ABSTRACT
Aluminum (Al) has been identified as a potential contributing factor in the etiology of several neurodegenerative disorders, but data regarding specific effects on neurotransduction, especially on dopaminergic neurotransduction, are lacking. The objective of this study was to determine the extent of expressional alterations in dopamine receptors (DRs) in two dopaminergic subtypes, D1 and D2, in low and high dose Al-treated mice. After administration of Al (four intraperitoneal injections of 30 or 60 mg/kg AlCl3.6H2O at 2 h intervals), expression of the dopamine D1-like and D2-like receptors (DRD1, DRD2) was examined in the cortex and striatum of mouse brain at bregma levels of 1.10, -0.10 and -1.34 mm. In the cortex, Al treatment decreased densities of DRD1 and DRD2 in a dose-dependent manner at all three bregma levels, especially in the high-dose Al group. Similarly, DRD1 and DRD2 expression in the striatum also exhibited dose dependency and statistically significant decreases were seen in the high-dose group, except in the striatum at bregma level - 1.34. These findings suggest that DR in the caudal striatum is more resistant to the effects of Al exposure than DR in the cortex or rostral striatum. In addition, our results suggest that disturbance of dopaminergic neurotransmission mediated by DRD1 and/or DRD2 may be involved in the pathogenesis of Al neurotoxicity.
Subject(s)
Aluminum Compounds/toxicity , Basal Ganglia/drug effects , Cerebral Cortex/drug effects , Chlorides/toxicity , Environmental Pollutants/toxicity , Receptors, Dopamine D1/drug effects , Receptors, Dopamine D2/drug effects , Aluminum Chloride , Aluminum Compounds/administration & dosage , Animals , Basal Ganglia/metabolism , Cerebral Cortex/metabolism , Chlorides/administration & dosage , Dose-Response Relationship, Drug , Down-Regulation , Environmental Pollutants/administration & dosage , Immunohistochemistry , Injections, Intraperitoneal , Male , Mice , Mice, Inbred C57BL , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolismABSTRACT
Diallyl disulfide (DADS) is one of the organosulfur compounds of garlic. The effects of DADS on neuronal cells have not clearly been established. We investigated its effects on the viability of neuronal cells (N18D3 cells), the levels of free radical and membrane lipid peroxidation, and the cell signals, such as phosphatidylinositol 3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3). When N18D3 cells were treated with several concentrations of DADS, the viability was not affected up to 25 microM, however, decreased at higher than 25 microM. The levels of free radicals and membrane lipid peroxidation were increased in a dose-dependent manner, especially at higher than 25 microM. The treatment of N18D3 cells with 25 microM DADS slightly increased the expressions of p85a PI3K, phosphorylated Akt and phosphorylated GSK-3, but the treatment with 100 microM significantly reduced them. To evaluate whether low concentration of DADS, up to 25 microM, had protective effect on oxidative stress-injured N18D3 cells, the viability of N18D3 cells (pretreated with DADS for 2h versus not pretreated) was evaluated 24h after their exposure to 100 microM H(2)O(2) for 30 min. Compared to the cells treated with only 100 microM H(2)O(2), the pretreatment with 25 microM DADS increased the viability, and the expressions of p85a PI3K, phosphorylated Akt and phosphorylated GSK-3. These results indicate that low concentration of DADS has protective effects on N18D3 cells, whereas high concentration is rather cytotoxic. Therefore, some specific optimum concentration of DADS may be a new potential therapeutic strategy for oxidative stress-injury in vitro model of neurodegenerative diseases.
Subject(s)
Allyl Compounds/pharmacology , Disulfides/pharmacology , Neurons/drug effects , Allyl Compounds/administration & dosage , Animals , Apoptosis/drug effects , Blotting, Western , Cell Differentiation/drug effects , Cell Line , Cell Survival/drug effects , Disulfides/administration & dosage , Dose-Response Relationship, Drug , Fluorescent Dyes , Free Radical Scavengers , Free Radicals/metabolism , Glycogen Synthase Kinase 3 , Indoles , Lipid Peroxidation/drug effects , Membrane Lipids/metabolism , Mice , Mice, Inbred BALB C , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Tetrazolium Salts , Thiazoles , Trypan BlueABSTRACT
3-monochloro-1,2-propanediol (3-MCPD) is a contaminant of acid-hydrolyzed vegetable protein. Several reports have suggested that chronic exposure to 3-MCPD could produce neurotoxicity in vitro or neurobehavioral effects in experimental animals. The present study further explored the in vitro neurotoxic effects of 0.1-100 microM 3-MCPD on PC12 and N18D3 cell lines. In addition, to investigate the effects of repeated ingestion of 3-MCPD on neurobehavioral impairments parameters in rats, motor activity, landing foot splay, and grip strength tests were performed, following treatment with 3-MCPD at dose levels of 10, 20, and 30 mg/kg per day for 11 weeks. We demonstrated that no significant neurotoxic effects were present in 3-MCPD-treated rats compared to saline-treated control rats, whereas, acrylamide, used as a positive control, induced significant deficits in all neurobehavioral parameters in both male and female rats. On the other hand, body weight gain was significantly decreased in high dose 3-MCPD-treated male rats as well as in acrylamide-treated rats. Taken together, these results suggest that 3-MCPD, at the dose levels used for this study, does not produce in vitro neurotoxicity or neuromotor deficits in vivo.
