Epilepsy Research (2014) 108, 405—410

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Effects of thiamine and thiamine pyrophosphate on epileptic episode model established with caffeine in rats Mehmet Ibrahim Turan a,∗, Huseyin Tan a, Nihal Cetin b, Halis Suleyman b, Atilla Cayir c a

Department of Pediatric Neurology, Faculty of Medicine, Ataturk University, Erzurum, Turkey Department of Pharmacology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey c Department of Pediatric Endocrinology, Research and Educational Hospital, Erzurum, Turkey b

Received 29 August 2013; received in revised form 3 November 2013; accepted 7 December 2013 Available online 30 December 2013

KEYWORDS Rat; Seizure; Thiamine; Thiamine pyrophosphate; Oxidant

Summary This study examines the effect of thiamine (TH) and thiamine pyrophosphate (TPP) on epileptic episode model induced in rats with caffeine. Animals were divided into groups and given TH or TPP at doses of 10, 30 or 50 mg/kg intraperitoneally. Subsequently, all animal groups were injected intraperitoneally with caffeine at a dose of 300 mg/kg. Time of onset of epileptic episode was recorded, and the latent period was calculated in seconds. At the end of the experiment, tGSH and MDA levels and SOD and MPO enzyme activities in extracted brain tissues were measured. Latent period duration in rats in the control group was 134 ± 3.2 s, compared to 144 ± 13.9, 147 ± 14.5 and 169 ± 15.1 s, respectively, in the TH10, TH30 and TH50 groups and 184 ± 8.54, 197 ± 9.1, 225 ± 8.37 s, respectively, in the TPP10, TPP30 and TPP50 groups. Latent period duration was 236 ± 6.7 in the diazepam group. Oxidant products were significantly lower in the TPP10, TPP30, TPP50 and diazepam groups compared to the control group (P < 0.05), while SOD activity and tGSH levels were significantly higher (P < 0.05). There was no significant difference between the TH10, TH30, TH50 groups and the control group in terms of oxidant and antioxidant levels (P > 0.05). In conclusions, TPP, especially at a dose of 50 mg/kg, significantly prolonged the latent period from administration of caffeine to time of episode and prevented oxidative damage. © 2013 Elsevier B.V. All rights reserved.

Introduction



Corresponding author. Present address: Department of Pediatric Neurology, Research and Educational Hospital, Diyarbakir, Turkey. Tel.: +90 505 2604621; fax: +90 0412 236 10 14. E-mail address: [email protected] (M.I. Turan).

Epileptic seizure is defined as a temporary function impairment of the brain, resulting in sudden and temporary motor, emotional, autonomic and psychological injury in association with abnormal discharge, of a repeating character, of hyperexcitable neurons in the brain. This clinical

