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Abdulhakeem A Al-Majed
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ABSTRACT: Oxidative stress and energy depletion are believed to participate in hippocampal neuronal damage after forebrain ischemia. This study has been initiated to investigate the potential neuroprotective effects of probucol, a lipid-lowering drug with strong antioxidant properties, against transient forebrain ischemia-induced neuronal damage and biochemical abnormalities in rat hippocampal CA1 region. Adult male Wistar albino rats were subjected to forebrain ischemia and injected with probucol for the next 7 successive days, and compared to controls. Forebrain ischemia resulted in a significant decrease in the number of intact neurons (77%), glutathione (GSH), and adenosine triphosphate (ATP), and a significant increase in thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite, (NO(x)) production in hippocampal tissues. The administration of probucol attenuated forebrain ischemia-induced neuronal damage, manifested as a complete reversal of the decrease in the number of intact neurons, ATP and GSH and the increase in TBARS and NO(x) in hippocampal tissues. This study demonstrates that probucol treatment abates forebrain ischemia-induced hippocampal neuronal loss, energy depletion, and oxidative stress in hippocampal CA1 region. Thus, probucol could be a promising neuroprotective agent in the treatment of forebrain ischemia.
Oxidative Medicine and Cellular Longevity 01/2011; 2011:471590.
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ABSTRACT: 1. The present study examined whether propionyl-L-carnitine (PLC) could prevent the development of cisplatin (CDDP)-induced acute renal failure in rats. 2. Forty adult male Wistar albino rats were divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 10 consecutive days, whereas the second group received PLC (250 mg/kg, i.p.) for 10 consecutive days. Animals in the third group were injected daily with normal saline for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). Rats in the fourth group received a combination of PLC (250 mg/kg, i.p.) for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). On Day 6 following CDDP treatment, animals were killed and serum and kidneys were isolated for analysis. 3. Injection of CDDP resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acid-reactive substances (TBARS) and total nitrate/nitrite (NO(x)), as well as a significant decrease in reduced glutathione (GSH), total carnitine, ATP and ATP/ADP in kidney tissues. 4. Administration of PLC significantly attenuated the nephrotoxic effects of CDDP, manifested as normalization of the CDDP-induced increase in serum creatinine, BUN, TBARS and NO(x) and the CDDP-induced decrease in total carnitine, GSH, ATP and ATP/ADP in kidney tissues. 5. Histopathological examination of kidney tissues from CDDP-treated rats showed severe nephrotoxicity, in which 50-75% of glomeruli and renal tubules exhibited massive degenerative changes. Interestingly, administration of PLC to CDDP-treated rats resulted in a significant improvement in glomeruli and renal tubules, in which less than 25% of glomeruli and renal tubules exhibited focal necrosis. 6. Data from the present study suggest that PLC prevents the development of CDDP-induced acute renal injury by a mechanism related, at least in part, to the ability of PLC to increase intracellular carnitine content, with a consequent improvement in mitochondrial oxidative phosphorylation and energy production, as well as its ability to decrease oxidative stress. This will open new perspectives for the use of PLC in the treatment of renal diseases associated with or secondary to carnitine deficiency.
Clinical and Experimental Pharmacology and Physiology 01/2008; 34(12):1252-9. · 1.85 Impact Factor
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Abdulhakeem A Al-Majed
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ABSTRACT: This study investigates whether or not carnitine deficiency is a risk factor and could contribute to cisplatin-induced liver toxicity. A total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, propionyl-l-carnitine (500 mg/kg), and d-carnitine (500 mg/kg), respectively, for 10 successive days. The fourth, fifth and sixth groups were injected intraperitoneally with the same doses of normal saline, propionyl-l-carnitine and d-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Administration of the standard nephrotoxic dose of cisplatin did not produce any changes in serum alanine transaminase and gamma-glutamyl transferase and no morphological changes in liver tissues. However, it did produce a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione content in liver tissues. On the other hand, combined treatment with cisplatin and d-carnitine induced a dramatic increase in serum alanine transaminase and gamma-glutamyl transferase, as well as progressive reduction in total carnitine and ATP content in liver tissue. Moreover, histopathological examination of liver tissues confirmed the biochemical data, where cisplatin and d-carnitine combination showed signs of liver injury manifested as focal necro-inflammatory changes and portal inflammation. Interestingly, in carnitine supplemented rats using propionyl-l-carnitine, cisplatin did not produce any biochemical and histopathological changes in liver tissues. In conclusion, data from this study suggest for the first time that (1) carnitine deficiency is a risk factor and could precipitate cisplatin-induced hepatotoxicity, (2) oxidative stress is not the main cause of cisplatin-related hepatotoxicity and (3) propionyl-l-carnitine prevents the development of cisplatin-induced liver injury.
