci Monit Basic Res, 2013; 19; 279-84, pmid: 24220642
11. Rytlewski K, Huras H, Kuśmierska-Urban K, Leptin and interferon-gamma as possible predictors of cesarean section among women with hypertensivedisorders of pregnancy: Med Sci Monit, 2012; 18(8); CR506-11, pmid: 22847200
12. Rytlewski K, Huras H, Kuśmierska-Urban K, Leptin and interferon-gamma as possible predictors of cesarean section among women with hypertensivedisorders of pregnancy: Med Sci Monit, 2012; 18(8); CR506-11, pmid: 22847200
13. Bonda DJ, Stone JG, Torres SL, Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance: J Neurochem, 2014; 128(1); 162-72, pmid: 23895348
14. Lieb W, Beiser AS, Vasan RS, Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging: JAMA, 2009; 302(23); 2565-72, pmid: 20009056
15. Doherty GH, Beccano-Kelly D, Yan SD, Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β: Neurobiol Aging, 2013; 34(1); 226-37, pmid: 22921154
16. Marwarha G, Dasari B, Prasanthi JR, Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices: J Alzheimers Dis, 2010; 19(3); 1007-19, pmid: 20157255
17. Querfurth HW, LaFerla FM, Alzheimer’s disease: N Engl J Med, 2010; 362(4); 329-44, pmid: 20107219
18. Lage R, Diéguez C, Vidal-Puig A, AMPK: a metabolic gauge regulating whole-body energy homeostasis: Trends Mol Med, 2008; 14(12); 539-49, pmid: 18977694
19. Steinberg GR, Kemp BE, AMPK in Health and Disease: Physiol Rev, 2009; 89(3); 1025-78, pmid: 19584320
20. Thornton C, Bright NJ, Sastre M, AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure: Biochem J, 2011; 434(3); 503-12, pmid: 21204788
21. Greco SJ, Sarkar S, Johnston JM, Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells: Biochem Biophys Res Commun, 2009; 380(1); 98-104, pmid: 19166821
22. Ravikumar B, Moreau K, Rubinsztein DC, Plasma membrane helps autophagosomes grow: Autophagy, 2010; 6(8); 1184-86, pmid: 20861674
23. Salminen A, Kaarniranta K, Haapasalo A, AMP-activated protein kinase: a potential player in Alzheimer’s disease: J Neurochem, 2011; 118(4); 460-74, pmid: 21623793
24. Yang C, Zhu B, Shen J, Rapamycin and mTOR inhibitors probably have therapeutic effects for post-operative cognitive dysfunction: Med Hypotheses, 2013; 81(3); 487-88, pmid: 23850396
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