Biomedical subjects

V Sava

Publications and source records attributed to V Sava.

18 recordsLinked to original sources

PubMed2006

Can low level exposure to ochratoxin-A cause parkinsonism?

Mycotoxins are fungal metabolites with pharmacological activities that have been utilized in the production of antibiotics, growth promoters, and other classes of drugs. Some mycotoxins have been developed as biological and chemical warfare agents. Bombs and ballistic missiles loaded with aflatoxin were stockpiled and may have been deployed by Iraq during the first Gulf War. In light of the excess incidence of amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert Storm, the potential for delayed neurotoxic effects of low doses of mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common mycotoxin with complex mechanisms of action, similar to that of the aflatoxins. Acute administration of OTA at non-lethal doses (10% of the LD(50)) have been shown to increase oxidative DNA damage in brain up to 72 h, with peak effects noted at 24 h in midbrain (MB), caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and its metabolites in the striatum (e.g., CP) were shown to be decreased in a dose-dependent manner. The present study focused on the effects of chronic low dose OTA exposure on regional brain oxidative stress and striatal DA metabolism. Continuous administration of low doses of OTA with implanted subcutaneous Alzet minipumps caused a small but significant decrease in striatal DA levels and an upregulation of anti-oxidative systems and DNA repair. It is possible that low dose exposure to OTA will result in an earlier onset of parkinsonism when normal age-dependent decline in striatal DA levels are superimposed on the mycotoxin-induced lesion.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Neuroanatomical mapping of DNA repair and antioxidative responses in mouse brain: Effects of a single dose of MPTP.

The primary objective of this study was to map the normal distribution of the base excision enzyme oxyguanosine glycosylase (OGG1) across mouse-brain regions as a prelude to assessing the effects of various neurotoxicants, ranging from highly selective molecules like MPTP to more global toxic agents. This research is based on the hypothesis that regional brain vulnerability to a toxicant is determined, in part, by variation in the intrinsic capacity of cellular populations to successfully repair oxidative DNA damage. After mapping the normal distributions of OGG1 and superoxide dismutase (SOD) across 44 loci dissected from mouse brain, MPTP, a mitochondrial toxicant with selective dopamine (DA) neuron cytotoxicity was used to elicit focal oxidative stress and DNA repair responses. A single dose of MPTP (20mg/kg, i.p.) elicited time- and region-dependent changes in both SOD and OGG1, with early increases in DNA repair and anti-oxidant activities throughout all regions of brain. In some sampled loci, notably the substantia nigra (SN) and hippocampus, the heightened DNA repair and antioxidant responses were not maintained beyond 48h. Other loci from cerebellum, cerebral cortex and pons maintained high levels of activity up to 72h. Levels of dopamine (DA) were decreased significantly at all time points and remained below control levels in nigro-striatal and mesolimbic systems (ventral tegmental area and nucleus accumbens). Assessment of apoptosis by TUNEL staining revealed a significant increase in number of apoptotic nuclei in the substantia nigra at 72h and not in other loci. The marked degree of apoptosis that became evident in SN at 72h was associated with large decreases in SOD and DNA repair activity at that locus. In conclusion, MPTP elicited global effects on DNA repair and antioxidant activity in all regions of brain, but the most vulnerable loci were unable to maintain elevated DNA repair and antioxidant responses.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

Acute neurotoxic effects of the fungal metabolite ochratoxin-A.