Basic & Clinical Pharmacology & Toxicology 04/2007; 100(3):145-50. · 2.18 Impact Factor
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Abdulhakeem A. Al-Majed
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ABSTRACT: Valerian (a natural psychotropic) has world-wide folkloric significance as anti-anxiety and a tranquilizing herbal drug. In view of its immense use and a paucity of literature on its toxicity, valerian was evaluated for its effects on spermatogenesis, genotoxicity, reproduction and biochemical changes in male Swiss albino mice. The mice were orally treated with different doses (125, 250 and 500 mg/kg/day) of the aqueous suspension of valerian for 90 days. The following parameters were studied: (1) reproductive organ weight (2) motility and content of sperms (3) spermatozoa morphology (4) cytology of the testis chromosomes (5) study on reproduction (6) biochemical study on proteins, nucleic acids, malonaldehyde (MDA) and non-protein sulfhydryl (NP-SH). The treatment induced significant increase in the weight of caudae epididymis and seminal vesicles and sperm count. There was no effect on sperm motility, morphology of spermatozoa, rate of pregnancy and pre- and post- implantation losses. However, the treatment was found to increase the frequency of chromosomal aberrations. The study on biochemical parameters showed depletion of nucleic acids, NP-SH and increase of MDA, which elucidated the role of free radical species in the induction of chromosomal aberrations. The influence of biochemical changes on induction of chromosomal aberrations and the lack of any effect on spermatogenic and reproductive function is discussed.
Journal of Medical Sciences. 01/2007;
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ABSTRACT: Valerian is widely known for its use as a sedative and an anti-anxiety drug in the folk medicine. Literature reports suggested valerian to induce genotoxicity in vitro (ECV304 cells) by reactive oxygen species-mediated mechanism; however, there are no reports on its genotoxicity and/or the epigenetic mechanism in vivo. In view of the folkloric significance, it was found worthwhile to (1) determine the genotoxic effects of valerian in somatic and germ cells of mice and (2) investigate the role of epigenetic mechanisms. The protocol included the oral treatment of mice with different doses (500, 1000 and 2000 mg/kg/day) of valerian for 7 days. The following experiments were conducted: (i) cytological studies on micronucleus test, (ii) cytogenetic analysis for meiotic chromosomes, (iii) cytological analysis of spermatozoa abnormalities, (iv) quantification of proteins and nucleic acids in testicular cells and (v) estimation of malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH) in hepatic and testicular cells. The treatment increased the frequency of micronuclei in the polychromatic erythrocytes (PCE) and decrease the ratio of PCE to normochromatic erythrocytes (NCE) in the femur. It caused aberrations in chromosomes of the testis and induced spermatozoa abnormalities. The concentration of nucleic acids was depleted in the testicular cells. These changes might be attributed to the epigenetic mechanisms as revealed by an increase in the concentrations of MDA and a decrease of NP-SH levels in hepatic and testicular cells observed in the present study. The observed changes may be ascribed to terpenoids (valepotriates) and flavonoids (6-methylapigenin and 2S(-)-hesperidin) present in valerian.
Food and Chemical Toxicology 12/2006; 44(11):1830-7. · 3.00 Impact Factor
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ABSTRACT: Ginkgo biloba (an herbal product), used as a folkloric medicine in the treatment of dementia, was evaluated for its effects on reproductive, cytological and biochemical toxicity in male Swiss albino mice. The mice were treated with different doses (25, 50 and 100mg/kg/day) of the aqueous suspension of Ginkgo biloba for 90 days by oral gavage. The following parameters were evaluated: (1) reproductive organ weight; (2) motility and content of sperms; (3) spermatozoa morphology; (4) cytology of the testes chromosomes; (5) study on reproduction; (6) biochemical study on proteins, nucleic acids, malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH). The treatment caused significant changes in the weight of caudae epididymis, prostate, chromosomal aberrations, rate of pregnancy and pre-implantation loss. However, the percent motility, sperm count and morphology of spermatozoa were not affected. Our study on biochemical parameters showed depletion of nucleic acids, NP-SH and increase of MDA, which elucidated the role of free radical species in the induced changes in testis chromosomes and the reproductive function. The exact mechanism is not known, however, the activation of GABA, glycine and glutamate under the influence of Ginkgo biloba and its constituents might have generated free radicals and depleted cellular glutathione by calcium influx and membrane depolarization. The observed toxicity is attributed to the toxic constituents (ginkgolic acids, biflavones, cardanols, cardols, bilobalides and quercetin) of Ginkgo biloba. Our results warrant careful use of Ginkgo biloba as a remedy for impotence and/or erectile dysfunction.
