Cortical tau burden and behavioural dysfunctions in mice exposed to monosodium glutamate in early life.

Although monosodium glutamate (MSG)-induced neurotoxicity has been recognized for decades, the potential similarities of the MSG model to Alzheimer's disease (AD)-type neuropathology have only recently been investigated. MSG-treated mice were examined behaviourally and histologically in relation to some features of AD. Four-week old mice received 5 subcutaneous MSG (2 g/kg) injections on alternate days, or saline. At age 10-12 weeks, they were given a battery of behavioural tests for species-typical behaviours and working memory. The mice were killed at 12 weeks and the brains excised. Accumulation of hyperphosphorylated tau protein was assessed in cortical and hippocampal neurons by immunohistochemistry, and in cerebral cortical homogenates. A 78% increase in cortical concentrations of phosphorylated tau protein was observed in the MSG mice. Intracellular hyperphosphorylated tau immunostaining was observed diffusely in the cortex and hippocampus, together with cortical atrophic neurons, extensive vacuolation and dysmorphic neuropil suggestive of spongiform neurodegeneration. Nest-building was significantly impaired, and spontaneous T-maze alternation was reduced, suggesting defective short-term working memory. Subcutaneous MSG treatment also induced a 56% reduction in exploratory head dips in a holeboard (P = 0.009), and a non-significant tendency for decreased burrowing behaviour (P = 0.085). These effects occurred in the absence of MSG-induced obesity or gross locomotor deficits. The findings point to subcutaneous MSG administration in early life as a cause of tau pathology and compromised species-typical behaviour in rodents. Determining whether MSG can be useful in modelling AD requires further studies of longer duration and full behavioural characterization.

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 Alzheimer's 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, ß-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 ß-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 ß-amyloid accumulation and Fas ligand, but did not ameliorate the neurobehavioural deficits induced by MSG. CONCLUSIONS: MSG treatment enhances ß-amyloid accumulation in the rat hippocampus. Our results suggest a role for AMPK reduction in mediating the neurotoxic effects of glutamate, including ß-amyloid accumulation.

Role of activation of 5'-adenosine monophosphate-activated protein kinase in gastric ulcer healing in diabetic rats.

BACKGROUND: The potential utility of 5'-adenosine monophosphate-activated protein kinase (AMPK)-activating agents, such as metformin, in inducing angiogenesis, could be a promising approach to promote healing of gastric ulcers complicated by diabetes mellitus. The aim of the present study was to assess the effect of a drug that activates AMPK, namely metformin, in gastric ulcer healing in streptozotocin-induced diabetic rats. METHODS: Forty male Wistar albino rats were made diabetic by intraperitoneal (i.p.) streptozotocin injection and 10 rats were injected i.p. by a single dose of physiological 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 1 (nondiabetic control), group 2 (streptozotocin-injected rats), groups 3-5 (streptozotocin-injected rats treated with metformin or metformin and an inhibitor of AMPK, namely compound C or pioglitazone) for 7 days following acetic acid application. RESULTS: Administration of metformin, but not pioglitazone, resulted in a significant decrease in the gastric ulcer area, a significant increase in epithelial regeneration assessed histologically, a significant increase in the number of microvessels in the ulcer margin, a significant increase in gastric vascular endothelial growth factor concentration and gastric von Willebrand factor as well as a significant increase in gastric phospho-AMPK. Compound C, an inhibitor of AMPK, blocked metformin-induced changes in assessed parameters suggesting that the effect of metformin was mediated mainly through activation of AMPK. CONCLUSION: Our results suggest the feasibility of a novel treatment strategy, namely drugs activating AMPK, for patients in whom impairment of ulcer healing constitutes a secondary complication of diabetes mellitus.

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 17ß-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 17ß-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 17ß-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.

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.

Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promising cardiotonic agents.

In an attempt to design new inotropic drugs for congestive heart failure (CHF) with less proarrhythmic potential, three series of compounds analogous to milrinone were prepared, namely, 4-aryl-6-(4-pyridyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 2a-g, 4-aryl-6-(4-pyridyl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles 3a-g and 2-amino-4-aryl-6-(4-pyridyl)-pyridine-3-carbonitriles 4a-g. The first series was prepared by reacting 4-acetyl pyridine with the appropriate aldehyde, ethyl cyanoacetate and ammonium acetate in ethanol. Reaction of 2a-g with phosphorus pentasulfide afforded the second series 3a-g. The third target compounds 4a-g were prepared applying the same procedure used to synthesize 2a-g using malononitrile instead of ethyl cyanoacetate. All the newly synthesized compounds were evaluated for their cardiotonic activity and their in vivo cardiovascular effects. In addition, their oral and parenteral acute toxicity were determined. Compounds 2a, 2b, 2c, 4c and 4f proved to exert cardiotonic activity comparable to that of milrinone using spontaneously beating atria model from reserpine-treated guinea pigs. In addition these compounds proved to be non-toxic and well tolerated by mice up to 250 mg kg(-1) orally and up to 125 mg kg(-1) through parenteral route.

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.