Azza Baraka

Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial agents

The synthesis of two novel series of structurally related 1H-pyrazolyl derivatives of thiazolo[4,5-d]pyrimidines is described. All the newly synthesised compounds were examined for their in vivo anti-inflammatory activity in two different bioassays namely; cotton pellet-induced granuloma and carrageenan-induced paw edema in rats. The in vitro inhibitory activity of the most active compounds towards human COX-1 and COX-2 enzymes was also estimated. In addition, the ulcerogenic effects and acute toxicity (LD(50)) values of these compounds were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The results revealed that compounds 5a, 9a, 9b, 10b and 12a exhibited anti-inflammatory activity comparable to that of indomethacin in both local and systemic in vivo animal models with no or minimal ulcerogenic effects (0-10%) and high safety margin (LD(50) > 500 mg kg(-1)). In addition, most of them displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 9a and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory activity in addition to their pronounced antibacterial activities comparable to ampicillin against Gram positive and -negative bacteria. Therefore, they are considered as successful dual anti-inflammatory-antimicrobial candidates.

Targeting apoptosis in the heart of streptozotocin-induced diabetic rats.

Objectives: The aim of the current study was to address the issue of cardiomyocyte apoptosis as a possible contributor in the development of diabetic cardiomyopathy and whether it would be possible to suppress this apoptosis by the use of a peroxisome proliferator-activated receptor (PPAR)-α agonist (fenofibrate) or a PPAR-γ agonist (rosiglitazone). Methods: Ten normal male albino rats (group I) were injected intraperitoneally (IP) by a single dose of saline and served as a control for group II. Thirty male albino rats were made diabetic by IP streptozotocin (STZ) injection and were divided into 3 groups: group II (nontreated diabetic rats), groups III and IV (diabetic rats treated with PPAR-γ agonist (rosiglitazone), and PPAR-α agonist (fenofibrate) respectively, for 12 weeks starting 1 week following STZ injection. Results: The studied drugs decreased left ventricular to body weight ratio and cardiac: caspase-3, tumor necrosis factor-α, hydroxyproline, free fatty acids (FFAs) as well as triglycerides (TGs) and improved oxidative stress parameters as well as left ventricular papillary muscle developed tension (DT). Conclusions: The results of the current study support the hypothesis that apoptosis plays a key role in the pathophysiology of diabetic cardiomyopathy and demonstrate that the use of PPAR-α and -γ agonists might have a protective role against diabetic cardiomyopathy.

The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease.

AIM The aim of the present study was to assess and compare the effect of 17β-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochemical alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats. MAIN METHODS 80 female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV-VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17β-estradiol, tamoxifen, raloxifene, PPT and DPN respectively for 5days before 6-OHDA and continued for further 2weeks. KEY FINDINGS Results showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concentrations. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17β-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochemical alterations induced by 6-OHDA. SIGNIFICANCE These findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD.

Cardioprotective Effect of Renalase in 5/6 Nephrectomized Rats

Cardiovascular disease (CVD) remains one of the most common causes of morbidity and mortality in patients with chronic renal disease. It has been recently postulated that the loss or reduced levels of renalase in patients with chronic renal disease are, at least in part, responsible for elevated plasma catecholamine levels, which leads to increased CVD. Therefore, the aim of the present study was to evaluate whether renalase administration might serve as a therapeutic drug, decreasing the severity of CVD in 5/6 nephrectomized (Nx) rats. The current study was conducted on 30 male Wistar albino rats divided into the following groups: group I: sham-operated rats that received phosphate-buffered saline (PBS) subcutaneously (s.c.) for 4 weeks following sham operation, group II: rats in which 5/6 Nx was done and then the rats received PBS daily s.c. for 4 weeks following 5/6 Nx, and group III: rats in which 5/6 Nx was done and then the rats received recombinant renalase daily s.c. for 4 weeks following 5/6 Nx. 5/6 nephrectomy resulted in a significant increase in mean arterial pressure, left ventricular (LV)/body weight ratio, LV hydroxyproline concentration, plasma creatinine, blood urea nitrogen (BUN), and noradrenaline (NA) levels as well as significant decrease in LV papillary muscle developed tension in group II compared with the sham-operated group I. Administration of renalase to group III resulted in significant amelioration of all studied parameters with the exception of plasma creatinine and BUN which were not significantly different from nontreated group II. The results of the current study identify renalase as a new therapeutic modality that might modulate cardiac function and systemic blood pressure in renalase-deficient states like chronic renal disease.

Study of the effect of inhibiting galanin in Alzheimer's disease induced in rats.

