Toxic Effects of Isoniazid and Rifampicin on Rat Brain Tissue

[Full title: Toxic Effects of Isoniazid and Rifampicin on Rat Brain Tissue: The Preventive Role of Caffeic Acid Phenethyl Ester]

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Life International Journal of Pharmacology ISSN 1811-7775 Life science alert ansinet Asian Network for Scientific Information

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International Journal of Pharmacology 8 (6): 555-560, 2012 ISSN 1811-7775 DOI: 10.3923/ijp.2012.555.560 2012 Asian Network for Scientific Information Toxic Effects of Isoniazid and Rifampicin on Rat Brain Tissue: The Preventive Role of Caffeic Acid Phenethyl Ester Mehmet Ugur Cevik, 'Abdullah Acar, Halis Tanriverdi, 'Sefer Varol, 'Adalet Arikanoglu, Yavuz Yucel. Esref Akil 'Muharrem Yunce and 'Aysun Ekinci 'Department of Neurology, 2Department of Family Medicine, Department of Medical Biochemistry, School of Medicine, Dicle University, Diyarbakir, Turkey Department of Medical Biochemistry, Diyarbakir Obstetrics and Pediatrics Hospital, Diyarbakir, Turkey Abstract: To the best of present knowledge, the possible protective effects of Caffeic Acid Phenethyl Ester (CAPE), on possible Isoniazid (INH) and Rifampicin (RIF) induced neurotoxic effects in brain tissue have not been investigated yet. As such, the purpose of this experimental study was to investigate the effects of CAPE, on INII and RIF induced neurotoxicity in rat brain tissue. We measured Total Antioxidant Capacity (TAC), Superoxide dismutase (SOD) activities, Malondialdehyde (MDA) and nitric oxide (NO) levels in the brain tissue of rats. Male Sprague-Dawley rats were divided into eight experimental groups, with ten animals in each group. These groups are consist of control group, INII-treated group, RIT-treated group, INII+RIF treated group, INII+CAPE treated group, RIF+CAPE treated group, INII-RIF-CAPE treated group and CAPE treated group. MDA and SOD levels in brain tissue were significantly higher and TAC levels were lower in the INII, RIF and INH | RIF treated groups (p<0.05) and TAC levels were lower in the INH, RIF and INH RIF groups than in the control group (p<0.05). CAPE plus INH and/or RIF treatment caused a significant decrease in MDA levels in brain tissue (p<0.05). In addition CAPE plus INH and/or RIF treatment caused a significant increase in TAC levels (p<0.05). In conclusion, we have shown that administration of INH and RIF is accompanied by increased lipid peroxidation and oxidants in rat brain tissue. CAPE may protect against NH and RIF-induced neurotoxicity. Therefore, CAPE supplementation may be used as a potential neuroprotective drug for antituberculosis therapy with TNH and/or RIF. Key words: Isoniazid, rifampicin, oxidative stress, caffeic acid phenethyl ester, neurotoxicity INTRODUCTION Tuberculosis is the world's second most common cause of death from infectious disease, after IIIV/AIDS (Frieden et al., 2003). Isoniazid (INH) and rifampicin (RIF), the most important first line antitubercular drugs have been used for the treatment of tuberculosis (Yossepowitch and Dan, 2007; Pal et al., 2008a). INH has been the mainstay of treatment of tuberculosis infection for 50 years (Lobue and Menzies, 2010). However, it is associated with adverse events, including peripheral neuropathies and seizures. Other presumed toxic reactions age autonomic neuropathy, encephalopathy, (Goldman and Braman, 1972; Cieck et al. 2005; Arbex et al., 2010). The concentration of RIF in the central nervous system is only 10-20% of the scrum concentration of the drug. However, it is enough for the drug to be clinically effective. Nevertheless, RIF is associated with adverse events such as dizziness. headache and ataxia (Cicek et al., 2005). The most effective antituberculosis therapy is a combination of comma 1 INII, RIF and pyrazinamide for eight weeks, followed by INII and RIT for a further four to seven months (Bass et al., 1994). INII-RIF are effective for the treatment of tuberculosis infection (Jasmer et al., 