Phosphodiesterase (1, 3 & 5) inhibitors attenuate diclofenac-induced acute kidney toxicity in rats.

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.

New insights into the effects of vinpocetine against neurobehavioral comorbidities in a rat model of temporal lobe epilepsy via the downregulation of the hippocampal PI3K/mTOR signalling pathway.

OBJECTIVES: As one of the most frequent worldwide neurological disorders, epilepsy is an alteration of the central nervous system (CNS) characterized by abnormal increases in neuronal electrical activity. The mammalian target of rapamycin (mTOR) signalling pathway has been investigated as an interesting objective in epilepsy research. Vinpocetine (VNP), a synthesized derivative of the apovincamine alkaloid, has been used in different cerebrovascular disorders. This study aimed to examine the modulatory effects of VNP on neurobehavioral comorbidities via the mTOR signalling pathway in a lithium-pilocarpine (Li-Pil) rat model of seizures. METHODS: In male Wistar rats, seizures were induced with a single administration of pilocarpine (60 mg/kg; i.p.) 20 hours after the delivery of a single dose of lithium (3 mEq/kg; i.p.). VNP (10 mg/kg; i.p.) was administered daily for 14 consecutive days before Li-Pil administration. KEY FINDINGS: VNP had a protective effect against Li-Pil-induced seizures. VNP improved both the locomotor and cognitive abilities, moreover, VNP exerted a neuroprotective action, as verified histologically and by its inhibitory effects on hippocampal glutamate excitotoxicity, mTOR pathway, and inflammatory and apoptotic parameters. CONCLUSIONS: VNP is a valuable candidate for epilepsy therapy via its modulation of the mechanisms underlying epileptogenesis with emphasis on its modulatory effect on mTOR signalling pathway.

Low dose gamma irradiation attenuates cyclophosphamide-induced cardiotoxicity in rats: role of NF-κB signaling pathway.

PURPOSE: Cyclophosphamide (Cyp) is one of the most commonly used, wide spectrum chemotherapeutic agents. Cyp has multi-organ toxicities that are dose limiting, thus it's mostly used in chemotherapeutic combinations. Radiation is well known as a hazardous sort of energy, recent studies are interested in studying the beneficial therapeutic effects of low-dose gamma radiation. This study examined the protective effect of two different doses/dose-rates of irradiation either alone or combined with telmisartan against Cyp-induced cardiotoxicity. MATERIALS AND METHODS: Rats were divided into seven groups; (1): Control, (2): Cyp, (3-4): 0.05 Gy low dose rate (LDR) irradiation, 0.25 Gy high dose rate (HDR) irradiation, respectively, prior to Cyp dose, (5-7): telmisartan either alone or with 0.05 Gy LDR-irradiation or 0.25 Gy HDR-irradiation, respectively, prior to Cyp dose. The current investigation studied the effect of Cyp alone or combined with different treatment regimens on serum cTn-I and LDH, nuclear factor-κB (NF-κB) pathway (p65/IκB/IKK-α/IKK-ß) in the myocardium. Pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were assessed in addition to histopathological examination of the heart. RESULTS: Low-dose irradiation attenuated cardiac enzymes, pro-inflammatory cytokines, NF-κB content, and histology, in both low and HDRs. Furthermore, the combination of low-dose irradiation with telmisartan (an angiotensin-II receptor type-1 blocker and a known cardio-protective drug) offered the best histological results. CONCLUSIONS: Low-dose irradiation-induced amelioration is partially but not completely through canonical activation of NF-κB, and may have another atypical pathway. While telmisartan probably ameliorates NF-κB totally through canonical pathway.

Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats.

