الفهرس 
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Abstract
Epilepsy is a neurological disorder attacks a considerable number of human populations without discriminations of age, gender or race. It appears as unprovoked and unpredictable seizures episodes which decreases the life quality of epileptic patients. It is also a long life curable disease. It either focal epilepsy occurs as a result of disorder in some cerebral neurons, and effectively treated with depakine, or which general epilepsy extends to all cerebral neurons effectively treated with epanutin.
The present investigation deals with the genotoxic effects of depakine drug and/or epanutin drug on bone marrow chromosomes, DNA content and histological structure of liver of male albino mice Mus musculus. A total number of sixty-five CD-1 male mice (16-17 weeks old and 26-30 g) were used. They were divided into thirteen groups. The first group consists of 5 mice and served as control. while 2nd and 8th groups were injected daily with depakine 25 mg/kg b.wt. for one and two weeks respectively. The 3rd and 9th groups were injected daily with depakine 50 mg/kg b.wt. for one and two weeks respectively. The 4th and 10th groups were injected daily with epanutin 3 mg/kg b.wt. for one and two weeks respectively. The 5th and 11th groups were injected daily with epanutin 6 mg/kg b.wt. for one and two weeks respectively. The 6th and 12th groups were injected daily with (depakine 25 + epanutin 3) mg/kg b.wt. for one and two weeks respectively. The 7th and 13th groups were injected daily with (depakine 50 + epanutin 6) mg/kg b.wt. for one and two weeks respectively. All animals were injected in intraperitoneal cavity and samples were collected via sacrificing.
Treatment with depakine and/or epanutin induced structural and numerical chromosomal aberrations on bone marrow, and these aberrations were increased by dose and time in the main groups. Structural aberrations in groups that were treated with depakine (25 or 50) mg/kg b.wt. were centromeric attenuation, ring, centric fusion, fragment, deletion, chromatid gap and numerical aberrations like polyploidy. Statistical analysis of depakine treated groups 25mg/kg b.wt. for one and two weeks showed significant increase (P < 0.005) in centromeric attenuation, ring and centric fusion in groups. It showed high significant increase (P < 0.001) in the same aberrations after the treatment with depakine 50mg/kg b.wt. for one and two weeks compared to control group.
Structural aberrations in groups that were treated with epanutin (3 or 6) mg/kg b.wt. were fragment, deletion, chromatid gap, ring, chromosomal gap, centric fusion, centromeric attenuation, end to end associations and numerical aberrations like polyploidy. Statistical analysis showed high significant increase (P < 0.001) in fragment, deletion, chromatid gap in all epanutin treated groups in comparison to control.
Structural aberrations in groups that were treated with depakine25+ epanutin3 or depakine50+ epanutin6 mg/kg b.wt. were centromeric attenuation, ring, centric fusion, fragment, deletion, chromatid gap and numerical aberrations like polyploidy. Statistical analysis showed high significant increase (P < 0.001) in centromeric attenuation, ring and centric fusion in all groups treated with depakine together with epanutin compared to control group.
The means of total aberrations were increased by dose and time in each main groups. The means of total aberrations in depakine treated groups showed significant level (P < 0.005). while means of total aberrations in epanutin treated groups and groups treated with depakine together with epanutin showed high significant level (P < 0.001) compared to control group.
Results of micronucleus assay showed that treatment with depakine and/or epanutin induced genotoxicity in bone marrow cells, and the number of micronucleated polychromatic erythrocytes (MnPCEs) was gradually increased by dose and time in the main treated groups. Statistical analysis showed significant level (P < 0.005) of increase in total means of (MnPCEs) after one week of treatment with either depakine 50mg/kg b.wt. or epanutin 3mg/kg b.wt. It showed high significant level (P < 0.001) after two weeks of treatment with either depakine 50mg/kg b.wt. or (depakine50 + epanutin6) mg/kg b.wt. compared to control group.
Also, cytotoxicity, expressed as the ratio of polychromatic erythrocytes (PCEs) /normochromatic erythrocytes (NCEs), showed that treatment with depakine and/or epanutin gradually increased cytotoxicity in bone marrow cells of male albino mice depending on the dose and time in the main groups. Statistical analysis showed significant level (P < 0.005) of increase in total means of cytotoxicity in the groups that were treated with depakine 25mg/kg b.wt. for one and two weeks, groups that were treated with depakine 50mg/kg b.wt. for one week, and groups that were treated with epanutin 6mg/kg b.wt. for two weeks. It showed high significant level (P < 0.001) in groups that were treated with depakine 50mg/kg b.wt. for one week, groups that were treated with epanutin 6mg/kg b.wt. for one week and groups that were treated with (depakine25+ epanutin3) mg/kg b.wt. for one and two weeks compared to control group.
The current results of comet assay showed that treatment with depakine and/or epanutin induced DNA damage in liver cells of the treated mice in dose and time dependent manner. Statistical analysis showed significant level (P < 0.005) of increase in the means of total comet score in groups that were treated with depakine 50mg/kg b.wt. for one week and groups that were treated with (depakine25 + epanutin3) mg/kg b.wt. for two weeks. It showed high significant level (P < 0.001) in groups that were treated with depakine 25 or 50mg/kg b.wt. for two weeks, all epanutin treated groups, groups that were treated with (depakine25+ epanutin3) mg/kg b.wt. for one week and groups that were treated with (depakine50+ epanutin6) mg/kg b.wt. for one and two weeks compared to control group.
However, the reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that treatment with depakine and/or epanutin induced regression in expressions of both NQO1 and Bcl-2 genes in hepatocytes of male albino mice depending on the dose and the time in comparison to control group. Statistical analysis showed that total means of expression levels of both genes in depakine treated groups represented a significant level of decrease (P < 0.005). Total means of expression levels of both genes in epanutin treated groups and groups treated with depakine together with epanutin showed high significant level (P < 0.001) compared to control group.
On the light microscopic level, histological examination of the liver revealed histopathological changes. The severity of these lesions has been observed to be time and dose dependent. The main histopathological features induced in the liver of mice by depakine were focal inflammation, cloudy swelling of hepatocytes cytoplasm and hepatic vascular congestion. While groups that were treated with epanutin only and groups that were treated with depakine together with epanutin showed approximately the same histopathological features in the liver of male albino mice in the form of multi-focal inflammatory areas, hydropic degenerative changes in hepatocytes cytoplasm with nuclear pyknosis, in addition to congestion accompanied with dilation in hepatic vascular system and blood sinusoids.
In addition, the biochemical analysis of hepatic aminotransferases showed that, treatment with depakine and/or epanutin resulted in increase the level of both ALT and AST concentration in blood serum of male albino mice, depending on the dose and time in comparison to control group. Statistical analysis showed that total means of serum concentration level of both ALT and AST in depakine treated groups represented a significant level (P < 0.005), while total means of serum concentration level of both enzymes in epanutin treated groups and groups treated with depakine together with epanutin showed high significant level (P < 0.001) compared to control group.
In conclusion, results of the present study most likely reveals that depakine and/or epanutin treatment induced damage in bone marrow chromosomes, damage in DNA content, hepatic histopathological changes and pathological increase in the level of hepatic aminotransferases in serum of male albino mice according to dose and time in main treated groups. Also, groups that were treated with epanutin only and groups that were treated with depakine together with epanutin showed approximately same results of all parameters.
Therefore, the using of depakine and/or epanutin should be restricted to a very narrow range border owing to its harmful genotoxic and cytotoxic effects. Besides, this study recommends applying the lowest possible concentration of both drugs according to the world health organization (WHO).