2000; Spyridis et al., 2007). INH and RIF continue to be effective drugs in treatment of tuberculosis (Pal et al., 2008b). RIF is a potent agent against actively dividing intracellular and extracellular organisms and has activity against semidonant bacilli that work primarily by inhibiting DNA dependent RNA polymerase, blocking RNA transcription. This given as a daily oral dose of 10 mg kg (Hershfield, 1999). Recent data indicate that TNH ankl RIF. appear in measurable quantities in the cerebrospinal fluid and pass to some degree through non-inflamed meninges (Holdiness, 1987). Although there are rare reports of a neurologic side effects with RIF, it is not known whether RIF increases INH-induced neurotoxicity (Arbex et al.. 2010). Which is mediated by induction of apoptosis (Bhadauria et al., 2007). INH metabolites have been identified, including hydrazine (HZ). ammonia and oxidizing free radicals. INH formation and elimination are Corresponding Author: Mehmet Ugur Cevik, Department of Neurology, School of Medicine, Dicle University, Diyarbakir, Turkey 555

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Int. J. Pharmacol., 8 (6): 555-560, 2012 genetically controlled. The mechanism underlying INH neurotoxicity has yet to be fully defined. However, several hypotheses have been suggested the metabolite(s) involved in this phenomenon remain obscure although a major role is clearly played by IIZ and possibly also by the ammonia it releases (Preziosi, 2007). MDA and NO increase markers of oxidative stress and decrease TAC (Preziosi, 2007; Ergul et al., 2010; Uzar et al., 2012). CAPE is a structural relative of flavonoids, has powerful antioxidant properties (Ilhan et al., 2004). It is a neuroprotective and antioxidant molecule, an active component of propolis from honeybees which can induce expression of heme oxygenase-1 (IIO-1) and Brain-derived Neurotrophic Factor (BDNF). Because HO-1 and BDNF induction has been suggested to profeel. neurons (Kurauchi et al., 2012). Combining INH and RIF with an antioxidant substance, such as CAPE, may reduce brain toxicity induced by INH and RIF. A previous study showed that CAPE, caused a neuroprotective effect on biochemical status in drug-induced oxidative damage in rat brain tissue (Uzar et al., 2010). The aim of the present study was to examine the protective effects of CAPE in INH and RIF induced brain neurotoxicity in a ral model of INH and RIF induced neurotoxicity. MATERIALS AND METHODS This study was approved by Dicle the University Animal Ethics Committee and it was performed in accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals, prepared by Diele University. Animal Ethics Commillee. Male Sprague-Dawley rats (aged 8-12 weeks) weighing 220±30 g (Mean+SD) were used in this experiment. The rats were placed in a temperature (22±2°C) and humidity (50-5%) controlled room in which 12 h light/dark cycles were maintained for one week before the start of the experiment. A standard diet and tap water were provided ad libitum. The rats were divided into eight experimental groups, with len animals in each group: Control, TNHtreated group, RIF treated group, INHIRIF treated group. INII-CAPE treated group, RIF-CAPE treated group, INH-RIF+CAPE treated group and CAPE treated group. The RIF doses and TNH doses of treated groups were 50 mg kg per day for both RIF/INH and these doses were given orally with tap water for 30 days (Attri et al., 2000, Gokalp et al., 2006). The control group was given plain lap waler CAPE was administered to the INH CAPE RIFICAPE, INH RIFICAPE and CAPE groups at a dose of 10 umol kg ip. as described. previously for 30 days (Gokalp et al., 2006). Isotonic saline solution (an equal volume of CAPE) was given i.p. for 30 days to the control group. After all the rats received the above treatments, they were fed ad libitum until midnight, then they were anesthetized with other and brain tissue samples were obtained. Half of these issues were stored at -50°C until biochemical analysis. Biochemical analyses: The excised brain