Liver fibrosis is one of the most serious conditions affecting patients worldwide. In the present study, the role of nitric oxide and KATP channel was investigated for the first time in the possible protection mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. Nicorandil (3 mg/kg/day) was given orally 24 h after bile duct ligation for 14 days till the end of the experiment. Nicorandil group showed marked improvement in liver function tests, hepatic oxidative stress and inflammatory markers as well as inducible and endothelial nitric oxide synthase protein expressions. Furthermore, nicorandil administration led to significant decrement of phosphorylated protein kinase C, fibrosis and hepatic stellate cells activation as indicated by decreased alpha smooth muscle actin expression. Oral co-administration of glibenclamide (5 mg/kg/day) (a KATP channel blocker) with nicorandil mostly showed similar improvement though not reaching to that of nicorandil group. However, co-adminstration of L-NAME (15 mg/kg/day) (an inhibitor of nitric oxide synthase) completely abolished the protective effects of nicorandil and produced more or less similar results to that of untreated bile duct ligated group. In conclusion, nicorandil is an effective therapy against the development of bile duct ligation-induced liver fibrosis in rats where nitric oxide plays a more prominent role in the protective effect of nicorandil than KATP channel opening.

A multicentre integration of a computer-led follow-up of prostate cancer is valid and safe.

OBJECTIVE: To test a computer-led follow-up service for prostate cancer in two UK hospitals; the testing aimed to validate the computer expert system in making clinical decisions according to the individual patient's clinical need with a valid model accurately identify patients with disease recurrence or treatment failure based on their blood test and clinical picture. PATIENTS AND METHODS: A clinical-decision support system (CDSS) was developed from European (European Association of Urology) and national (National Institute for Health and Care Excellence) guidelines along with knowledge acquired from Urologists. This model was then applied in two UK hospitals to review patients after prostate cancer treatment. These patients' data (n = 200) were then reviewed by two independent urology consultants (blinded from the CDSS and the other consultant's rating) and the agreement was calculated by kappa statistics for validation. The second endpoint was to verify the system by estimating the system reliability. RESULTS: The two individual urology consultants identified 12% and 15% of the patients to have potential disease progression and recommended their referral to urology care. The kappa coefficient for the agreement between the CDSS and the two consultants was 0.81 (P < 0.001) and 0.84 (P < 0.001). The agreement amongst both specialist was also high with k = 0.83 (P < 0.001). The system reliability was estimated on all cases and this demonstrated 100% repeatability of the decisions. CONCLUSION: A CDSS follow-up is a valid model for providing safe follow-up for prostate cancer.

Evaluation of the relaxant effect of levetiracetam on isolated rat duodenum.

Levetiracetam (LEV) is an approved drug for the treatment of some epileptic disorders. With few and controversial reports addressing its possible pharmacodynamic interactions, the current study aimed at studying the effect of LEV on isolated rat duodenal strips to enlighten its possible intestinal adverse effects using the isolated smooth muscle strips of rat duodenum. LEV showed a dose-dependent inhibition in KCl (80 mm)-induced contractions in normal Tyrode's solution. Moreover, preincubation with LEV (3 mm) in K+ -rich/Ca2+ -free medium led to a significant decrease in the maximum contractions (Emax ) coupled to a right shift of the cumulative CaCl2 concentration curves implying a possible Ca2+ channel blocking potential. In addition, LEV exhibited a typical noncompetitive inhibition in the cumulative carbachol concentration curves evidenced as a decrease in Emax without the alteration of EC50 , thus eliminating any possible role of the muscarinic receptors in the relaxant effect. To rule out other possible relaxant mechanisms, tests were conveyed in Tyrode's solution containing either 100 µm l-NAME or 10 µm glimepiride to test the possible relaxant roles exhibited by nitric oxide (NO) and KATP channel opening, respectively. None of the tested pathways was involved in LEV-mediated relaxation. Taken altogether, the results of the current study entail that LEV might exert a relaxant effect on intestinal smooth muscles through blocking L-type voltage-operated calcium channels, but not involving either NO release or KATP channel opening.

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson's Disease: Modulation of Mitochondrial Perturbations.

