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V Kostic

Publications and source records attributed to V Kostic.

At least 19 recordsLinked to original sources
PubMed2002

Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients.

Levels of the potent pro-inflammatory prostaglandin E(2) (PGE(2)) are elevated in postmortem spinal cords from patients with ALS, and inhibition of a key PGE(2)-synthesizing enzyme, cylcooxygenase-2, is neuroprotective in an in vitro model of ALS. The authors report that 82% of the patients with ALS studied had 2 to 10 times higher PGE(2) levels in CSF compared with normal control subjects. That affected areas of the CNS are inflamed in ALS supports this. CSF PGE(2) measurement may be useful in monitoring treatment for ALS.

Adult↗
PubMed2002

Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University.

OBJECTIVES: To determine prevalence and characteristics of menstrually related migraine and nonmigraine headache in female students of Belgrade University. METHODS: A questionnaire was administered to female students during randomly selected classes of the Schools of Medicine and Pharmacy. Diagnoses were assigned according to the criteria of the International Headache Society and MacGregor's stricter definition of "menstrual" migraine. RESULTS: Of 1943 female students (18 to 28 years old), 1298 (66.8%) had primary headaches. Among 1298 students with headache, 245 (12.6%) had migraine and 1053 (54.2%) had nonmigraine headache. The prevalence rates of migraine versus nonmigraine headache in relation to the menstrual cycle were: premenstrual, 0.9% versus 4.4%; menstrual, 1.5% versus 1.5%; menstrually associated, 6.1% versus 10.1%; menstrually unchanged, 2.7% versus 19.2%; and menstrually unrelated, 1.4% versus 18.9%. Female students with migraine had menstrually related attacks more frequently than students with nonmigraine headache (67.7% versus 29.5%). This difference was most prominent among students with menstrual migraine compared with students with menstrual nonmigraine headache (12.2% versus 2.7%). Exacerbation of migraine during menstruation was slightly more severe and more complex than exacerbation of nonmigraine headache. Female students with migraine versus nonmigraine headache did not differ significantly in age, age at onset of menarche, or age at onset of headache. Female students with migraine were significantly more likely to report a positive family history for migraine and menstrual migraine, severe attacks, reduced work activity, and aura. CONCLUSION: The results obtained are in accord with the prevailing opinion that there is a relationship between migraine and female sex hormones, and suggest that women with nonmigraine headache are also susceptible to hormonal fluctuations.

Adult↗
PubMed2000

Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres: the ApoEurope study. ApoEurope group.

As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p<0.001). In addition, serum total cholesterol and triglyceride concentrations were lower in Alzheimer's disease (p<0.001), while that of apo Al was not affected. The decrease in serum apo E concentration was not accounted for by the epsilon4 allele, age or gender, suggesting that apo E concentration might represent an additional risk factor for Alzheimer's disease, complementary and independent of the epsilon4 allele. Further analysis will be aimed at determining whether the quantitative link between apo E concentration and Alzheimer's disease occurs through the effect of apo E genotype on lipid parameters or by other mechanisms.

Age Factors↗
PubMed2000

The status of SCA1, MJD/SCA3, FRDA, DRPLA and MD triplet containing genes in patients with Huntington disease and healthy controls.

A number of human hereditary neuromuscular and neurodegenerative disorders are caused by the expansion of trinucleotide repeats within certain genes. Here we report the results of the analysis of five trinucleotide repeats containing genes (SCA1, MJD/SCA3, DRPLA, FRDA and MD) in HD patients and in a group of healthy controls. Allelic frequency distributions for SCA1 and FRDA genes were shifted toward larger alleles in the group of unrelated HD patients, compared to healthy controls. This linkage disequilibrium suggests a possible existence of a common mechanism of trinucleotide repeats expansion in these loci.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression.

