Abstract
Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180–200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study.
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Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F et al (2008) Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 6:37
Aghaei I, Shabani M, Doustar N, Nazeri M, Dehpour A (2014) Peroxisome proliferator-activated receptor-γ activation attenuates motor and cognition impairments induced by bile duct ligation in a rat model of hepatic cirrhosis. Pharmacol Biochem Behav 120:133–9
Bartesaghi S, Marinovich M, Corsini E, Galli CL, Viviani B (2005) Erythropoietin: a novel neuroprotective cytokine. Neurotoxicology 26:923–8
Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6:484–94
Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–7
Butterworth RF (2011) Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 53:1372–6
Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albrecht J, Blei AT (2009) Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29:783–8
Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 412:641–7
Felipo V (2013) Hepatic encephalopathy: effects of liver failure on brain function. Nature Reviews Neuroscience
García-Ayllón M-S, Cauli O, Silveyra M-X, Rodrigo R, Candela A, Compañ A et al (2008) Brain cholinergic impairment in liver failure. Brain 131:2946–56
Hagemeyer N, Boretius S, Ott C, von Streitberg A, Welpinghus H, Sperling S et al (2012) Erythropoietin attenuates neurological and histological consequences of toxic demyelination in mice. Mol Med 18:628
Haghani M, Shabani M, Moazzami K (2013) Maternal mobile phone exposure adversely affects the electrophysiological properties of Purkinje neurons in rat offspring. Neuroscience 250:588–98
Hamidi G, Arabpour Z, Shabrang M, Rashidi B, Alaei H, Sharifi MR et al (2013) Erythropoietin improves spatial learning and memory in streptozotocin model of dementia. Pathophysiology 20:153–8
Huang L-T, Tiao M-M, Tain Y-L, Chen C-C, Hsieh C-S (2009) Melatonin ameliorates bile duct ligation-induced systemic oxidative stress and spatial memory deficits in developing rats. Pediatr Res 65:176–80
Javadi-Paydar M, Ghiassy B, Ebadian S, Rahimi N, Norouzi A, Dehpour AR (2013) Nitric oxide mediates the beneficial effect of chronic naltrexone on cholestasis-induced memory impairment in male rats. Behav Pharmacol 24:195–206
Leke R, Oliveira DL, Forgiarini LF, Escobar TD, Hammes TO, Meyer FS, et al. (2012) Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation. Metabolic brain disease :1–6
Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM (2009) Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation. J Hepatol 51:528–34
Marti HH, Bernaudin M, Petit E, Bauer C (2000) Neuroprotection and angiogenesis: dual role of erythropoietin in brain ischemia. Physiology 15:225–9
Miskowiak K, O'Sullivan U, Harmer CJ (2007) Erythropoietin enhances hippocampal response during memory retrieval in humans. The Journal of Neuroscience 27:2788–92
Nasehi M, Ahmadzadeh O, Rezayof A, Zarrindast M-R (2013a) Does CA1 dopaminergic system play a role in cholestasis induced hypothermia? Pathophysiology 20:181–9
Nasehi M, Tackallou SH, Hasani I, Nasehi M (2013b) Cholestasis impaired spatial and non-spatial novelty detection in mice. Journal of Paramedical Sciences (JPS) Winter 4:2008–4978
Nasehi M, Yavari SA, Zarrindast MR (2013c) Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice. Psychopharmacology :1–14
Park KH, Choi N-Y, Koh S-H, Park H-H, Kim YS, Kim M-J et al (2011) L-DOPA neurotoxicity is prevented by neuroprotective effects of erythropoietin. Neurotoxicology 32:879–87
Ponce LL, Navarro JC, Ahmed O, Robertson CS (2012) Erythropoietin neuroprotection with traumatic brain injury. Pathophysiology
Probert PM, Ebrahimkhani MR, Oakley F, Mann J, Burt AD, Mann DA, et al. (2014) A reversible model for periportal fibrosis and a refined alternative to bile duct ligation. Toxicology Research
Razavinasab M, Shamsizadeh A, Shabani M, Nazeri M, Allahtavakoli M, Asadi-Shekaari M, et al. (2012) Pharmacological blockade of TRPV1 receptors modulates the effects of 6-OHDA on motor and cognitive functions in a rat model of Parkinson’s disease. Fundamental & clinical pharmacology
Shabani M, Hosseinmardi N, Haghani M, Shaibani V, Janahmadi M (2011) Maternal exposure to the CB1 cannabinoid agonist WIN 55212–2 produces robust changes in motor function and intrinsic electrophysiological properties of cerebellar Purkinje neurons in rat offspring. Neuroscience 172:139–52
Shabani M, Nazeri M, Parsania S, Razavinasab M, Zangiabadi N, Esmaeilpour K et al (2012) Walnut consumption protects rats against cisplatin-induced neurotoxicity. Neurotoxicology 33:1314–21
Singh HJ, Syeda TU, Rahul KM, Prasad VV, Diwan PV (2013) Erythropoietin protects Polychlorinated biphenyl (Aroclor 1254) induced neurotoxicity in mice. European journal of pharmacology
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Funding for this study was provided by Kerman University of Medical sciences. The results described in this paper were part of PhD student thesis.
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Iraj Aghaei and Masoud Nazeri are contributed to the work as a first author
Highlights
• Spatial and passive avoidance learning impairments is observed in BDL rats.
• ERP has protective effect against motor and cognitive impairments induced by BDL.
• BDL rats had an increased level of hepatic enzymes and bilirubin.
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Aghaei, I., Nazeri, M., Shabani, M. et al. Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis. Metab Brain Dis 30, 197–204 (2015). https://doi.org/10.1007/s11011-014-9600-x
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DOI: https://doi.org/10.1007/s11011-014-9600-x