0920-1211/$ — see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.12.006

406 picture is generally brief, lasting a few seconds or minutes (Chang and Lowenstein, 2003; Remy and Beck, 2006). Epileptic seizure is the most common neurological disease in developed countries (Chang and Lowenstein, 2003; Lipson et al., 2002). Epileptic animal models provide data concerning the physiopathology of various types of epilepsy, the effectiveness of novel molecules and the functioning of the central nervous system (CNS). In addition, epileptic animal models play an important role in research into and evaluation of novel therapeutic drugs and the discovery of new techniques (Crepeau et al., 2012). Caffeine, a methylxanthine-type alkaloid, can quickly lead to generalized tonic clonic episodes when administered by the appropriate route, the episode-inducing effect of which has been shown in studies not to be attributable to a single mechanism, was used to establish the epileptic model in this study (Georgiev et al., 1993; Johansson et al., 1996). Although there are currently a large number of antiepileptic drugs in use, epilepsy and its complications still pose serious problems (Crepeau et al., 2012). In addition, one-third of patients exhibit resistance to drugs despite receiving appropriate doses of antiepileptic therapy (French et al., 2004; Kwan and Brodie, 2000). Research into novel antiepileptic drugs with few side-effects and high efficacy is therefore continuing. The most commonly accepted view in the pathophysiology of epilepsy is that seizures develop as a result of neuronal hyperexcitability resulting from imbalance between inhibitory and excitatory amino acids. Much research is today being performed into the neurochemical causes of episode development (Georgiev et al., 1993). An excessively prolonged epileptic episode will lead to a series of interconnected changes in neuronal cells (Johansson et al., 1996). Oxidative damage may develop in association with an increase in free oxygen radicals related to mitochondrial dysfunction resulting from changes in neuronal cells (Loscher, 2002; Markowitz et al., 2010). Research is therefore taking place into molecules with a powerful antiepileptic property, that can prevent oxidative stress and that will have few side-effects (Loscher, 2007). The thiamine (TH) investigated in this study was vitamin B1. Thiamine pyrophosphate (TPP) is an active metabolite of thiamine. Thiamine deficiency leads to neurological disorders, such as Wernicke encephalopathy and beriberi (Ferraro et al., 1999). Previous experimental studies of ours examining the effects of TH and TPP on oxidative damage caused by drugs with toxic effects on the CNS have shown that TPP has positive effects on oxidative damage (Turan et al., 2013a,b). To the best of our knowledge, the literature contains no previous data or findings regarding the protective effects of TH and TPP against epileptic seizure induced with caffeine and against oxidative stress in the rat CNS. The aim of this study was therefore to investigate the effects of TH and TPP on oxidative stress in an epileptic model induced in rats using caffeine.

Materials and methods Animals Forty-eight male albino Wistar rats weighing 210—230 g were obtained from the Ataturk University Medicinal

M.I. Turan et al. and Experimental Application and Research Center, Erzurum, Turkey. Animals were allowed 7 days to acclimatize before the experiments commenced. They were kept in a 12:12 h light/dark cycle (lights on 07:00—19:00 h) in an airconditioned constant temperature (22 ± 1 ◦ C) colony room, with free access to water and 20% (w/w) protein commercial chow. All studies were performed in accordance with the ethical guidelines set out by the local ethical committee that were fully compatible with the ‘‘NIH Guide for the Care and Use of Laboratory Animals’’.

Chemical substances TH and TPP were provided by Biopharma, Russia. Thiopental sodium and diazepam were obtained from IE Ulagay, Turkey, and Deva, Turkey, respectively.

Pharmacological procedures Animals were randomly divided into 8 groups of 6 animals each before the experimental procedures began (TH10, TH30, TH50, TPP10, TPP30, TPP50, diazepam and control groups). All doses were administered intraperitoneally (ip) as milligrams per kilogram. The TH10 group was given 10 mg/kg thiamine, the TH30 group 30 mg/kg thiamine, the TH50 group 50 mg/kg thiamine, the TPP10 group 10 mg/kg TPP, the TPP30 group 30 mg/kg TPP, the TPP50 group 50 mg/kg TPP and the diazepam group 2 mg/kg diazepam, all ip. The control group was given saline solution ip. One hour after the administration of TH, TPP, diazepam or saline solution, all animals were injected with 300 mg/kg of caffeine ip, and time of administration was recorded. The 1-h interval was due to the Tmax (the time after administration of a drug when the maximum plasma concentration is reached) value for diazepam having been reported as 1 h and the elimination half-life as 1.4 h when given ip (Loscher, 2007; Markowitz et al., 2010). Animals’ clinical condition was observed, and the time between caffeine administration and seizure onset was defined as the latent period. The animals were observed for the appearance of generalized tonic—clonic convulsive episodes as described by Ferraro et al. (1999). They described generalized convulsions as episodes characterized by generalized whole-body clonus involving all four limbs and tail, and wild running and jumping, followed by sudden loss of upright posture and autonomic signs, such as defecation and hypersalivation (Ferraro et al., 1999). Time of onset of epileptic seizure was recorded, and the latent period was calculated in seconds. Animals dying post-epileptic seizure were recorded. At the end of the study period, immediately after the end of clinical episode, surviving animals were sacrificed with a high dose of anesthesia (50 mg/kg sodium thiopental). Brains were extracted from both sacrificed animals and those during the study. The cerebrum was used after recovery of the upper layer, and biochemical examination was performed. The results from the TH10, TH30, TH50, TPP10, TPP30 and TPP50 groups were compared with those from the diazepam and healthy groups.