Journal of Ethnopharmacology 10/2006; 107(2):222-8. · 3.01 Impact Factor
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ABSTRACT: Increasing evidence demonstrates that oxidative stress plays an important role in brain injury in experimental models of brain ischemia. Thymoquinone, the main constituents of the volatile oil from Negella sativa seeds, is reported to possess strong antioxidant properties. Hence, the present study was undertaken to evaluate the neuroprotective effect of thymoquinone against transient forebrain ischemia-induced neuronal damage in the rat hippocampus. Rats were divided randomly into five groups: control, sham, ischemia, thymoquinone and ischemia+thymoquinone. Transient forebrain ischemia was induced with bilateral occlusion of both common carotid arteries for 10 min followed by 7 days of reperfusion. Thymoquinone was administered (5 mg/kg/day p.o.) 5 days before ischemia and continued during the reperfusion time. Animals were sacrificed, and brain tissues were isolated for histopathological examination. Hippocampal tissues were also used for determination of malondialdehyde levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant and the activities of the antioxidant enzymes catalase and superoxide dismutase (SOD). Thymoquinone and its metabolite thymohydroquinone were tested as inhibitors of the in vitro non-enzymatic lipid peroxidation induced by iron-ascorbate in the hippocampal homogenate. Forebrain ischemia-reperfusion neural injury in rats was demonstrated by histopathological observation, which revealed significant neural cell death in the hippocampus CA1 area 7 days post-ischemia (77% cell loss). Additionally, forebrain ischemia-reperfusion oxidative injury in rats was demonstrated by a significant increase in malondialdehyde and a significant decrease in GSH contents, catalase and SOD activities in the hippocampal tissue compared to the control or sham-operated groups. Pretreatment of thymoquinone attenuated forebrain ischemia-induced neuronal damage manifested by significantly decreasing the number of dead hippocampal neuronal cells (24% in thymoquinone-treated versus 77% for ischemia, P<0.001), which confirm the protective role of thymoquinone in ischemia-reperfusion injury. Also, pretreatment of ischemic rats with thymoquinone decreased the elevated levels of malondialdehyde and increased GSH contents, catalase and SOD activities to normal levels. Thymoquinone and thymohydroquinone inhibited the in vitro non-enzymatic lipid peroxidation in hippocampal homogenate induced by iron-ascorbate. The IC50 for thymoquinone and thymohydroquinone were found to be 12 and 3 microM respectively. This suggests that the protection of thymoquinone and its metabolite involve increased resistance to oxidative stress. In conclusion, thymoquinone is effective in protecting rats against transient forebrain ischemia-induced damage in the rat hippocampus. This spectacular protection makes thymoquinone a promising agent in pathologies implicating neurodegenaration such as cerebral ischemia.
European Journal of Pharmacology 09/2006; 543(1-3):40-7. · 2.52 Impact Factor
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ABSTRACT: 1. The present study investigated whether propionyl-L-carnitine (PLC) has neuroprotective effects, similar to those reported for acetyl-L-carnitine (AC), against transient forebrain ischaemia-induced neuronal damage and biochemical derangement in the rat hippocampal CA1 region. 2. In total, 105 adult male Wistar albino rats were divided into seven groups of 15 animals each. The first three groups were injected i.p. with normal saline, AC (300 mg/kg) or PLC (300 mg/kg) for 7 successive days. The next three groups were injected i.p. with the same doses of normal saline, AC or PLC immediately after the induction of 10 min forebrain ischaemia and i.p. injections were continued for 7 successive days. Rats in the seventh group were subjected to sham-operated ischaemia and injected with normal saline for 7 successive days. 3. Seven days after treatment, animals were killed and their brains isolated for histopathological examination and biochemical studies. 4. Forebrain ischaemia resulted in a significant decrease in the number of intact neurons (77%), ATP concentration (51%) and glutathione content (32%), whereas there was a significant increase in the production of thiobarbituric acid-reactive substances (TBARS; 71%) and total nitrate/nitrite (NOx; 260%) in hippocampal tissues. 5. Administration of either AC or PLC attenuated forebrain ischaemia-induced neuronal damage, manifested by a greater number of intact neurons, ATP and glutathione, as well as a decrease in TBARS and NOx in hippocampal tissues. 6. Results from the present study suggest, for the first time, that PLC attenuates forebrain ischaemia-induced neuronal injury, oxidative stress and energy depletion in the hippocampal CA1 region. Propionyl-L-carnitine has neuroprotective effects similar to AC and could have a potential use in the treatment of neurodegenerative diseases. 7. The results of the present study will open up new perspectives for the use of PLC in the treatment of neurodegenerative diseases associated with, or secondary to, myocardial ischaemia-reperfusion injury and chronic circulatory failure.