Polygenic factors play important roles in animal models of substance abuse and susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play central roles in drug reward and is believed to be a primary site of action for cocaine reward. This transporter is necessary for the action of selective dopaminergic neurotoxins, and is uniquely expressed on neurons that are the primary targets of Parkinsonian neurodegeneration. To study possible influences of variant DAT expression on these processes, we have constructed transgenic mice (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of a rat DAT cDNA variant, increase striatal DAT expression by 20-30%, and provide modest alterations in striatal levels of dopamine and its metabolites. THDAT mice habituate more rapidly to a novel environment than wildtype littermates. These animals display enhanced reward conferred by cocaine, as measured by conditioned place preference. However, locomotor responses to cocaine administration are similar to those of wildtype mice, except at high cocaine doses. THDAT mice display more than 50% greater losses of dopaminergic neurons following a course of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant effects in murine models of human substance abuse vulnerability and dopaminergic neurodegeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Correlation between triplet repeat expansion and computed tomography measures of caudate nuclei atrophy in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, progressive disorder characterized by choreic movements, cognitive decline, and psychiatric manifestations. Eleven patients with HD were retrospectively selected from a larger group of 42 patients based on the similar, early onset of the disease (between 21 and 30 years) and the same duration of HD at the moment of computed tomography (CT) examination (5 years). A significant correlation between the number of CAG trinucleotides and the bicaudate index or the frontal horn index, two indices of caudate atrophy, was found in this group of patients. Our results, although in a small number of patients, suggest that the striatal degeneration, assessed by CT measures, is primarily regulated by the size of expanded CAG repeats.

Adult↗
PubMed1997

VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity.

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

Amphetamine↗
PubMed1997

Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93. It did not, however, alter the duration of the disease. Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis has been linked in 15% of families to mutations in the gene encoding for copper-zinc superoxide dismutase (Cu/Zn-SOD), a key enzyme in the cellular defense mechanisms against free radical attack. We used a transgenic mouse model of familial amyotrophic lateral sclerosis (transgenic G1H mice) based on expression of mutant human Cu/Zn-SOD to examine the influence of the transgene expression on midbrain dopaminergic neurons, cells that contain conspicuous amounts of this enzyme. At the time that 50% of motor neurons of the spinal cord were lost, we observed concurrent reductions in dopamine levels in the caudate-putamen and the nucleus accumbens of transgenic G1H mice. In addition, numbers of tyrosine hydroxylase-immunostained neurons were significantly reduced in both the substantia nigra (26%) and the ventral tegmental area (16%) compared to those in their nontransgenic littermates. Similar abnormalities were not observed in the brains of transgenic mice overexpressing wild-type Cu/Zn-SOD. These findings indicate that overexpression of the mutated Cu/Zn-SOD protein caused a significant loss of midbrain dopaminergic neurons in addition to the loss of spinal motor neurons. The potential of the mutated enzyme to induce cell death extending beyond the motor neurons is consistent with the description of substantia nigra degeneration in some patients with familial amyotrophic lateral sclerosis. Furthermore, if mutated Cu/Zn-SOD is conclusively shown to kill cells by oxidative stress, such an observation would be in keeping with the known sensitivity of dopaminergic neurons to free radical attack.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Increased superoxide dismutase activity improves survival of cultured postnatal midbrain neurons.

Copper/zinc superoxide dismutase (Cu/Zn-SOD) is a major free radical scavenging enzyme. Increased Cu/Zn-SOD activity protects cells against oxidative stress mediated by different mechanisms. However, there is also in vitro and in vivo evidence that, in the absence of abnormal oxidative stress, chronic increased Cu/Zn-SOD activity is detrimental to living cells. To address this issue, we examined the fate of mature midbrain neurons from transgenic mice expressing human Cu/Zn-SOD and from their nontransgenic littermates. Midbrain from transgenic pups had about threefold higher Cu/Zn-SOD activity than that from nontransgenic pups. Virtually all transgenic neurons were strongly immunoreactive for human Cu/Zn-SOD protein in their cell bodies and processes. The number of midbrain neurons decreased over time in both transgenic and nontransgenic cultures, but to a significantly smaller extent in the transgenic cultures. Postnatal midbrain neurons died by either necrosis or apoptosis, and increased Cu/Zn-SOD activity attenuated both forms of cell death. Furthermore, increased Cu/Zn-SOD activity better prevented the loss of dopaminergic neurons than GABAergic neurons. We also found that neuronal processes were dramatically denser in transgenic cultures than in nontransgenic cultures. These results indicate that chronic increased Cu/Zn-SOD activity does not appear to be detrimental, but rather promotes cell survival and neuronal process development in postnatal midbrain neurons, probably by providing more efficient detoxification of free radicals. They also show that increased Cu/Zn-SOD activity does not seem to play a critical role in determining the mode of cell death in this culture system.