sample were weighed and immediately stored al. -50°C. Assays were performed on the supernatant of the homogenate which was prepared at 14, 000 rpm for 30 min at +4°C. The protein concentration of the tissues was measured by the Lowry method (Lowry et al., 1951). Superoxide dismutase (SOD) activity was measured according to the method described by Fridovich (1974). Lipid peroxidation level in the cerebrum was expressed as MDA and measured according to the procedure proposed by Ohkawa et al. (1979). NO levels were determined by the Griess method (Cortas and Wakid, 1990). The TAC of supernatant fractions was evaluated using a novel automated and colorimetric measurement method developed by Erel (2004) The TAC results are expressed as nmol Trolox equivalent/mg protein. The assay was calibrated with hydrogen peroxide and the results are expressed in terms of mol H₂O equivalent/mg protein (Hu et al., 1993; Aycicek et al., 2005). The unit of cerebrum tissue TAC was μmole II₂O₂ equivalent/gram protein and mmole IIO₂ equivalent/gram protein, respectively. Statistical analyses: Data are expressed as Mean SD. The normality of the distribution for all variables was assessed by the Kolmogorov-Smirnov test. The MannWhitney U-test was used for variables that do not meet. the normality assumption. A one-way Analysis of Variance (ANOVA) and post-hoc multiple comparison tests (LSD) were performed on the data of biochemical variables to examine differences among groups. A p-value of p<0.05 was considered statistically significant. RESULTS Biochemical results of the Tal brain tissue are shown in Table 1. MDA, NO and SOD levels were higher in the INII group than in the control group (p = 0.036, p = 0.001 and p = 0.001 respectively), while TAC levels were significantly lower in the TNH group than in the control group (p = 0.008). CAPE INH treatment caused a significant decrease in the MDA and NO levels compared to INH alone (for each parameter, p = 0.001). In addition, CAPE INH realment caused a significant increase in TAC levels compared to NH alone (p-0.001). MDA and NO levels were significantly higher in the RIF group than those of the control group (p = 0.006 and p = 0.001, respectively). CAPE-RIF treatment caused a significant decrease in MDA and NO levels compared to RIF alone 556

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Int. J. Pharmacol., 8 (6): 555-560, 2012 Table 1: Biochemical parameters in the brain tissue of rats Groups 1: Control 2: CAPE 3: INH TAC (mmol trolox meq. g¹protein) 0.53±0.7 MDA (nmol gwet tissue) 213.0-44.7 SOD (IU mg protein) NO (umol g protein) 244.3±18.8 27.55.4 0.60±0.35 193.5-32.6 244.6±27.6 31.56.8 0.34±0.2 254.4-28.9 306.2±77.6 61.3±12.5 4: RIF S: RIF-INH 0.28±0.4 267.7=43.4 408.947.8 58.3±22.3 0.28±0.2 255.2=42.6 409.9±29.6 38.3±10.2 6: INH+CAPE 0.71±0.1 169.3-21.9 240.119.1 36.9±3.9 7: RIF-CAPE 0.51±0.8 1881-49.3 239.2+42.6 34.2±4.7 8: RIF-INH+CAPE 0.55±0.6 211.6=37.1 263.6±35.8 38.5±9.1 p-values 1-3 0.008 0.036 0.001 0.001 1-4 0.001 0.006 0.001 0.001 1-5 0.001 0.033 0.001 0.055 3-6 0.001 0.001 0.001 0.001 4-7 0.002 0.001 0.001 0.001 5-8 0.001 0.028 0.001 0.971 3-5 0.380 0.970 0.510 0.001 4-5 0.080 0.520 0.960 0.001 1-2 0.330 0.320 0.990 0.473 NS: Not significant, MDA: Malondialdelryde, SOD: Superoxide dismutase, NO: Nitric cocide (for each parameter, p-0.001). TAC level activities were lower in the RIF group than in the control group (p 0.001) and SOD activities were higher in the RIF group than in the control group (p = 0.001). CAPE+RIT treatment caused a significant decrease in MDA, SOD, NO activity in brain tissue compared to RIF alone (for each parameter p = 0.001). Moreover, CAPE+RIT Treatment caused a significant increase in TAC levels compared to RIF alone (p-0.002). MDA and NO levels in the INH-RIF group were higher than those of the control group (p 0.033 and p 0.055, respectively). CAPE+INII-RIF treatment caused a decrease in MDA generation in brain tissue compared to the LNH-RIF group (p = 0.028). TAC levels were lower in the INH RIF group than