Clinical and Experimental Pharmacology and Physiology 09/2006; 33(8):725-33. · 1.85 Impact Factor
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ABSTRACT: To study the effect of Corynanthe Yohimbe (Yohimbe) on germ cells in Swiss albino mice.
Adult male mice were orally (gavage) treated with different doses (188, 375 and 750 mg/[kg x day]) of aqueous suspension of Yohimbe for 90 days. The following parameters were evaluated: (i) reproductive organ weight, (ii) motility and count of sperm, (iii) study on rate of pregnancy and mean implants, (iv) spermatozoa morphology, (v) cytology of the testes chromosomes, and (vi) biochemical study on estimation of proteins, RNA, DNA, malondialdehyde, nonprotein sulfhydryl (NP-SH) and hormones.
The treatment caused significant increase in the weight of seminal vesicles, motility and count of spermatozoa, pre- and post-implants. Male fertility was decreased. These results are confirmed by our data on spermatozoa abnormalities and chromosomal aberrations. The data on biochemical parameters showed increase of malondialdehyde and depletion of NP-SH, proteins, RNA and DNA in the testicular cells.
Our results elucidated the role of free radical species in cytological and reproductive changes, possibly, under the influence of yohimbine (principal constituent of Yohimbe) on neurotransmitters, including norephinephrine. These data warrant careful use of Yohimbe.
Asian Journal of Andrology 08/2006; 8(4):469-76. · 1.52 Impact Factor
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ABSTRACT: Oxidative stress is believed to contribute to neurodegeneration following ischemic injury. The present study was undertaken to evaluate the possible antioxidant neuroprotective effect of curcumin (Cur) on neuronal death of hippocampal CA1 neurons following transient forebrain ischemia in rat. Treatment of Cur (200 mg/kg/day, i.p.) at three different times (immediately, 3 h and 24 h after ischemia) significantly (P<0.01) reduced neuronal damage 7 days after ischemia. Also, treatment of ischemic rats with Cur decreased the elevated levels of MDA and increased GSH contents, catalase and SOD activities to normal levels. In the in vitro, Cur was as potent as antioxidant (IC(50) = 1 microM) as butylated hydroxytoluene. The present study demonstrates that curcumin treatment attenuates forebrain ischemia-induced neuronal injury and oxidative stress in hippocampal tissue. Thus treatment with curcumin immediately or even delayed until 24 h may have the potential to be used as a protective agent in forebrain ischemic insult in human.
Neurochemical Research 05/2006; 31(5):611-8. · 2.24 Impact Factor
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ABSTRACT: This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-L-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg(-1)), and d-carnitine (500 mg kg(-1)) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and D-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg(-1)). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO(x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO(x), and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.
Pharmacological Research 04/2006; 53(3):278-86. · 4.44 Impact Factor
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Abdulhakeem A. Al-Majed
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ABSTRACT: Paulinia cupana (Guarana) was evaluated for cytological and biochemical toxicity in male mice. Mice were orally treated with 133, 265 and 530 mg/kg/day of the aqueous suspension of Guarana for 7 consecutive days. The following parameters were evaluated: (i) studies on micronucleus test, (ii) analysis of spermatozoa abnormalities, (iii) analysis of meiotic chromosomes, (iv) quantification of proteins, Ribose Nucleic Acid (RNA) and Deoxy Ribose Nucleic Acid (DNA) in hepatic and testicular cells and (v) estimation of malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH) in hepatic and testicular cells. The treatment caused significant changes in the frequency of micronuclei in the femoral cells and induced testicular chromosomal aberrations. However, there was no effect on the morphology of spermatozoa. The study on biochemical parameters showed increase of MDA and depletion of NP-SH, RNA and DNA in both hepatic and testicular cells. Present data elucidated the role of free radical species in cytological and biochemical changes in both somatic and germ cells. The exact mechanism of the genesis of lipid peroxides is not known, however, this might be related to the influence of the tannin contents of Guarana. It is suggested that, in view of the observed cytological and biochemical effects of Guarana, it may be subjected to a thorough evaluation of toxicity before it is available for human use.