Animals↗
PubMed1992

Superoxide dismutase, catalase, and glutathione peroxidase activities in copper/zinc-superoxide dismutase transgenic mice.

Copper/zinc-superoxide dismutase (CuZn-SOD) transgenic mice overexpress the gene for human CuZn-SOD. To assess the effects of the overexpression of CuZn-SOD on the brain scavenging systems, we have measured the activities of manganese-SOD (Mn-SOD), catalase, and glutathione peroxidase (GSH-Px) in various regions of the mouse brain. In nontransgenic mice, cytosolic CuZn-SOD activity was highest in the caudate-putamen complex; this was followed by the brainstem and the hippocampus. The lowest activity was observed in the cerebellum. In transgenic mice, there were significant increases of cytosolic CuZn-SOD activity in all of these regions, with ratios varying from a twofold increase in the brainstem to 3.42-fold in the cerebellum in comparison with nontransgenic mice. Particulate Mn-SOD was similarly distributed in all brain regions, and its levels also were significantly increased in superoxide dismutase (SOD)-transgenic mice. In the brains of nontransgenic mice, cytosolic catalase activity was similar in all brain regions except the cortex, which showed less than 50% of the activity observed in the other regions. In transgenic mice, cytosolic catalase activity was significantly increased, with the cortex showing the greatest changes (133%) in comparison with nontransgenic mice. The smallest increases were observed in the hippocampus (34%). In contrast to what was observed for SOD and catalase, there were no significant changes in cytosolic GSH-Px activity in any of the brain regions examined. The present results indicate that, in addition to displaying marked increases in the levels of brain CuZn-SOD activity, SOD-transgenic mice also exhibit increases in other enzymes that scavenge oxygen-based radicals.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitrole↗
PubMed1992

Motor blocks in Parkinson's disease.

Freezing episodes and related phenomena (as a general term, motor blocks [MBs]) are poorly understood, particularly disabling, and a therapeutically frustrating problem in Parkinson's disease (PD). Epidemiologic and clinical characteristics of MBs, as well as risk factors to develop MBs, have never been fully addressed. Herein, we report our database survey on 990 PD patients, of whom 318 (32%) had MBs. The majority of MBs were linked to gait. Start hesitation occurred in 86%, blocking on turning in 45%, and blocking in narrow spaces in 25% of patients. Initial parkinsonian symptoms in the upper body and tremor as the initial motor symptom were less likely to be associated with the presence of MBs (odds ratios [OR] 0.6 and 0.7, respectively), while initial symptoms affecting gait or trunk had higher association with MBs (OR = 1.58). Longer disease duration, higher Hoehn and Yahr stage, and longer duration of levodopa treatment are all significantly associated with the presence of MBs. We observed significant association between the existence of MBs and levodopa-induced dyskinesias to suggest similar pathophysiology. We propose that MBs in PD are abnormal retrieval or execution of complex motor tasks that can occur as a result of disease progression or as short- or long-term side effects of levodopa treatment.