in the control group (p = 0.001). CAPE+INII+RIT Irealment caused a significant increase in TAC levels and a significant decrease in SOD activity compared to the INH-RIF group (both parameters, p = 0.001). DISCUSSION Free radicals are characteristically toxic. They able to damage molecules (nucleic acids, lipids, proteins). Fortunately, cells possess appropriate deferise mechanisms in the form of free radical scavengers and enzymes which metabolize free radicals or their precursors INH and/or RIF which can cause oxidative damage in tissues (Cicek et al., 2005; Bhadauria et al., 2007; Warlow et al., 2008; Uduman et al., 2011). MDA is the breakdown product of the major chain reactions that lead oxidation of polyunsaturated fatty acids and thus serves as a reliable marker of oxidative stress. It is known that. increased levels of MDA, are the marker of extent of lipid peroxidation, in the brain (Shivarajashankara et al., 2003; Erel, 2004; Cieck et al., 2005). T. also has been revealed that increased Lipid Peroxidation (LPC) correlates with the degree of oxidative effects of INH in rat hippocampus (Cicck et al., 2005). INH has been shown to cause a significant increase in MDA levels of rat erythrocyte and co-administration of CAPE with LNH decreased the MDA levels (Gokalp et al, 2006; Ergul et al., 2010; Kerman et al., 2012). There are rare reports of a neurologic side effect with RTF (Arbex et al., 2010). However, il is nol. known if RIF increases INH-induced neurotoxicity. Chen et al. (2011) reported that increased lipid peroxidation by TNH and RTF induced hepatic injury in rats (Chen et al., 2011). Combination treatments (INII plus RIF) increased lipid peroxidation products (Saad et al., 2010). We found that both INH and RIF caused a significant increase in MDA levels in rat brain tissues. Our study has three main findings. First, we found that INH and/or RIF administration at a dose of 50 mg kg per day resulted in a significant increase in NO and MDA levels and SOD activity in ral brain tissue, on the other hand they caused significant decreases in TAC levels. Second CAPE significantly decreased MDA and NO levels and SOD activity and significantly increased TAC levels when applied to the rats subjected to INII and/or RIF toxicity. Our third main finding is that there was no significant difference in neurotoxicity in rat brain tissue between INH+RIF treatment and LNH treatment alone. RIF plus NH compared to NH alone does not lead to any significant increase in neurotoxicity in the rat brain. INII exposure causes increased Reactive Oxygen Species (ROS) generation along with alteration in levels of enzymatic antioxidants such as SOD (Bhadauria et al., 2007). RIF is considered a powerful inducer of mixedfunction oxidase that increases the hepatotoxicity of isoniazid by enhancing the production of toxic metabolites from acetylhydrazine (Samma et al., 1986). 557

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Int. J. Pharmacol., 8 (6): 555-560, 2012 increases Nevertheless, it is not known whether RIF INH-induced neurotoxicity in rat brains. Anti-tubercular drug mediated oxidative damage is generally attributed to the formation of highly ROS, which act as stimulators of lipid peroxidation and a source of destruction and damage to the cell membrane (Pal et al., 2008a, b) Furthermore, alterations of various cellular defense mechanisms consisting of enzymatic and non-enzymatic components have been reported to be involved in INII and RIF-induced hepatotoxicity (Attri et al., 2000; Sand et al., 2010). We found that both TNH and RTF led to significant increases in NO and MDA levels in rat brain tissue; the increases may be due to overproduction or decreased discharge of oxidant substances. Increased lipid peroxidation and oxidant generation in the brain tissue of rats receiving both INH and RIF suggests that the neurotoxic effect was caused by oxidative insult. Present results suggest that INH and RIF augments oxidative stress either by modulating the proxluction of free radicals, ROS. In