International Journal of Pharmacology. 01/2006;
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ABSTRACT: Carboplatin (CP), a second generation platinum compound, is effective against various types of cancers, producing less nephrotoxicity and ototoxicity but more myelotoxicity than cisplatinum. CP-myelosuppression is the rate-limiting step of its clinical use. Prevention of CP-myelosuppression is a major target in the field of chemotherapy. Therefore, the present study investigates the use of L-carnitine (LCR)-an antioxidant, cardioprotective, neuroprotective, and immunostimulant nontoxic natural compound-to protect against CP-induced myelosuppression. The viability of BMC was studied using a trypan blue exclusion technique following incubation with CP and/or LCR as a function of time and concentration. Apoptosis was tested for by detecting the amount of DNA fragmentation and the visualization of DNA ladders upon gel electrophoresis. Bone marrow progenitor cell function was examined by colony forming unit assay. Cellular contents of glutathione (GSH) and malondialdehyde (MDA) were also estimated. Results revealed that LC50 of CP is 4.7 mM and the highest safe concentration of LCR is 5 mM. Co-exposure of LCR+CP rescued BMC viability by 37% compared to the CP-treated cultures. The LCR halts CP-induced apoptosis and it significantly improves the function of the bone marrow progenitors by increasing the number of colony-forming units as a response to granulocyte/macrophage colony stimulating factors. Finally, LCR restores CP-induced GSH depletion and prevents MDA elevation in BMC. In summary, the results suggest that LCR is able to protect against CP-induced myelosuppression, which suggests its use as an adjuvant therapy. This finding merits further investigation into the mechanism(s) of such protection as well as its interaction with CP antitumor activity.
Archive für Toxikologie 08/2005; 79(7):406-13. · 4.67 Impact Factor
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ABSTRACT: 1. In the present study, the effect of taurine, on cyclophosphamide (CP)-induced urinary bladder toxicity was investigated. 2. Administration of a single dose of CP (150 mg/kg, i.p.) induced cystitis, as manifested by marked congestion, oedema and extravasation in rat urinary bladder, as well as a marked desquamative damage to the urothium, severe inflammation in the lamina propria, focal erosions and polymorphonuclear leucocytes associated with occasional lymphocyte infiltration as determined by macroscopic and histopathological examination. 3. A significant decrease in the endogenous anti-oxidant compound glutathione and elevation of lipid peroxidation also resulted in rat urinary bladder tissue. 4. Cyclophosphamide-induced cystitis markedly affected the contractile function of the urinary bladder, as revealed by a significant inhibition of tissue responsiveness to acetylcholine (ACh) at different molar concentrations in vitro. 5. Conversely, pretreatment with taurine (1% in drinking water to reach a dose of 1 g/kg per day) for 7 days before and 1 day after CP injection produced a significant decrease in urinary bladder weight (oedema) and a marked decrease in vascular congestion and haemorrhage, as well as a profound improvement in histological structure. Moreover, taurine pretreatment resulted in a significant decrease in lipid peroxide in urinary bladder tissue and glutathione content was greatly restored. 6. Urinary bladder rings isolated from rats treated concurrently with taurine and CP showed a significant increase in their responsiveness to ACh compared with the CP group. 7. These results suggest that taurine offers a protective effect against CP-induced urinary bladder toxicity and may, therefore, decrease the limitation on its clinical application. These results merit extension and further investigation of the impact of taurine on CP antitumour activity.