Ochratoxin-A (OTA) is a fungal metabolite with potential toxic effects on the central nervous system that have not yet been fully characterized. OTA has complex mechanisms of action that include evocation of oxidative stress, bioenergetic compromise, inhibition of protein synthesis, production of DNA single-strand breaks and formation of OTA-DNA adducts. The time course of acute effects of OTA were investigated in the context of DNA damage, DNA repair and global oxidative stress across six brain regions. Oxidative DNA damage, as measured with the "comet assay", was significantly increased in the six brain regions at all time points up to 72 h, with peak effects noted at 24 h in midbrain (MB), CP (caudate/putamen) and HP (hippocampus). Oxidative DNA repair activity (oxyguanosine glycosylase or OGG1) was inhibited in all regions at 6 h, but recovered to control levels in cerebellum (CB) by 72 h, and showed a trend to recovery in other regions of brain. Other indices of oxidative stress were also elevated. Lipid peroxidation and superoxide dismutase (SOD) increased over time throughout the brain. In light of the known vulnerability of the nigro-striatal dopaminergic neurons to oxidative stress, levels of striatal dopamine (DA) and its metabolites were also measured. Administration of OTA (0-6 mg/kg i.p.) to mice resulted in a dose-dependent decrease in striatal DA content and turnover with an ED50 of 3.2 mg/kg. A single dose of 3.5 mg/kg decreased the intensity of tyrosine hydroxylase immunoreactivity (TH(+)) in fibers of striatum, TH(+) cells in substantia nigra (SN) and TH(+) cells of the locus ceruleus. TUNEL staining did not reveal apoptotic profiles in MB, CP or in other brain regions and did not alter DARPP32 immunoreactivity in striatum. In conclusion, OTA caused acute depletion of striatal DA on a background of globally increased oxidative stress and transient inhibition of oxidative DNA repair.

Animals↗

PubMed2004

Rubratoxin B elicits antioxidative and DNA repair responses in mouse brain.

Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not yet been characterized. Based on existing evidence that RB interferes with mitochondrial electron transport to produce oxidative stress in peripheral tissues, we hypothesized that RB would produce oxidative damage to macromolecules in specific brain regions. Parameters of oxidative DNA damage and repair, lipid peroxidation, and superoxide dismutase (SOD) activity were measured across six mouse brain regions 24 h after administration of a single dose of RB. Lipid peroxidation and oxidative DNA damage were either unchanged or decreased in all brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant with these decreased indices of oxidative macromolecular damage, SOD activity was significantly increased in all brain regions. Oxyguanosine glycosylase activity (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased in three brain regions--cerebellum (CB), caudate/putamen (CP), and cortex (CX)--but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB-enhanced OGG1 catalytic activity in these brain regions was not due to increased OGG1 protein expression, but was a result of enhanced catalytic activity of the enzyme. In conclusion, specific brain regions responded to an acute dose of RB by significantly altering SOD and OGG1 activities to maintain the degree of oxidative DNA damage equal to, or less than, that of normal steady-state levels.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1999

Synthesis of 3-aryl-1-[(4-phenyl-1-piperazinyl)butyl]indazole derivatives and their affinity to 5-HT1A serotonin and dopamine D1 receptors.

Eight 3-arylindazole derivatives have been synthesized and their affinity to 5-HT1A serotonin and D1 dopamine receptors was investigated by radioligand analysis. Quantitative structure-activity relationships were studied using the Free-Wilson model. An increase in affinity to dopamine D1 receptors within substituents Br > Cl > CH3 at the 5-position of the 3-arylindazole molecule has been observed. Addition of a chlorine atom to the ortho-position the of phenyl ring let to even highest activity. Replacement of the hydrogen atom at the first position of the 3-arylindazole on the (phenylpiperazine)butyl substituent caused an increase of affinity and did not change the trends of affinity dependence on structure. An inverse dependence on the structure of the studied compounds was observed for the serotonin 5-HT1A receptors. Compounds containing a methyl group at the 5-position of molecule were more active than compounds containing halogens. A chlorine atom at the ortho-position of the phenyl ring decreased affinity. Replacement of the hydrogen atom at the first position of the molecule on the phenylpiperazine)butyl substituent led to an increase in affinity. Selectivity of the studied compounds varied within a wide range. Generally, the presence of the 3-aryl-indazole fragment in the new buspirone analogues increased their affinity to dopamine receptors and reduced their affinity to serotonin receptors. Compounds containing a bromine atom in the 3-arylindazole moiety may be promising ligands for D1 receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1975