Thiamine pyrophosphate effects on a seizure model

Biochemical analysis of brain tissue In this part, 0.2 g of whole brain tissue was weighed for each brain. The samples were homogenized in ice with 2-mL buffers consisting of 0.5% HDTMAB [0.5% hexadecyltrimethyl ammonium bromide] pH: 6 potassium phosphate buffer for myeloperoxidase analysis, consisting of 1.15% potassium chloride solution for thiobarbituric acid reactions (TBARS) analysis and pH: 7.5 phosphate buffer for the superoxide dismutase, total glutathione analysis. They were then centrifuged at 4 ◦ C, 10,000 rpm for 15 min. The supernatant part was used as the analysis sample. Lipid peroxidation or malondialdehyde (MDA) analysis The concentrations of brain tissue lipid peroxidation were determined using the TBARS, a modified version of the method used by Nabavi et al. (2012). The rat brains were promptly excised and rinsed with cold saline. The cerebrum tissue was scraped, weighed (0.2 g), and homogenized in 10 mL of 100 g/L KCl. The homogenate (0.5 mL) was added to a solution containing 0.2 mL of 80 g/L sodium lauryl sulfate, 1.5 mL of 200 g/L acetic acid, 1.5 mL of 8 g/L 2-thiobarbiturate, and 0.3 mL distilled water. The mixture was incubated at 98 ◦ C for 1 h. After cooling, 5 mL of n-butanol:pyridine (15:l) was added. The mixture was vortexed for 1 min and centrifuged for 30 min at 4000 rpm. The absorbance of the supernatant was measured at 532 nm. The standard curve was obtained by using 1.1.3.3-tetramethoxypropane. The results were expressed as nmol MDA eq/g tissue. Myeloperoxidase (MPO) analysis The activity of MPO in the total homogenate was measured following the method described by Wei and Frenkel (1991), with some modifications. The sample was weighed 0.2 g, homogenized in 2 ml of 50 mmol/L phosphate buffer containing 0.5% hexadecyltrimethyl ammonium bromide (HDTMAB) and centrifuged at 3500 rpm for 60 min at 4 ◦ C. The supernatant was used to determine MPO activity using 1.3 mL 4-aminoantipyrine—2% phenol (25 mM) solution. 25 mmol/L 4-aminoantipyrine—2% phenol solution and 0.0005% 1.5 mL H2 O2 were added and equilibrated for 3—4 min. After establishing the basal rate, a 0.2 mL sample suspension was added and quickly mixed. Increases in absorbance at 510 nm for 4 min at 0.1-min intervals were recorded. Absorbance was measured at 412 nm using a spectrophotometer. Superoxide dismutase (SOD) analysis Measurements were performed according to the method described by Sun et al. (1988). SOD forms when xanthine is converted into uric acid by xanthine oxidase. If nitro blue tetrazolium (NBT) is added to this reaction, the SOD reacts with NBT and a purple-colored formazan dye forms. The sample was weighed and homogenized in 2 ml of 20 mmol/L phosphate buffer containing 10 mmol/L EDTA at pH 7.8. The sample was centrifuged at 6000 rpm for 10 min. The brilliant supernatant was then used as an assay sample. The measurement mixture containing 2450 ␮L measurement mixture (0.3 mmol/L xanthine, 0.6 mmol/L EDTA, 150 ␮mol/L NBT, 0.4 mol/L Na2 CO3 , 1 g/l bovine serum albumin), 500 ␮L

407 supernatant and 50 ␮L xanthine oxidase (167 U/L) was vortexed and then incubated for 10 min. Formazan appeared at the end of the reaction. The absorbance of the purple formazan was measured at 560 nm. The more of the enzyme is present, the less O2− radical that reacts with NBT occurs.