It is recently reported that galanin plays a role in memory decline that is the primary behavioral symptom of Alzheimers disease. The aim of the present study was to study the impact of administration of two antidiabetic drugs that might inhibit galanin, namely glibenclamide and pioglitazone, on the behavioral, and neurochemical changes in Alzheimers disease--induced in rats by intracerebroventricular (i.c.v.) injection of beta amyloid (Abeta). The present study was conducted on 60 male Wistar rats that were divided into 6 groups: group I (control group) which received i.c.v. scrambled peptide, group II (i.c.v.-Abeta group) which received i.c.v.-Abeta, groups III and IV that received, respectively, glibenclamide and pioglitazone daily orally for 3 weeks following scrambled peptide administration as well as groups V and VI that received, respectively, glibenclamide and pioglitazone daily orally for 3 weeks following Abeta administration. i.c.v.-Abeta resulted in significant behavioral alterations suggesting Alzheimers disease, where there was significant impairment in spatial cognition, evaluated by Morris water maze task, and in learning and memory performance, assessed using passive-avoidance learning task. i.c.v.-Abeta also resulted in significant increase in hippocampal hyperphosphorylated tau protein as well as galanin. Administration of studied antidiabetic drugs, glibenclamide and pioglitazone, resulted in significant improvement in spatial cognition and in learning and memory performance, as well as significant decrease in hippocampal hyperphosphorylated tau protein and hippocampal galanin. Our findings suggest that a pharmacologic approach to inhibit galanin in the brain, either by glibenclamide or pioglitazone might dramatically improve symptoms in Alzheimers disease.

Role of modulation of vascular endothelial growth factor and tumor necrosis factor-alpha in gastric ulcer healing in diabetic rats

The aim of the present study was to assess the effect of drugs that increase gastric vascular endothelial growth factor (VEGF) and suppress gastric tumor necrosis factor-alpha (TNF-alpha) in gastric ulcer healing in streptozotocin-induced diabetic rats. Sixty male albino rats were made diabetic by intraperitoneal (i.p.) streptozotocin injection and ten rats were injected i.p. by a single dose of saline. Six weeks following streptozotocin or saline injection, gastric ulcers were induced by serosal application of acetic acid. Three days after acetic acid application, rats were divided into: group I (non-diabetic control), group II (streptozotocin-injected), groups III-VII (streptozotocin-injected rats treated with insulin, insulin and pentoxifylline, insulin and simvastatin, pentoxifylline as well as simvastatin, respectively, for 7 days following acetic acid application. The use of insulin, combinations of insulin and pentoxifylline or simvastatin resulted in a significant decrease in gastric ulcer area, significant increase in epithelial regeneration assessed histologically, significant increase in gastric VEGF concentration, and gastric von Willebrand factor (vWF) as well as significant decrease in gastric TNF-alpha. A significant difference in gastric ulcer area as well as in gastric TNF-alpha, VEGF and vWF levels could be observed between rats that received combinations of insulin and pentoxifylline or simvastatin compared to rats that received either drug alone. Our results suggest the feasibility of a novel treatment strategy, namely pentoxifylline and simvastatin, for patients in whom impairment of ulcer healing constitutes a secondary complication of diabetes mellitus.

Do Desipramine [10,11-Dihydro-5-[3-(methylamino) propyl]-5H-dibenz[b,f]azepine monohydrochloride] and Fluoxetine [N-Methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine] Ameliorate the Extent of Colonic Damage Induced by Acetic Acid in Rats?

The present study was designed to compare the anti-inflammatory and antioxidant effects of two antidepressant drugs, desipramine [10,11-dihydro-5-[3-(methylamino) propyl]-5H-dibenz-[b,f]azepine monohydrochloride] and fluoxetine [N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine], administered with variable doses, on experimentally induced colitis in rats. Two doses for each drug (10 and 20 mg/kg/day i.p.) were injected in 48 adult male albino rats for 2 weeks after induction of colitis by intracolonic administration of 2 ml of 3% acetic acid. Several parameters, including macroscopic (ulcer score index) and biochemical such as myeloperoxidase (MPO), reduced glutathione (GSH), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, were measured using standard assay procedures. The study demonstrates that both desipramine and fluoxetine significantly attenuated the extent and the severity of the macroscopic signs of cell damage. Both drugs significantly reduced tissue MPO activity in a dose-dependent manner. Both desipramine and fluoxetine, at either dose, significantly increased GSH in colonic tissue. Desipramine and fluoxetine, at either dose, significantly reduced TNF-α and IL-β. Desipramine at the dose of 20 mg/kg produced more decrease in the level of TNF-α compared with the effect of the smaller dose, but fluoxetine at 10 mg/kg diminished more in the level of IL-1β compared with the effect of the larger dose. The present data indicate that both desipramine and fluoxetine have anti-inflammatory and antioxidants effects in experimentally induced colitis in rats, opening the avenue to their possible protective role in patients with inflammatory bowel disease.

