Sawsan A. Zaitone

Acetyl-l-carnitine and α-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson's disease therapy

Although the mechanisms of neurodegeneration in Parkinsons disease are not fully understood, mitochondrial dysfunction, oxidative stress and environmental toxins may be involved. The current research was directed to investigate the protective role of two bioenergetic antioxidants, acetyl-L-carnitine and α-lipoic acid, in rotenone-parkinsonian rats. Ninety six male rats were divided into five groups. Group I is the vehicle-injected group, group II is the disease control group and was injected with six doses of rotenone (1.5 mg/kg/48 h, s.c.). Groups III, IV and V received rotenone in addition to acetyl-L-carnitine (100 mg/kg/day, p.o.), α-lipoic acid (50 mg/kg/day, p.o.) or their combination, respectively. Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field and square bridge tests. In addition, ATP level was decreased whereas lipid peroxides and protein carbonyls increased in the striata of rotenone-treated rats as compared to vehicle-treated rats. Treatment with acetyl-L-carnitine or α-lipoic acid improved the motor performance and reduced the level of lipid peroxides in rat brains as compared to rotenone group. Further, ATP production was enhanced along with acetyl-L-carnitine treatments (p≤0.05). Taken together, our study reinforces the view that acetyl-L-carnitine and α-lipoic acid are promising candidates for neuroprotection in Parkinsons disease.

Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF.

Several reports highlighted the cardioprotective effect of statins after different types of ischemic injury. We studied the effect of rosuvastatin on acute myocardial infarction induced experimentally in rats focusing on angiogenesis as a potential mechanism underlying the drug effect. Acute myocardial infarction was induced by injecting the rats with two doses of isoproterenol (85 mg/kg/24 h, s.c.). Rats were examined for their electrocardiographic pattern and myocardial fibrosis one week after injection of isoproterenol (time for initiating therapy) and eight weeks thereafter (the end of therapeutic period) to examine the progression of the injury. Examination of the heart tissues at the end of week 9 showed a non significant decrease in the degree of myocardial fibrosis compared to those observed at week 1, indicating a slow rate of recovery from isoproterenol-induced injury. Treatment with rosuvastatin (5 or 10 mg/kg) for 8 weeks in myocardial-infarct rats enhanced the electrocardiographic pattern, reduced serum cardiac biomarkers, reduced tissue tumor necrosis factor-α (TNF-α) and upregulated vascular endothelial growth factor (VEGF) level. In addition, immunohistochemical staining revealed higher expression of inducible nitric oxide synthase (iNOS), VEGF and CD(34) (a marker for microvessel density) in the cardiac tissues after treatment with rosuvastatin compared to control group. The immunostaining for VEGF was positively correlated with microvessel density and iNOS. Overall, the current results provide evidence that the effect of rosuvastatin on myocardial-infarct rats involves induction of angiogenesis.

Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats.

Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done. Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P < 0.05). Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinsons disease.

Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease.

Insulin resistance, oxidative stress and cytokine imbalance are key pathophysiological mechanisms in non-alcoholic fatty liver disease (NAFLD). This study aimed at evaluating the effect of treatment with the insulin sensitizer, pioglitazone, the tumor necrosis factor-α inhibitor, pentoxifylline, and the antioxidant, melatonin and their combinations in rats with NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. For an additional eight weeks, rats were fed the HFD along with pioglitazone, pentoxifylline, melatonin alone or in combination. Liver index and insulin resistance index were calculated. Serum liver enzyme activities, total cholesterol, triglycerides and tumor necrosis factor-α (TNF-α) were determined. Tissue triglycerides, malondialdehyde and reduced glutathione were measured and liver injury was evaluated by histopathological examination. HFD induced severe hepatic steatosis, inflammation and fibrosis. In addition, liver index, insulin resistance index, activities of liver enzymes and serum level of total cholesterol, triglycerides and TNF-α were elevated. This was coupled with an increase in tissue triglycerides, malondialdehyde and depletion of reduced glutathione. Pioglitazone, pentoxifylline and melatonin, alone or in combination; reduced the insulin resistance index, activities of liver enzymes, hepatic malondialdehyde and increased hepatic reduced glutathione level. Pentoxifylline led to a decrease in serum TNF-α level, however, pioglitazone and melatonin reduced serum total cholesterol and triglycerides. In conclusion, data in this study indicate that pentoxifylline and melatonin can be used as promising adjuvant therapies to pioglitazone in the clinical management of NAFLD.