Total glutathione (tGSH) analysis The amount of GSH in the total homogenate was measured following the method described by Sedlak and Lindsay (1968), with some modifications. The sample was weighed (0.2 g) and homogenized in 2 mL of 50 mmol/L Tris—HCl buffer containing 20 mmol/L EDTA and 0.2 mmol/L sucrose at pH 7.5. The homogenate was immediately precipitated with 0.1 mL of 25% trichloroacetic acid. The precipitate was removed after centrifugation at 4200 rpm for 40 min at 4 ◦ C, and the supernatant was used to determine GSH level. A total of 1500 ␮L of measurement buffer (200 mmol/L Tris—HCl buffer containing 0.2 mmol/L EDTA at pH 7.5), 500 ␮L supernatant, 100 ␮L DTNB (10 mmol/L) and 7900 ␮L methanol was added to a tube and vortexed and incubated for 30 min at 37 ◦ C. 5,5-Dithiobis (2-nitrobenzoic acid) (DTNB) was used as chromogen and formed a yellow complex with sulfhydryl groups. The absorbance was measured at 412 nm using a spectrophotometer (Beckman DU 500, USA). The standard curve was obtained using reduced glutathione.

Statistical analysis All data were subjected to one-way analysis of variance using SPSS 18.0 (Armonk, NY, USA) software. Differences among groups were determined using the least significant difference option, and significance was set at P ≤ 0.05. The results are expressed as mean ± SEM.

Results Latent period results Data for the groups administered saline, TH (10—30—50 mg/kg), TPP (10—30—50 mg/kg) or diazepam (2 mg/kg) ip 1 h before induction of epileptic seizure with caffeine are given in Fig. 1. All rats in the control group died. Latent period duration in the control group rats was 134 ± 3.2 s. Three rats in the TH50 group died, and all those in the TH10 and TH30 groups. Latent period durations in the TH10, TH30 and TH50 groups were 144 ± 13.9, 147 ± 14.5 and 169 ± 15.1 s, respectively. One rat died in the TPP10 group, but none in the TPP30 or TPP50 groups. Latent period durations in these three groups were 184 ± 8.54, 197 ± 9.1 and 225 ± 8.37 s, respectively. No deaths were observed in the diazepam group, in which latent period duration was 236 ± 6.7 s. No statistically significant difference in terms of latent periods was observed between the control and TH10 and TH30 groups (P > 0.05). Latent periods in the TH50, TP10, TP30, TP50 and diazepam groups were significantly longer compared to those of the rats in the control group (P < 0.05).

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Biochemical results TBARS levels and MPO activity in the TPP 10, TPP30, TPP50 and diazepam groups were significantly low compared to the control group (P < 0.05), while SOD activity and tGSH levels were significantly higher (P < 0.05). No statistical difference was determined between the TH10, TH30 and TH50 groups and the control group in terms of TBARS and tGSH levels and MPO and SOD activities (P > 0.05). Table 1 shows statistical comparisons and data regarding TBARS, MPO, SOD and tGSH levels. Figure 1 Comparison of latent periods in the thiamine (10—30—50 mg/kg), thiamine pyrophosphate (10—30—50 mg/kg) and diazepam groups versus the control group. Notes: One-way analysis of variance post hoc least significant difference analysis was performed. The time between caffeine administration and first contraction was defined as the latent period. This was calculated in seconds (s). Bars are means ± SEM. TH10 group, given 10 mg/kg thiamine; TH30 group, given 30 mg/kg thiamine; TH50 group, given 50 mg/kg thiamine; TPP10 group, given 10 mg/kg thiamine pyrophosphate; TPP30 group, given 30 mg/kg thiamine pyrophosphate; TPP50 group, given 50 mg/kg thiamine pyrophosphate; DG, diazepam group; CG, caffeine-induced epilepsy group, given saline. *P ≤ 0.05 was significant.

Table 1

Discussion In this study, an epileptic seizure model was established in rats by ip administration of caffeine. The efficacy of TH and TPP was evaluated by measuring the time from drug administration to onset of clinical seizure and examining their effects on oxidative stress. The data obtained were compared with those of the control group. While the latent period was prolonged at all doses in the groups given TPP compared to the TH groups, TPP at a dose of 50 mg/kg significantly prolonged the latent period compared to the control group. All animals were clinically monitored postepisode, and mortality rates were determined. All animals in the control, TH10 and TH30 groups died from seizures, while only three animals died from contraction in the TH50 group. When administered at a dose of 50 mg/kg in particular, TH had a significant positive effect on latent period

Comparison of groups’ oxidant and antioxidant parameters.