this study, CAPE, decreased lipid peroxidation and oxidants in a significant manner. MDA and NO levels were reduced by CAPE and TAC levels were increased. These results indicate that CAPE might be a novel agent to protect the brain tissue from oxidative. stress due to INII and RIF neurotoxicity. In addition, the fact that CAPE normalizes both MDA and TAC levels in brain tissue, which are respectively increased and decreased due to antituberculosis medication tissue may indicate that CAPE is effective in brain tissue. NO is a free radicals that becomes elevated with cerebral neuronal damage. It reacts with, particularly the fatty acid component of membrane phospholipids (Lizasoain et al., 2006). Increasing evidence has suggested that NO has an important role in modulating oxidant stress and tissue damage (Koc et al., 2005). The primary product of the interaction between NO and superoxide anion is peroxynitrite. Which is a potent cellular oxidant (IIabib and Ali, 2011). Peroxynitrite, as a short-lived ROS, is quickly protonated and then decays generating the highly toxic hydroxyl radical, which explains the cytotoxicity associated with the raised level of NO (Kim et al., 2005). The present study first indicated the marked elevation in NO level in brain tissue of INH and/or RIF-treated rats and CAPE significantly alterated this increment. SOD catalyzes the conversion of superoxide radicals to ILO. It protects cells against the toxic effects of superoxide radicals (Gokalp et al., 2006). In the brains of the treated TNH+RIF group, there was a significant. increase in SOD activity, which may be another sign of increased oxidative stress in brain tissue. CAPE might be a scavenger of free oxygen radicals and it serves to prevent oxidative stress in the TNH+RIF treated rat brain. Therefore, il prevents the elevation of SOD enzyme activities in INH-RIF rat brain. We show that a combine therapy of TNH and RIF increased MDA and NO levels and decreased TAC levels in rat brain tissue. CAPE efficiently decreased MDA and NO levels and increased TAC levels. When the combined therapy of INII and RIF was applied. However, no differences were seen in the biochemical results between the rals that received INH or RIF therapy alone and those that received the combination INTI+RIF therapy. In conclusion our findings suggest that CAPE supplementation may be used as a potential neuroprotective drug for antituberculosis therapy with INH and/or RIF. This protective effect may be due to the antioxidant properties of CAPE, which scavenges the free radicals that can cause brain cell damage. REFERENCES Arbex, M.A., C. Varella Mde, H.R. Siqueira and F.A. Mello, 2010. Antituberculosis drugs: Drug interactions, adverse effects and use in special situations. Part 1: First-line drugs. J. 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M.S.T.S., Int. J. Pharmacol., 8 (6): 555-560, 2012 Uduman, R. Sundarapandian, A. Muthumanikkam, G. Kalimuthu S.A. Parameswari. T.R.V. Srinivas and G. Karunakaran, 2011. Protective effect of methanolic extract of Annona squamosa Linn in isoniazid-rifampicin induced hepatotoxicity in rats. Pak. J. Pharm. Sci., 24: 129-134. Uzar, E., H.R. Koyuncuoglu H.R. Yilmaz, E. Uzand A. Songar et al., 2010. Ameliorating role of Caffeic Acid Phenethyl Ester (CAPE) against methotrexate-induced oxidative stress in the sciatic nerve, spinal cord and brain stem lissues of rats. Turk. J. Neurol., 16: 12-20. Czar, E., H. Alp, M.U. Cevik, U. Firat, O. Evliyaoglu, A. Tufck and Y. Altun, 2012. Ellagic acid attenuates oxidative stress on brain and sciatic nerve and improves histopathology of brain in streptozotocin-induced diabetic rats. Neurol. Sci., 33: 567-574. Warlow, C., L.V.G., M. Dennis, J. Wardlaw, J. Bamford and G. Hankey et al., 2008. Stroke: Practical Management. 3rd Edn., John Wiley and Sons Inc., New York, USA., ISBN-13: 9780470695654, Pages: 1008. Yossepowitch, O. and M. Dan 2007. Tuberculosis in the 21st century. Harefuah, 1-16: 206-211. 560

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