Dyskinesia, Drug-Induced↗
PubMed1992

Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson's disease. It has been suggested that the mechanism by which MPTP kills dopamine (DA) neurons involves an energy crisis due to the inhibition of mitochondrial complex I. In addition, superoxide radicals (O2-), generated subsequent to the blockade of mitochondrial complex I, may also be involved in MPTP-induced neurotoxicity. Superoxide dismutase (SOD) is a scavenger enzyme that protects cells from the hazard of O2- radicals. To evaluate further the role of O2- radical in MPTP-induced toxicity, we tested the effects of MPTP in transgenic mice with increased SOD activity. In nontransgenic littermates with normal SOD activity, MPTP injection causes a marked reduction in striatal levels of DA and its metabolites as well as in striatal and nigral 3H-DA uptake; these findings are consistent with a loss in dopaminergic neurons. In contrast, in transgenic mice with increased SOD activity, MPTP injection does not cause any significant changes either in levels of DA and metabolites or in 3H-DA uptake. We show that this lack of toxicity is not due to a lower delivery of MPTP to the brain following its intraperitoneal injection, to reduced brain biotransformation of MPTP to N-methyl-4-phenylpyridinium ion (MPP+), to diminished striatal mitochondrial monoamine oxidase B activity, to decreased synaptosomal uptake of MPP+, to lower potency of MPP+ to inhibit the complex I of the mitochondrial electron transport chain, or to faster brain elimination of MPP+. These results suggest that increased SOD activity is, most likely, the protective factor that confers resistance to transgenic mice against MPTP-induced neurotoxicity. Thus, this study provides further evidence that some of the deleterious effects of MPTP may be mediated by O2- radicals. The similarity between the MPTP model and Parkinson's disease further raises the possibility that oxy-radicals may play a significant role in the etiology of this neurodegenerative disorder.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Sham transplantation protects against 6-hydroxydopamine-induced dopaminergic toxicity in rats: behavioral and morphological evidence.

Administration of the neurotoxin 6-hydroxydopamine (6-OHDA) to rat brain causes biochemical and neuroanatomical changes to the nigrostriatal dopaminergic pathway similar to those observed in Parkinson's disease (PD). Although the cause of PD is unknown, it has been hypothesized that the neurodegenerative changes seen in PD might result from exposure to a neurotoxin. Therefore, strategies for limiting neurotoxin-induced dopaminergic damages, like those caused by 6-OHDA, may be of both clinical and basic interest. Accordingly, we tested the ability of both fetal neural (striatum) and fetal non-neural (liver) tissue implants to protect the rat striatum against the toxic effects of a subsequent intrastriatal injection of 6-OHDA. Non-grafted rats (lesion only) showed amphetamine-induced rotational behavior and a decrease in striatal [3H]mazindol-labeled dopamine uptake sites after 6-OHDA injection. In contrast, the animals grafted with striatum or liver showed no behavioral or biochemical changes. Interestingly, sham-transplanted control animals were also protected against the 6-OHDA-induced toxicity. These results suggest that the resistance of the dopaminergic system against 6-OHDA neurotoxicity observed in grafted and sham-transplanted animals is likely to be related to the surgical procedure itself. This observation points to a possible role for surgery-related events in the clinical improvement described in PD patients who underwent intracerebral transplantation.

Analysis of Variance↗
PubMed1991

Long-term behavioral and biochemical effects of 6-hydroxydopamine injections in rat caudate-putamen.

Unilateral injections of 6-hydroxydopamine into the rat striatum result in amphetamine-induced circling behavior. This rotational behavior was associated with an almost complete disappearance of desmethylimipramine-insensitive [3H]mazindol binding sites--which represent dopamine uptake sites-in the ipsilateral caudate-putamen (CPu), the substantia nigra pars compacta (SNpc), and in the ventral tegmental area (VTA). There were significant increases in [3H]spiperone-labeled dopamine (DA) D2 receptors in specific subdivisions of the ipsilateral CPu, with the dorsolateral (DL) and ventrolateral (VL) regions showing significant increases in DA D2 receptors. There were nonsignificant increases in the dorsomedial (DM) aspects of the ipsilateral CPu whereas there were no changes in the ventromedial (VM) aspects of that structure. In contrast, there were no significant changes in [3H]SCH 23390-labeled DA D1 receptors in any of the subdivisions of the CPu ipsilateral to the 6-OHDA-induced lesions. These results provide evidence that intrastriatal injections of 6-OHDA result in biochemical changes in rat brain which are almost identical to those observed after 6-OHDA-induced lesions of the substantia nigra. These long-term biochemical effects caused by intrastriatal 6-OHDA injections provide further support for the idea that the nigral DA cell loss observed in the brains of parkinsonian patients could be secondary to retrograde changes due to oxyradicals generated during the metabolism of catecholamines within the caudate-putamen.

Animals↗