Control n:6 Diazepam group n:6 Thiamine 10 mg/kg group n:6 Thiamine 30 mg/kg group n:6 Thiamine 50 mg/kg group n:6 TPP 10 mg/kg group n:6 TPP 30 mg/kg group n:6 TPP 50 mg/kg group n:6

TBARS (nmolMDA eq/g tissue)

MPO (U/g)

SOD (U/g)

tGSH (nmol/g protein)

7.58 ± 0.7

4.1 ± 0.3

2.12 ± 0.18

1.32 ± 0.21

2.12 ± 0.24 P < 0.05* 7.12 ± 0.45 P > 0.05

1.32 ± 0.2 P < 0.05* 3.9 ± 0.23 P > 0.05

6.3 ± 0.32 P < 0.05* 2.19 ± 0.18 P > 0.05

3.49 ± 0.6 P < 0.05* 1.58 ± 0.1 P > 0.05

6.7 ± 0.2 P > 0.05

3.78 ± 0.5 P > 0.05

2.3 ± 0.7 P > 0.05

1.74 ± 0.67 P > 0.05

6.2 ± 0.16 P > 0.05

3.4 ± 0.33 P > 0.05

3 ± 0.39 P > 0.05

1.99 ± 0.32 P > 0.05

4.49 ± 0.27 P < 0.05*

2 ± 0.1 P < 0.05*

3.9 ± 0.4 P < 0.05*

2.36 ± 0.24 P < 0.05*

3.5 ± 0.42 P < 0.05*

1.72 ± 0.43 P < 0.05*

4.44 ± 0.67 P < 0.05*

2.9 ± 0.43 P < 0.05*

2.6 ± 0.1 P < 0.05*

1.49 ± 0.7 P < 0.05*

5.79 ± 0.2 P < 0.05*

3.2 ± 0.13 P < 0.05*

Notes: According to one-way analysis, comparing the activities of MPO and SOD, levels of tGSH and TBARS of each group versus control group. All the values are expressed as mean ± standard error of the mean. SOD; superoxide dismutase MDA, malondialdehyde; MPO, myeloperoxidase; tGSH, total glutathione; TPP, thiamine pyrophosphate; n, number of animals. * P ≤ 0.05 was significant.

Thiamine pyrophosphate effects on a seizure model and mortality. No animals in the TPP or diazepam groups died, and all those animals followed a natural clinical course post-episode. These data show the protective effect of TH, and particularly of TPP, against caffeine given in a lethal dose. TPP at all three doses had a positive effect on the oxidant/antioxidant balance. MDA is the final product of lipid peroxidation and is an important parameter in the evaluation of oxidative damage associated with epileptic episode (Chowdhury et al., 2013). Lipid peroxidation leads to compromise of cell membrane permeability, a decrease in membrane potential and to cell damage. Cell damage intensifies still further with the formation of MDA (Girotti, 1998). Another parameter known as an oxidant in cells is the enzyme MPO. This reduces hydrogen peroxide to hypochloric acid in the presence of chloride ions. Hypochloric acid is a powerful oxidant and leads to tissue damage by easily entering into reaction with several biological molecules (Lavelli et al., 2000). Studies with experimental epileptic episode models have reported increased levels of MDA and MPO in tissues containing damaged neuronal cells (Johansson et al., 1996; Liu et al., 2010). These data from the literature are in agreement with those from our own study.tGSH and SODs are known antioxidant parameters (Bowler and Crapo, 2002; Kinnula et al., 2004). Antioxidants suppress radical formation, scavenge damaged molecules, repair oxidative damage, prevent mutations and neutralize various reactive side-products (Sorg, 2004). The significantly high level of GSH and SOD in brain tissue in all the groups given TPP compared to the control group suggests that TPP possesses antioxidant activity. The caffeine we used to establish a lethal dose is a methylxanthine-type alkaloid. By interacting with the GABAA /benzodiazepine receptor complex in the brain, caffeine has the potential to cause disinhibition and the stimulation associated with this. However, this effect is not to be expected at pharmacological doses. Caffeine’s interaction with the GABAA /benzodiazepine receptors partly explains its CNS effects and convulsant activities at high doses (Marangos et al., 1981; Vellucci and Webster, 1984). The stimulant effect of caffeine is also associated with its antagonization of the adenosine released in the nerve endings of the adenosynergic neuromodulator system in the CNS. Adenosine is an important neuromediator in the synapses in the hippocampus, cerebral cortex and cerebellar cortex. Adenosine causes postsynaptic inhibition, as well as inhibiting neurotransmitter release by causing presynaptic inhibition. When injected into the brain ventricles it has a sedative and anticonvulsant effect (De Sarro et al., 1999; Nehlig et al., 1992). On the basis of these data, we think that adenosine may have mediated the positive effects of TPP in particular, but also of TH, on latent period and mortality in an episode model induced with the injection of caffeine in rats. TH, also known as vitamin B1 , is a colorless, watersoluble vitamin with the chemical formula C12 H17 ClN4 OS. TPP, the active form of TH, forms following the phosphatization of TH with thiamine pyrophosphokinase in the liver (Pavia et al., 2006). TPP plays a role as a coenzyme of several enzymes, such as two-carbon unit transfer and the dehydrogenation of 2-oxoacids. Pyruvate dehydrogenase (PDH) participates in the synthesis of adenosine triphosphate, the main energy source for the mitochondrial part of cells. In the