Clinical and Experimental Pharmacology and Physiology 04/2005; 32(3):167-72. · 1.85 Impact Factor
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ABSTRACT: The present study was undertaken to evaluate whether stimulation or inhibition of Nitric Oxide (NO) synthesis could affect lung toxicity induced by acute administration of paraquat (PQ) in mice. L-arginine (L-arg.), N<sup>G</sup>-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG) were employed as NO precursor, competitive and specific NO synthesis inhibitors, respectively. PQ was administered intraperitoneally to Swiss albino mice at a single dose of 50 mg kg<sup>-1</sup>. L-arg. (700 mg kg<sup>-1</sup> day<sup>-1</sup>), L-NAME (150 mg kg<sup>-1</sup> day<sup>-1</sup>) or AG (100 mg kg<sup>-1</sup> day<sup>-1</sup>) was given in drinking water of mice for 5 days before and one day after PQ administration. Appropriate controls were performed. PQ administration resulted in a pronounced elevation in lipid peroxides (157%) as well as decreased activity of alkaline phosphatase [ALP] (48%) and non-protein thiols (40%) in lung tissue compared to control non-treated mice as evidences of lung injury. Serum level of NO end products, nitrate and nitrite significantly elevated due to PQ administration (150%) as compared to control level. In mice given combined treatment of L-arg. and PQ, a remarkable rise in the serum level of nitrate and nitrite (140%) compared to the PQ group was observed. In addition, L-arg. ameliorated the increased level of lipid peroxides and non-protein thiols depletion as well as the decreased activity of ALP caused by PQ respectively. On the other hand, L-NAME and AG potentiated the deleterious effects of PQ on serum NO, lung lipid peroxides content, non-protein thiols content and alkaline phosphatase activity. In conclusion, PQ-induced lung injury in mice is alleviated by L-arg. but exacerbated by L-NAME and AG supplementation. This could point out to a possible protective role of NO in PQ lung toxicity.
International Journal of Pharmacology. 01/2005;
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ABSTRACT: This investigation was performed to evaluate the effects of nimesulide (NIM), a selective cyclo-oxygenase-2 (COX-2) inhibitor, on forebrain ischemia-induced in vivo oxidative stress damage in the rat hippocampus. Hippocampal tissue glutathione (GSH) and malondialdehyde (MDA) contents, the activities of the antioxidants superoxide dismutase (SOD) and catalase as well as nitric oxide (NO) concentration were estimated. A clinically relevant dose of NIM (18 mg x kg(-1) x d(-1), p.o.) was administered immediately after induction of forebrain ischemia for 7 consecutive days. Forebrain ischemia induced oxidative stress after 7 days manifested by significant decrease in GSH and increase in MDA levels as compared to control (p < 0.05). Also, in rats subjected to ischemia, SOD and catalase activities were decreased significantly compared to the control group (p < 0 .05). On the other hand, ischemic rats showed a significant increase in NO concentration compared to those in the control group (p < 0.05). Treatment with NIM protected the rats from ischemia-induced oxidative stress as evident by normalization of measured parameters. The present study indicates the ability of NIM to reduce oxidative stress induced by transient forebrain ischemia. This suggests that the induction of COX-2 might be involved in transient forebrain ischemia-induced oxidative damage and hence the selective COX-2 inhibitors might be a valuable therapeutic strategy against ischemic brain injury.
Research communications in molecular pathology and pharmacology 01/2004; 115-116:49-62.
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ABSTRACT: It has been recently postulated from our laboratory that Arabic gum (AG) offers a protective effect in the kidney of rats against nephrotoxicity induced by gentamicin via inhibiting lipid peroxidation. It has also recently shown a powerful antioxidant effect through scavenging superoxide anions. In this study we utilized a rat model of cisplatin (CP)-induced nephrotoxicity to determine its peak time following (1, 2, 5, and 7 days) of a single CP (7.5 mg/kg, i.p.) injection. Also, a possible protective effect of cotreatment with AG (7.5 g/kg/day p.o.) on CP-induced nephrotoxicity was investigated. Biochemical as well as histological assessments were carried out. CP-induced nephrotoxicity was manifested by significant elevations of the functional parameters blood urea, serum creatinine, and kidney/body weight ratio. Maximum toxic effects of CP were observed 5 days after its injection, while it started after day 1 in the biochemical parameters, such as glutathione depletion in the kidney tissue with concomitant increases in lipid peroxides and platinum content. Additionally, severe necrosis and desquamation of tubular epithelial cells in renal cortex as well as interstitial nephritis were observed after 5 days in CP-treated animals. Five days after AG cotreatment with CP did not protect the kidney from the damaging effects of CP. However, it significantly reduced CP-induced lipid peroxidation. These findings suggest that lipid peroxidation is not the main cause of CP-induced nephrotoxicity but it is rather more dependent on other factors such as platinum disposition in renal interstitial tubules.