Monosodium glutamate neurotoxicity increases beta amyloid in the rat hippocampus: a potential role for cyclic AMP protein kinase.

BACKGROUND Glutamate excitotoxicity and cyclic AMP-activated protein kinase (AMPK) are both recognized as important mediators in neurodegenerative disorders including Alzheimers disease (AD). OBJECTIVES To investigate whether oral or subcutaneous monosodium glutamate (MSG) neurotoxicity mimics some features of AD and whether these can be reversed by the AMPK activator Pioglitazone. METHODS Male Wistar rats aged 5 weeks were administered oral or subcutaneous MSG for 10 days with or without daily oral Pioglitazone. Two additional groups given only saline orally or subcutaneously acted as controls. At age 10 weeks the rats were subjected to neurobehavioral testing, then sacrificed for measurement of AMPK, β-amyloid and Fas ligand in the hippocampus. RESULTS Oral and subcutaneous MSG both induced a lowering of hippocampal AMPK by 43% and 31% respectively (P<0.05 for both) and >2-fold increase in hippocampal Fas ligand, a mediator of apoptosis (P<0.001 for both). MSG treatment also induced a significant increase in β-amyloid in the hippocampus by >4-fold and >5-fold in the oral and subcutaneous groups. This was associated with increased latency before crossing to the white half in the black-white alley and before the first rear in the holeboard test, suggesting increased anxiety. Pioglitazone decreased hippocampal β-amyloid accumulation and Fas ligand, but did not ameliorate the neurobehavioural deficits induced by MSG. CONCLUSIONS MSG treatment enhances β-amyloid accumulation in the rat hippocampus. Our results suggest a role for AMPK reduction in mediating the neurotoxic effects of glutamate, including β-amyloid accumulation.

Effect of Targeting Mitogen-Activated Protein Kinase on Cardiac Remodeling in Rats

Background: Increasing evidence suggests that the activation of p38 mitogen-activated protein kinase (p38MAPK) plays a role in cardiac remodeling. Targeting p38MAPK using drugs reported to interfere with its phosphorylation, namely statins and all-trans retinoic acid (atRA), might play a role in ameliorating this remodeling. Methods and Results: Cardiac remodeling was induced in male albino rats by chronic inhibition of nitric oxide (NO) synthesis by N-nitro L-arginine methyl ester (L-NAME). Daily oral administration of L-NAME for 4 weeks resulted in the elevation of mean arterial blood pressure (MABP) together with cardiac remodeling evidenced by an increase in left ventricular-body weight ratio together with an increase in cardiac hydroxyproline concentration and a decrease in left ventricular papillary muscle-developed tension. An elevation in cardiac phosphorylated p38MAPK concentration, tumor necrosis factor alpha concentration and in cardiac caspase 3 activity was also observed. Administration of either rosuvastatin or all-trans retinoic acid (atRA), starting 4 weeks after L-NAME administration, ameliorated remodeling and improved all studied parameters. Conclusions: Targeting MAPK might represent a useful therapeutic avenue to ameliorate cardiac remodeling and support the notion that atRA and statins are potential candidates for the prevention and therapy of cardiac remodeling.

β2-adrenoceptor agonists as potential therapeutic drugs in diabetic peripheral neuropathy

OBJECTIVES the aim of the current study was to assess the effect of a β2-adrenoceptor agonist; namely salbutamol, on hyperalgesic as well as nerve dysfunction components of diabetic peripheral neuropathy. MATERIAL AND METHODS the present study was conducted on 60 male Wistar albino rats divided into six groups. Groups I and II were normal control rats injected by a single i.p. injection of normal saline and received 2% gum acacia (Group I) or salbutamol (Group II) for six weeks, starting one week following saline injection. Groups III-VI: rats that were rendered diabetic by a single i.p. injection of STZ and received either 2% gum acacia, salbutamol, salbutamol and propranolol or salbutamol and atenolol, respectively daily orally for six weeks, starting one week following STZ injection. RESULTS vehicle-treated diabetic rats exhibited: significant sciatic nerve dysfunction in the form of significantly prolonged distal latency and significantly decreased maximum peak and peak to peak amplitude of compound muscular action potential, significant thermal and mechanical hyperalgesia evidenced by significant decrease in hot plate latency, tail-flick latency and vocalization threshold, respectively. Salbutamol administration improved nerve dysfunction as well as thermal and mechanical hyperalgesia. These effects of salbutamol are most likely mediated by β2-adrenoceptors evidenced by significant abolishment of salbutamol effects after administration of the non-selective rather than the selective beta blockers; propranolol and atenolol, respectively. CONCLUSIONS chronic administration of salbutamol could ameliorate DPN, an effect which is most likely mediated by β2-adrenoceptors.