Abdulhakeem A. Al-Majed

Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats

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.

Carnitine esters prevent oxidative stress damage and energy depletion following transient forebrain ischaemia in the rat hippocampus.

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.

REVERSAL OF CISPLATIN‐INDUCED CARNITINE DEFICIENCY AND ENERGY STARVATION BY PROPIONYL‐l‐CARNITINE IN RAT KIDNEY TISSUES

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 (NOx), 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 NOx 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.

Acacia senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity

Cylophosphamide (CYCL) is a strong anticancer and immunosuppressive agent but its urotoxicity presents one of the major toxic effects that limit its wide usage particularly in high dose regimens. Therefore, this study aimed to investigate Acacia Senegal gum exudate, Gum Arabic (GA), for its possible role as a natural, nontoxic agent against CYCL-induced urotoxicity. Male Swiss albino rats were exposed to CYCL (150 mg/kg BW, once i.p) with or without GA oral supplementation (7.5 g/kg/day for 6 days) through drinking water. Glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO) bladder contents were assessed. Responsiveness of the bladder rings to acetylcholine (ACh) in vitro, microscopic and macroscopic features are also investigated. CYCL produced pronounced harmful effects on bladder urothelial lining with significant increases in (MDA) and NO levels in the tissue homogenates. Bladder-GSH content is dropped by over 60% following CYCL injection. Bladder contractility, as measured by its responsiveness to ACh, recorded a marked reduction. The isolated bladders exhibited such macroscopic changes as severe edema, inflammation and extravasation. The bladder weight increased as well. Histological changes were evident in the form of severe congestion, petechial hemorrhage and chronic inflammatory reaction in the lamina propria accompanied with desquamated epithelia. GA, a potential protective agent, produced an almost complete reversal of NO induction, lipid peroxidation or cellular GSH bladder contents in the GA + CYCL-treated group. Likewise, bladder inflammation and edema were reduced. Bladder rings showed a remarkable recovery in their responsiveness to ACh. Bladder histological examination showed a near normal configuration and structural integrity, with a significant reduction in inflammation and disappearance of focal erosions. These remarkable effects of GA may be attributed to its ability to neutralize acrolein, the reactive metabolite of CYCL and/or the resultant reactive oxygen metabolites, through a scavenging action. GA may limit the cascading events of CYCL-induced damage, initiating a cytoprotective effect leading to structural and functional recovery of the bladder tissues.

ALPHA-LIPOIC ACID AMELIORATES MYOCARDIAL TOXICITY INDUCED BY DOXORUBICIN

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.

Potentiation of diclofenac-induced anti-inflammatory response by aminoguanidine in carrageenan-induced acute inflammation in rats: the role of nitric oxide.

AbstractObjective: To investigate whether aminoguanidine (AG) treatment enhances the anti-inflammatory effect of diclofenac in an acute inflammation model in rats. Material and methods: In 48 rats carrageenan-induced paw edema was used as an acute inflammation model. Inflammatory activity was assessed at 1.5, 3 and 6 h after sub-planter injection of carrageenan (0.1 ml of a 1% solution in 0.85% saline). The anti-inflammatory effect of diclofenac (25 mg/kg, i.p.) was studied in comparison to that of the selective inducible nitric oxide synthase (iNOS) inhibitor, AG, and of nitric oxide donor, sodium nitroprusside (SNP). Results: AG, failed to inhibit inflammation during the first 3 h following carrageenan administration, but caused a slight, although statistically insignificant inhibition at 6 h. Diclofenac significantly reduced the carrageenan-induced edema in rat paw at all the time points studied. Administration of diclofenac after AG pretreatment caused significant (P < 0.001) reduction in edema that was double that of diclofenac alone 6 h after carrageenan injection. Administration of SNP as a single dose after AG pretreatment prevented any potentiation of anti-inflammatory response that was observed in the case of AG combined with diclofenac treatment. Conclusion: These results show that AG markedly potentiates the anti-inflammatory activity of diclofenac at 6 h and this potentiation effect is nitric oxide-dependent.

Protective effect of taurine against cyclophosphamide-induced urinary bladder toxicity in rats

1. In the present study, the effect of taurine, on cyclophosphamide (CP)‐induced urinary bladder toxicity was investigated.

Probucol attenuates oxidative stress, energy starvation, and nitric acid production following transient forebrain ischemia in the rat hippocampus.

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, (NOx) 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 NOx 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.