409 nervous system, PDH plays a role in the acetylcholine and neurotransmitter synthesis required for myelin production (Butterworth, 2005). Endogenously synthesized lipoic acid binds to specific proteins with a covalent bond and serves as a cofactor with TPP in dehydrogenase enzyme complexes (Costa et al., 2004). One study investigating the anticonvulsive effect of lipoic acid measured its effect on the refractory period until seizure onset in seconds and reported that lipoic acid establishes its anticonvulsant effect on GABA and glycine (de Freitas et al., 2011). These data from the literature suggest that the positive effect of TPP on latent period and oxidative damage may be associated with lipoic acid. The lack of sufficient information about the pathogenesis of various types of epilepsy and the failure to reveal the basic defects underlying them represents a significant obstacle to determining the effect mechanisms of antiepileptic drugs. However, the fact that some of these investigations were performed at high concentrations above therapeutic levels and that drugs needed to be administered at excessive concentrations in order for a specific effect to emerge reduces the importance of elementary effects in terms of contributing to antiepileptic effect mechanisms (Remy and Beck, 2006). There are various limitations to this study:

(1) No experiments were performed to identify mechanisms behind the effects of TH and TPP. For example, adenosine and/or adenosine antagonist were not used since this might limit the episode-inducing effect of caffeine. (2) Objective measuring techniques such as electroencephalography or histopathological examination by which the effect of TH and TPP on the seizure model could have been examined were excluded for lack of technical facilities. (3) Cerebrospinal fluid and blood concentrations of TH and TPP could not be measured, again due to lack of technical facilities.

In conclusion, this study investigated the previously untested effects of TPP and TH, the absence of which causes significant neurological symptoms and findings, on an episode model induced in rats with caffeine. TH had a dosedependent positive effect on patent period and mortality, although it did not exhibit the expected effect on oxidative stress. This may probably be attributed to TH entering different metabolic pathways after entering the body and to the desired concentration of TPP failing to emerge as a result of the insufficiency of the TH activation period. TPP, especially at a dose of 50 mg/kg, significantly prolonged, in a manner that is still unclear, the latent period from administration of caffeine up to episode onset. It also had a significant, positive effect on mortality and oxidative stress.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Conflict of interest The authors have no conflict of interest.

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Effects of thiamine and thiamine pyrophosphate on epileptic episode model established with caffeine in rats.

This study examines the effect of thiamine (TH) and thiamine pyrophosphate (TPP) on epileptic episode model induced in rats with caffeine. Animals wer...
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