Journal of Clinical Pathology and Forensic Medicine
Subscribe to JCPFM
Full Name*
Email Address*

Article Number - 486DE1C3075

Vol.4(1), pp. 6 - 14 , August 2013
DOI: 10.5897/JCPFM2013.0045
ISSN: 2141-2405

Full Length Research Paper

Neuronal alterations in the prefrontal cortex of rats with carbon tetrachloride (CCl4) induced hepatic damage

Adedayo Damilare Adekomi1,2*, Olusola Bolaji Adewale3, Ola Adulrasheed Muhameed4, Adedoyin Mojeed Agbaje5 and Tajudeen Oyesina Oyesomi5

1Department of Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria.

2Department of Anatomy and Cell Biology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.

3Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria.

4Histopathology Unit, Pathology Department, University of Ilorin Teaching Hospital, Ilorin, Nigeria

5Department of Anatomy, Ekiti State University, Ado Ekiti, Nigeria.


 Accepted: 05 July 2013  Published: 31 August 2013

Copyright © 2013 Author(s) retain the copyright of this article.
This article is published under the terms of the Creative Commons Attribution License 4.0

In cirrhosis, some toxic substances accumulate in the brain and modify its functional integrity. In this study, we investigate the impacts of liver damage on the neuronal profile of the prefrontal cortex (PFC) in a rat model of hepatic damage induced with carbon tetrachloride (CCl4). This study also evaluated the possible role of liver dysfunction in the etiology of neurodegenerative characteristics associated with the PFC. Ten male Wistar rats weighing 120 to 190 g body weight were used for this study. The rats were divided into 2 groups (A and B) of 5 rats each. The rats in group A (control group) were treated with phosphate buffered saline (PBS) solution only while the rats in group B (treatment group) were treated with carbon tetrachloride (CCl4). The prefrontal cortices of the rats were excised from skulls of the rats, fixed in formol calcium, while the livers were excised from the abdomen of the rats and were fixed in formol saline for cytoarchitectural study using Cresyl fast violet and hematoxylin and eosin stains respectively. The main neuropathological findings observed in this study include cortical necrosis, uneven neuronal loss with varying range of vacuolations in the prefrontal cortices of the CCl4 treated rats when compared with the PBS treated rats. It was observed that the administration of CCl4 induces changes in hepatocellular morphology of the treated rats and these include moderate vascular congestion and extensive cytoplasmic damage in the hepatocytes. These results could be due to loss of hepatic functions.


Key words: Liver damage, neuropathology, neurons, prefrontal cortex, rat.