The recent emergence of ursodeoxycholic acid (UDCA) as a contender in modifying neurotoxicity in human dopaminergic cells as well as its recognized anti-apoptotic and anti-inflammatory potentials in various hepatic pathologies raised impetus in investigating its anti-parkinsonian effect in rat rotenone model. UDCA prominently improved motor performance in the open field test and halted the decline in the striatal dopamine content. Meanwhile, it improved mitochondrial function as verified by elevation of ATP associated with preservation of mitochondrial integrity as portrayed in the electron microscope examination. In addition, through its anti-inflammatory potential, UDCA reduced the rotenone-induced nuclear factor-κB expression and tumor necrosis factor alpha level. Furthermore, UDCA amended alterations in Bax and Bcl-2 and reduced the activities of caspase-8, caspase-9, and caspase-3, indicating that it suppressed rotenone-induced apoptosis via modulating both intrinsic and extrinsic pathways. In conclusion, UDCA can be introduced as a novel approach for the management of Parkinson's disease via anti-apoptotic and anti-inflammatory mechanisms. These effects are probably linked to dopamine synthesis and mitochondrial regulation.

Comparative study on induction and effects of surgical menopause in a female rat model: a prospective case control study.

OBJECTIVE: To compare induced surgical menopause in rat models following hysterectomy with ovarian preservation, unilateral or bilateral oophorectomy, versus control. Secondary objective was evaluation of certain physiological changes in the animal following the induced menopause. DESIGN: A prospective case control study. SETTING: University Research Centre. METHODOLOGY: 80 female rats were divided into four groups (n=20). HG: hysterectomy with ovarian preservation, UOG: unilateral oophorectomy, BOG: bilateral oophorectomy and CG: control rats. Blood tests were done at day 0, one week and one month post-procedure for hormonal profile including FSH and E2, and lipid profile including cholesterol, LDL and HDL. Behavioral tests (Learning and memory tests) were also done. RESULTS: Menopause was successfully induced by the three used surgical methods. After one week, no significant difference in FSH level between CG and HG. But its level was significantly increased in BOG and UOG. E2 level was significantly decreased in HG, UOG and BOG in comparison to CG. Its level in BOG was significantly lower than that of UOG and HG. Cholesterol level was significantly higher in HG, UOG and BOG in comparison to CG, also its level was significantly increased in UOG and BOG in comparison to HG (P<0.001). Long term memory was affected in BOG and UOG, one week and one month post-menopausal induction in comparison to the control. CONCLUSION: surgical menopause, induced by hysterectomy alone, unilateral, or bilateral oophorectomy has a negative impact on reproductive hormonal function, as well as cognitive & cardiovascular integrity. We suggest a possibility of early ovarian failure after hysterectomy alone or with unilateral oophorectomy.

Sulforaphane increases the survival rate in rats with fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide.

Fulminant hepatic failure (FHF) is a life-threatening clinical syndrome, with liver transplantation being the only effective therapy. Sulforaphane (SFN) is a natural compound that is extracted from cruciferous vegetables and possesses potent anti-inflammatory, antioxidant, and anticancer activities. This study was designed to test the hypothesis that SFN (3 mg/kg) may protect against FHF induced in rats by administering a combination of D-galactosamine (GalN; 300 mg/kg) and lipopolysaccharide (LPS; 30 µg/kg). The rats were given a single intraperitoneal injection of SFN, 1 hour before the FHF induction. Sulforaphane reduced the mortality and alleviated the pathological liver injury. In addition, SFN significantly reduced the increase in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in the GalN/LPS group, and this decrease was attenuated by SFN. Increases in serum tumor necrosis factor α, interleukin-6, and interleukin-10, which were observed in GalN/LPS-treated rats, were significantly reduced after using SFN. The GalN/LPS treatment increased the expression of superoxide dismutase-1, glutathione peroxidase 2, catalase, and heme oxygenase-1 genes. Sulforaphane inhibited the induction of reactive oxygen species scavenging proteins. Moreover, SFN inhibited GalN/LPS-induced caspase-3 activation and suppressed FAS and FASL expression. These findings suggest that SFN alleviates GalN/LPS-induced liver injury, possibly by exerting antioxidant, anti-inflammatory, and antiapoptotic effects and modulating certain antioxidant defense enzymes.