Journal of Biochemical and Molecular Toxicology 02/2003; 17(3):146-53. · 1.38 Impact Factor
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ABSTRACT: The effect of alpha-lipoic acid (LA) on the cardiotoxicity induced by doxorubicin (DOX) was investigated. A single dose of DOX (15 mg kg(-1), i.p) induced cardiotoxicity manifested biochemically by a significant elevation of serum creatine phosphokinase (CK; EC: 2.7.3.2) and lactate dehydrogenase (LDH; EC: 1.1.1.27) 48 h later. Moreover, cardiotoxicity was further confirmed by the significant increase in lipid peroxides measured as malondialdehyde (MDA), and significant decrease in protein thiols (Protein-SH) content in heart tissues. Administration of LA (100 mg kg(-1)) orally for 5 days before and 2 days after DOX injection produced a significant protection against cardiotoxicity induced by DOX. The amelioration of cardiotoxicity was evident by significant reductions in serum CK and LDH. Moreover, LA prevented the rise of MDA as well as the significant reduction of Protein-SH. These results may suggest that LA has a protective effect against cardiotoxicity induced by DOX and it may, therefore, improve the therapeutic index of DOX.
Pharmacological Research 01/2003; 46(6):499-503. · 4.44 Impact Factor
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ABSTRACT: Arabic gum (AG) is a complex polysaccharide used as suspending agent. It has been widely used by eastern folk medicine practitioners as a restorative agent and is thought to be an excellent curative for renal failure patients. We therefore tested these folkloric claims using a rat model of gentamicin (GM)-induced nephrotoxicity. AG (7.5g 100ml(-1), in drinking water) was administered orally for 8 days concurrently with GM (80mgkg(-1) per day, i.p.). Estimation of urine volume, serum creatinine and urea concentrations, kidney tissue malondialdehyde (MDA) contents and glutathione (GSH) were carried out after the last dose of GM. Kidneys were also examined for histological changes. GM caused a marked nephrotoxicity as evidenced by significant increases in urine volume (295%), serum creatinine (318%) and urea (258%) and a significant decrease in creatinine clearance (Ccr) (26%). Treatment with AG protected the rats from GM-induced nephrotoxicity as evident by normalisation of these parameters. In addition there was about 187% increase in kidney tissue MDA contents above the control with GM treatment. AG totally prevented the GM-induced rise in kidney tissue contents of MDA. Kidney histology of the tissue from GM-treated rats showed necrosis and desquamation of tubular epithelial cells in renal cortex as well as interstitial nephritis. Whereas it was very much comparable to control when AG was co-administered with GM. In conclusion, AG protected the rats from GM-induced nephrotoxicity, possibly, at least in part through inhibition of the production of oxygen free radicals that cause lipid peroxidation.
Pharmacological Research 12/2002; 46(5):445-51. · 4.44 Impact Factor
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ABSTRACT: The effects of Ginkgo biloba extract (EGb 761) and L-carnitine on bleomycin (BLM)-induced lung fibrosis were studied in rats. BLM (cumulative dose of 180 mgkg(-1)) was given intraperitoneally (i.p.) three times weekly for 4 consecutive weeks. Treatment with BLM enhanced the responsiveness of isolated pulmonary arterial rings to serotonin (5-HT), significantly increased the normal serum level of tumour necrosis factor (TNF-alpha) by approximately 105% and markedly elevated the level of lipid peroxide (LPO) and collagen content in the lung homogenates by 34 and 83%, respectively. EGb 761 (100 mgkg(-1) ), given in drinking water for the whole study period, totally abolished the BLM-induced alterations in the measured biochemical and pharmacological parameters. Meanwhile, L-carnitine (500 mg kg(-1) ), administered in drinking water, significantly decreased the BLM-induced elevations of serum TNF-alpha, LPO level in lung tissues and the enhanced responsiveness of pulmonary arterial rings to 5-HT. However,L-carnitine did not reduce the increase in the collagen content produced by BLM. The results of the present study indicate the beneficial effects of EGb 761 and L-carnitine against lung toxicity induced by BLM treatment. Furthermore, the present data shows the advantageous use of EGb 761 as a protective agent in BLM-induced lung fibrosis under the experimental circumstances.
Pharmacological Research 07/2002; 45(6):461-7. · 4.44 Impact Factor