Adewole SO, Salako AA, Doherty OW, Naicker T (2007). Effect of Melatonin on Carbon Tetrachloride-Induced Kidney Injury in Wistar Rats. Afr. J. Bio. Res. 10: 153 - 164.
Batuev AS, Kursina NP Shutov AP (1990). Unit activity of the medial wall of the frontal cortex during delayed performance in rats. Behav. Brain Res. 41: 95–102.
Boer LA, Panatto JP, Fagundes DA, Bassani C, Jeremias IC Daufenbach JF, Rezin GT, Constantino L, Dal-Pizzol F, Streck EL (2009). Inhibition of mitochondrial respiratory chain in the brain of rats after hepatic failure induced by carbon tetrachloride is reversed by antioxidants. Brain Res. Bull. 80: 75-78.
Bray TM (1999). Antioxidants and oxidative stress in health and disease: introduction. Proc. Soc. Exp. Biol. Med. 222: 195.
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.
Cabre M, Comps J, Paternain JL, Ferre N, Joven J (2000). Time course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. Clin. Exp. Pharmacol. Physiol. 27: 694-699.
Carbonell T, Rama R (2007). Iron, oxidative stress and early neurological deterioration in ischemic stroke. Curr Med Chem. 14: 857-874.
Castillo T, Koop DR, Kamimura S, Triadafilopoulos G, Tsukamodo H (1992). Role of cytochrome P-450 2E in ethanol carbon tetrachloride and iron-dependent microsomal lipid peroxidation. Hepatol. 16: 992-996.
Cauli O, López-Larrubia P, Rodrigo R, Agusti A, Boix J, Nieto- Charques L, Cerdán S, Felipo V (2011). Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology. 140: 638-45.
Charles G, Emdadul H, Mohammad I (2012). The chemopreventive effects of Thysanolaena latifolia against carbon tetrachloride (CCl4)-induced oxidative stress in rats. J. Exp. and Integ. Med. 2(4):345-355.
Chen JP (2007). Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: refractory global coronary microvascular spasm. J. Invasive. Cardiol. 19: E89-E92.
Chin HC, Hsiu CC, Yi TC, Hsin YH, Pi YC, Tzong HL, Ching KL (2009). Antioxidant activity of some plant extracts towards xanthine oxidase, lipoxygenase and tyrosinase. Molecules. 14:2947-58.
Crawford JM (2002). Liver cirrhosis. In: MacSween RN, et al., editors. Pathology of the liver. London: Churchill Livingstone, pp. 576-7.
Diemer NH (1997). Glial and neuronal alterations in the corpus striatum of rats with CCl4 induced liver disease. A quantitative morphological study using an electronic image. Acta. Neural. Scan. 55:16-32.
Duguay L, Coutu D, Hetu C, Joly JG (1982). Inhibition of liver regeneration by chronic alcohol administration. Gut. 23:8–13.
PMid:7056500 PMCid:PMC1419599
Felipo V, Butterworth RF (2002). Neurobiology of ammonia. Prog. Neurobiol. 67:259-79.
Floyd RA (1990). Role of oxygen free radicals in carcinogenesis and brain ischemia. FASEB J. 4:2587-97.
Fregozo SC, Beltrán MML, Soto FME, Vega FMI, Zárate BC, Ruiz HL (2012). Expression of NMDA receptor subunits in rat prefrontal cortex with CCL4-induced hepatic damage after a treatment with Rosmarinus officinalis L. Neurología. 27(5):261-267
Fridovich I (1988). The Biology of Oxygen Radicals: General Concepts, Upjohn Co., Bethesda, MD, USA, pp 1-8.
Fuster JM (1997). Network memory. Trends Neurosci. 20:451–459.
Goldman-Rakic PS (1994). Working memory dysfunction in schizophrenia. J. Neuropsych. Clin. Neurosci. 6:348–357.
Goldman-Rakic PS (1995). Cellular basis of working memory. Neuron 14:477-485.
Görg B, Qvartskhava N, Bidmon HJ, Palomero-Gallagher N, Kircheis G, Zilles K, Häussinger D (2010). Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology.52:256-65.
PMid:20583283 PMCid:PMC3395472
Hartley DP, Kolaja KL, Reinchord J, Peterson DR (1999). 4- Hydroxynonenal and malondialdehyde hepatic protein adducts in rats treated with carbon tetrachloride: immunochemical detection and lobular localization. Toxicol. Appl. Pharmacol. 161: 23-33.
Hong R, Matsuyama E, Nur K (1991). Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA 265: 1152-1154.
Jeon TI, Hwang SG, Park NG, Jung YR, Shin SI, Choi SD, Park DK (2003). Antioxidative effect of chitosan on chronic carbon tetrachloride induced hepatic injury in rats. Toxicol. 187: 67-73.
Junnila M, Rahko T, Sukura A, Lindberg LA (2000). Reduction of carbon tetrachloride-induced hepatotoxic effects by oral administration of betaine in male Han-Wistar rats: A morphometric histological study. Vet. Pathol. 37:231-238.
Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997). Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci. Lett. 229:201-3
Konopacka A, Zielinska M, Albrecht J (2008). Ammonia inhibits the C-type natriuretic peptide-dependent cyclic GMP synthesis and calcium accumulation in a rat brain endothelial cell line. Neurochem. Int. 52: 1160-1166.
Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N (2002). Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem. Funct. 20: 171-175.