Potential protective effect of taurine against dibromoacetonitrile-induced neurotoxicity in rats.

Dibromoacetonitrile (DBAN) is a disinfection by-product of water chlorination. Epidemiological studies indicate that it might present a potential hazard to human health. The present study aimed to investigate the possible neurotoxicity of DBAN in rats and possible protection by taurine. Based on initial dose-response experiment, DBAN (60 mg/kg) was administrated orally for 7 days. DBAN administration significantly impaired behavior of rats. Further, DBAN produced significant decrease of monoamines, γ-aminobutyric acid (GABA), glutamate contents, acetylcholinestrase (AChE) and aspartate aminotransferase (AST) activities, in rat brain. On the other hand, a significant increase in malondialdehyde (MDA), nitric oxide (NO) contents and lactic dehydrogenase (LDH) activity was observed. Co-administration of taurine (200mg/kg, i.p.) with DBAN mitigated most tested parameters. In conclusion, the present study indicates that DBAN has the propensity to cause significant oxidative damage in rat brain. However, taurine has a promising role in attenuating the obtained hazardous effects of DBAN.

Cardioprotective effects of ozone oxidative preconditioning in an in vivo model of ischemia/reperfusion injury in rats.

BACKGROUND: Several studies have demonstrated the beneficial effects of ozone oxidative preconditioning in several pathologies characterized by cellular oxidative and inflammatory burden. The present study was designed to investigate the cardioprotective effects of oxidative preconditioning in ischemia/reperfusion (I/R) injury. METHODS: Rats were randomly assigned into five groups. Groups 1 and 2 were normal and I/R groups, respectively. Two of the other groups received two different doses of ozone therapies by rectal insufflations. The last group received vehicle (oxygen). Rats were subjected to myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects. RESULTS: Both doses of ozone therapy were equally protective in reducing CK-MB release. However, the higher dose was more effective in reducing oxidative stress, lactate accumulation, elevated MPO activity and plasma NO(x) as well as preserving myocardial adenine nucleotides. Histological examination also revealed better improvement with a higher dose of ozone therapy compared to the I/R group. CONCLUSION: Ozone therapy can afford significant cardioprotection against biochemical and histological changes associated with I/R injury.

Comparative study of the cardioprotective effects of local and remote preconditioning in ischemia/reperfusion injury.

AIMS: Though the cardioprotective effects of local or remote preconditioning have been estimated, it is still unclear which of them is more reliable and provides more cardioprotection. The present investigation was directed to compare, in one study, the cardioprotective effects of different cycles of local or remote preconditioning in ischemia/reperfusion (I/R)-induced electrophysiological, biochemical and histological changes in rats. MAIN METHODS: Rats were randomly assigned into 10 groups. Groups 1 and 2 were normal and I/R groups, respectively. Other groups were subjected to 1, 2, 3, 4 cycles of local or remote preconditioning before myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects of the effective cycle of local or remote preconditioning. KEY FINDINGS: In general, local preconditioning was more effective than remote preconditioning in reducing ventricular arrhythmias, CK-MB release, lactate accumulation and elevated MPO activity as well as preserving adenine nucleotides. Concerning the most effective group in each therapy, 3 cycles of local preconditioning provided more cardioprotection than that of remote preconditioning in the histological examination. SIGNIFICANCE: Despite being invasive, local preconditioning provided more effective cardioprotection than remote preconditioning in ameliorating the overall electrophysiological, biochemical and histological changes.

Dietary honey and ginseng protect against carbon tetrachloride-induced hepatonephrotoxicity in rats.