Role of Metformin in Suppressing 1,2-Dimethylhydrazine-Induced Colon Cancer in Diabetic and Non-Diabetic Mice: Effect on Tumor Angiogenesis and Cell Proliferation

Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv–v): metformin (100 or 200 mg/kg) and (vi–vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

Antioxidant potential of melatonin enhances the response to L-dopa in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-parkinsonian mice

BACKGROUND Parkinsons disease is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of dopaminergic neurons in substantia nigra pars compacta, and can be modeled by the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current research was directed to investigate the role of melatonin in preventing the gradual decrease in the response to L-dopa in MPTP-induced parkinsonism in mice. METHODS Eighty four male Swiss mice were divided into seven groups. Group I is the saline group. The other six groups were injected with MPTP (20 mg/kg/2 h). Group II is the MPTP control group. Group III was treated with L-dopa/carbidopa (100/10 mg/kg, po). Group IV and V were treated with melatonin (5 or 10 mg/kg, po), respectively. Group VI and VII received L-dopa/carbidopa in combination with melatonin in the same above-mentioned doses, respectively. RESULTS Results showed that MPTP-treated mice exhibited low striatal dopamine level accompanied by motor impairment and increased oxidative stress. Treatment with L-dopa improved the motor performance of mice. Addition of melatonin to L-dopa therapy improved the motor response to L-dopa and increased striatal dopamine level. This combination reduced lipid peroxidation, ameliorated reduced glutathione and improved antioxidant enzyme activities (p ≤ 0.05). CONCLUSIONS Overall, our study suggests that the antioxidant potential of melatonin makes it a promising candidate to L-dopa in treating Parkinsons disease.

Synthesis and biological evaluation of new pyrazolone-pyridazine conjugates as anti-inflammatory and analgesic agents.

A new series of pyrazolone-pyridazine conjugates 3 and 4a-l were synthesized and characterized by spectroscopic means and elemental analyses. All compounds were tested in vivo for their anti-inflammatory and analgesic properties against diclofenac, as reference compound. The synthesized compounds were also evaluated for their ability to inhibit the production of certain inflammatory cytokines such as TNF-α and IL-6 in serum samples. The ulcerogenic potential of the synthesized compounds was also determined. IC50 values for inhibition of COX-1 and COX-2 enzymes were investigated in vitro for the most active candidates. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Among the synthesized derivatives, compounds 4c and 4e showed good analgesic and anti-inflammatory activities with lower ulcer index than the reference drug.

Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma

This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlichs ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.

Olmesartan potentiates the anti-angiogenic effect of sorafenib in mice bearing Ehrlich's ascites carcinoma: role of angiotensin (1-7).

Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1–7) agonist or an angiotensin (1–7) antagonist in Ehrlichs ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlichs ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1–7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1–7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer.

Addition of a low dose of rimonabant to orlistat therapy decreases weight gain and reduces adiposity in dietary obese rats

The aim of the present study was to determine whether the addition of a subeffective dose of rimonabant (1 mg/kg) to orlistat would be beneficial in the treatment of diet‐induced obesity in rats compared with orlistat monotherapy. Male rats were divided into five groups: (i) rats fed a low‐fat diet for 4 months; (ii) rats fed a high‐fat diet (HFD) for 4 months and treated daily with vehicle (0.2% Tween‐80 solution); (iii) orlistat (10 mg/kg per day)‐treated HFD‐fed rats; (iv) rimonabant (1 mg/kg per day)‐treated HFD‐fed rats; and (v) HFD‐fed rats treated with a combination of orlistat plus rimonabant. Fasting blood glucose, serum insulin, leptin and adiponectin levels were measured. Liver and adiposity indices were calculated and liver and adipose tissues were processed for histological examination. Over the 4 months of the study, vehicle‐treated HFD‐fed rats exhibited increased cumulative food intake, bodyweight and liver and adiposity indices. Moreover, vehicle‐treated HFD‐fed rats exhibited a deterioration in liver function and an abnormal lipid profile. Insulin resistance and serum leptin were increased in this group, whereas serum adiponectin levels were decreased. Orlistat monotherapy or combination therapy with orlistat plus rimonabant improved all these parameters. The addition of the low subeffective dose of rimonabant to orlistat therapy ameliorated HFD‐induced obesity to a much greater extent than orlistat monotherapy. This combination showed better weight control and metabolic profile compared with orlistat alone. Therefore, the results of the present study encourage reassessment of the use of a low dose of rimonabant to potentiate the effect of orlistat in the clinical management of obesity if proper clinical safety data are available.