Kung SW, Chan YC, Tse ML, Lau FL, Chau TL, Tam MK (2008). Acute renal failure and hepatitis following ingestion of carp gallbladder. Clin. Toxicol. 46: 753-757.
Lockwood AH, Yap EW, Wong WH (1991). Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J. Cereb. Blood Flow Metab. 11:337-41.
Melin AM, Perromat A, Deleris G (2000). Pharmacologic application of Fourier transform IR spectroscopy: in vivo toxicity of carbon tetrachloride on rat liver. Biopolym. 57: 160-168.<160::AID-BIP4>3.0.CO;2-1
Michalak A, Butterworth RF (1997). Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5- fluorowillardiine in the brains of rats with acute liver failure. Hepatol. 25:631-5.
Mu˜noz TE, Paz-Bouza JI, Abad-Hernández MM, Alonso-Martin MJ, López BA (1988). Experimental carbon tetrachloride-induced cirrhosis of the liver. Int. J. Tissue React.10:245-51.
Nakayama T, Kimura T, Kadama T, Nagata C (1983). Generation of hydrogen peroxide and superoxide anion from active metabolites of napthylamines and amino-azodyes. Carcinogen. 4:765-9.
Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C (2010). Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease. Neurosci. Lett. 469:6-10.
Peterson C, Giguere JF, Cotman CW, Butterworth RF (1990). Selective loss of N-methyl-d-aspartatesensitive L-[3H] glutamate binding sites in rat brain following portacaval anastomosis. J Neurochem. 55:386-90.
Prakash R, Mullen KD (2010). Mechanisms, diagnosis and manage-ment of hepatic encephalopathy. Nat Rev Gastroenterol. Hepatol. 7:515-25.
Quiroz ME, Flores YN, Aracena B, Granados-García V, Salmerón J, Pérez R, Guillermo C, Roshan B (2010). Estimating the cost of treating patients with liver cirrhosis at the Mexican Social Security Institute. Salud. Publica. Mex. 52:493-501.
Rautou PE, Cazals-Hatem D, Moreau R, Francoz C, Feldmann G, Lebrec D, Ogier-Denis E, Bedossa P, Valla D, Durand F (2008). Acute Liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy. Gastroenterol. 135:840-848
Sakurai Y, Sugimoto S (1986). Multiple unit activity of prefrontal cortex and dorsomedial thalamus during delayed go/no-go alternation in the rat. Behav. Brain Res. 17:213–219.
Saleem TSM, Chetty CM, Ramkanth S, Rajan VST, Kumar KM, Gauthaman K (2010). Hepatoprotective herbs – a review. Int. J. Pharm. Sci. Res. 1:1-5.
Sayre LM, Perry G, Smith MA (2008). Oxidative stress and neurotoxicity. Chem. Res. Toxicol. 21: 172-188.
Scarpelli DG, Iannaccone PM (1990). Cell injury and errors of metabolism. In: Kissane JM, Editor, (9th ed.), Anderson's Pathology. CV Mosby, St. Louis, pp. 16-17.
Sheweita PM, El-Gabar M, Bastawy M (2001). Carbon tetrachloride changes the activity of cytochrome P450 system in the liver of male rats: role of antioxidants. Toxicol. 169: 83-92.
Slater TF, Sawyer BC (1971). The stimulatory effects of carbon tetrachloride and other halogenoalkanes on peroxidative reaction in rat liver fractions in vitro. Inhibitory effects of free radical scavengers and other agents. J. Biochem. 123: 823-828.
Szymonik-Lesiuk S, Czechowska G, Stryjecka-Zimmer M, Słomka M, Madro A, Celiński K, Wielosz M (2003). Catalase, superoxide dismutase, and glutathione peroxidase activities in various rat tissues after carbon tetrachloride intoxication. J. Hepatobil. Panc. Surg. 10: 309-315.
Vessey DA (1996); In: Hepatology: a textbook of liver disease, D.B. Zakin and T.D. Goyer (eds). (WB Saunders, Philadelphia), pp; 875-890
Wang AM, Suojanen JN, Colucci VM, Rumbaugh CL and Hollenberg NK (1990). Cacaine- and methamphitamine-induced acute cerebral vasospasm; an angiographic study in rabbits. Am. J. Neuroradiol. 11: 1141-1146
Wijetunga M, Seto T, Lindsay J and Schatz I (2003). Crystal methamphetamine associated cardiomyopathy: tip of the iceberg? J. Toxicol. Clin. Toxicol. 41: 981-986
Zhao GX, Gu ZM, Zeng L, Chao JF, Wood KU, Kozlowski JK, Mclaughlin JL (1995). The absolute configuration of trilobacin and trilobin, a novel highly potent acetogenin from the stem bark of Asimina triloba (Annonaceae). Tetrahedron. 51:7149-7160.


APA (2013). Neuronal alterations in the prefrontal cortex of rats with carbon tetrachloride (CCl4) induced hepatic damage. Journal of Clinical Pathology and Forensic Medicine, 4(1), 6 - 14.
Chicago Adedayo Damilare Adekomi, Olusola Bolaji Adewale, Ola Adulrasheed Muhameed, Adedoyin Mojeed Agbaje and Tajudeen Oyesina Oyesomi. "Neuronal alterations in the prefrontal cortex of rats with carbon tetrachloride (CCl4) induced hepatic damage." Journal of Clinical Pathology and Forensic Medicine 4, no. 1 (2013): 6 - 14.
MLA Adedayo Damilare Adekomi, et al. "Neuronal alterations in the prefrontal cortex of rats with carbon tetrachloride (CCl4) induced hepatic damage." Journal of Clinical Pathology and Forensic Medicine 4.1 (2013): 6 - 14.
DOI 10.5897/JCPFM2013.0045

Subscription Form