Liver diseases are amongst the most serious health problems in the world today and hepatocellular carcinoma is one of the world's deadliest cancers. The aim of the current study was to evaluate the protective effect of sider honey and/or Korean ginseng extract (KGE) against carbon tetrachloride (CCl(4))-induced hepato-nephrotoxicity in rat. Eighty male Sprague-Dawley (SD) rats were allocated into different groups and over a 4-week period, they orally received honey and/or KGE or were treated either with CCl(4) alone (100 mg/kg b.w) or with CCl(4) after a pretreatment period with honey, KGE or a combination of both. Clinical, clinico-pathological and histopathological evaluations were done and CCl(4)-treated groups were compared with rats receiving no treatment and with rats given honey, KGE or a combination of these substances. The results indicated that oral administration of CCl(4) induced severe hepatic and kidney injury associated with oxidative stress. The combined treatment with CCl(4) plus honey and/or KGE resulted in a significant improvement in all evaluated parameters. This improvement was prominent in the group receiving CCl(4) after combined pretreatment with honey and KGE. Animals receiving honey and/or KGE (without CCl(4)-treatment) were comparable to the control untreated group. It could be concluded that honey and KGE protect SD rats against the severe CCl(4)-induced hepatic and renal toxic effects. Our results suggest that the protective activity of honey and KGE may have been related to their antioxidant properties.

Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats.

The present investigation was designed to study the cardioprotective effects of nicorandil and pioglitazone preconditioning in myocardial ischemia/reperfusion-induced hemodynamic, biochemical and histological changes in rats. Oral doses of nicorandil (3 or 6 mg/kg) and pioglitazone (10 or 20mg/kg) were administered once daily for 5 consecutive days. Rats were then subjected to myocardial ischemia/reperfusion (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, plasma creatine kinase-MB activity and total nitrate/nitrite were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances, reduced glutathione and myeloperoxidase activity were estimated in the heart left ventricle. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Nicorandil (3 or 6 mg/kg) was effective in attenuating the ischemia/reperfusion-induced ventricular arrhythmias, creatine kinase-MB release, lactate accumulation and oxidative stress. Nicorandil (3 mg/kg) was more effective in improving the energy production and lowering the elevated myeloperoxidase activity. Both doses of pioglitazone (10 or 20 mg/kg) were equally effective in reducing lactate accumulation and completely counteracting the oxidative stress. Pioglitazone (10 mg/kg) was more effective in improving energy production and reducing ventricular arrhythmias, plasma creatine kinase-MB release and total nitrate/nitrite. It seems that selective mitochondrial K(ATP) channel opening by lower doses of nicorandil and pioglitazone in the present study provided more cardioprotection against ventricular arrhythmias and biochemical changes induced by ischemia/reperfusion. Histological examination revealed also better improvement by the lower dose of nicorandil than that of pioglitazone.

Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats.

OBJECTIVES: To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischaemia/reperfusion-induced functional, metabolic and cellular alterations in rats. METHODS: Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35(min)/10(min)). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO(x)) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. KEY FINDINGS: Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO(x) contents. CONCLUSION: Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.

Laparoscopic excision of large ovarian cysts.

OBJECTIVE: The aim of this study was to check the ability of operative laparoscopy to help in the management of large ovarian cysts that may reach above the level of the umbilicus. MATERIAL AND METHODS: Fifteen cases of large ovarian cysts reaching above the level of the umbilicus were chosen. Clinical and ultrasonic diagnosis denied any signs of malignancy. Pneumoperitoneum and a 5 mm trocar were inserted safely in the left midclavicular line below the ninth costal margin. This trocar allowed us to inspect the peritoneal cavity thoroughly. Another 5 mm trocar was inserted suprapubically in the contralateral side of the cyst and better inspection of the cyst and peritoneal cavity was then done. In the case of an apparently benign cyst, aspiration of the cyst fluid was done after puncturing its wall, then the cyst was removed as usual. RESULTS: In all of these cases, there was no laparoconversion and no other complications were recorded. Nine cases were mucinous and six were serous cystadenomas. The mean operation time was 53.66 +/- 14.7 min. CONCLUSION: Laparoscopic excision of large ovarian cysts is possible, and safe in suitable conditions, with immediate laparoconversion at hand at any time.