Biomedical subjects

V Kostic

Publications and source records attributed to V Kostic.

30 records · Page 2Linked to original sources

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↗

PubMed1991

Partial attenuation of chronic fluphenazine-induced changes in regional monoamine metabolism by D-alpha-tocopherol in rat brain.

Recent evidence has suggested a role for free radicals in tardive dyskinesia. We, therefore, investigated the effects of chronic administration of fluphenazine decanoate (FLU) and/or vitamin E (VIT E) on regional monoamine metabolism in rat brain. Chronic FLU caused significant increases in dopamine (DA) in nucleus accumbens and brainstem, significant decreases in dihydroxyphenylacetic acid (DOPAC) in frontal cortex, nucleus accumbens and hippocampus and significant decreases in homovanillic acid (HVA) in nucleus accumbens, caudate-putamen and brainstem. Coadministration of FLU and VIT E normalized HVA in caudate-putamen, nucleus accumbens and brainstem as well as DOPAC in nucleus accumbens and hippocampus. Chronic FLU caused significant increases in norepinephrine (NE) levels in all regions studied. VIT E attenuated FLU-induced increases in NE levels in nucleus accumbens and hippocampus. Significant increases in serotonin (5-HT) levels occurred in nucleus accumbens and hippocampus whereas significant decreases in 5-hydroxyindole-acetic acid (5-HIAA) occurred in all brain regions after chronic FLU. Coadministration of VIT E attenuated the changes observed in hippocampal 5-HIAA but potentiated the FLU-induced increases in 5-HT in this region. Our data suggest that VIT E can attenuate some of the FLU-induced changes in monoamine metabolism. Results are discussed in relation to possible involvement of free radicals in monoamine metabolism during chronic neuroleptic use.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Quantitative autoradiographic distribution of [3H]-MPTP binding in the brains of superoxide dismutase transgenic mice.

Recently, we have shown that transgenic mice which exhibit increased superoxide dismutase (SOD) activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Increased SOD activity has been related to impairment of cell membrane characteristics and enhanced lipid peroxidation. Thus it was thought that resistance to MPTP might possibly be attributable to alteration in the distribution of MPTP which is a highly lipophilic compound. This idea was stimulated by a previous suggestion that the resistance manifested by rats to MPTP might be due to a low level of [3H]-MPTP binding sites in brain regions which are critical to MPTP-induced toxicity. The comparison of the binding of [3H]-MPTP in the brain of SOD-transgenic mice and their nontransgenic littermates did not reveal any significant difference in either brain distribution or in concentrations of [3H]-MPTP binding between the two groups. Our data indicate that the observed lack of MPTP-induced toxicity of SOD-transgenic mice is not related to abnormal binding of the toxin in the brain of these transgenic animals which exhibit 2.07 to 3.48 higher SOD activity than their nontransgenic littermates. In addition, this study provides a normative description of the regional distribution of [3H]-MPTP binding in the brain of normal mice.

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

PubMed1991

Effect of unilateral perinatal hypoxic-ischemic brain injury in the rat on dopamine D1 and D2 receptors and uptake sites: a quantitative autoradiographic study.

The effect of a unilateral perinatal hypoxic-ischemic brain injury on dopamine D1 and D2 receptors and uptake sites was investigated in rats by using in vitro quantitative binding autoradiography, 2-3 weeks after the insult. We observed significant decreases in the Bmax and KD for [3H]SCH 23390-labeled D1 and in the Bmax for [3H]spiperone-labeled D2 receptors in the lesioned caudate-putamen in rats with moderate brain injury (visible loss in hemispheric volume ipsilateral to the injury) compared with the nonlesioned contralateral caudate-putamen or with control rats. Changes in [3H]SCH 23390 and [3H]spiperone binding predominated in the dorsolateral part of the lesioned caudate-putamen. Pronounced reduction in [3H]SCH 23390 binding was also observed in the substantia nigra pars reticulata on the side of the lesion. In contrast, we did not observe any significant change in Bmax or KD for [3H]mazindol-labeled dopamine uptake sites. Similarly, no significant changes in the levels of dopamine or its metabolites were found on the side of the lesion. The observed reductions in striatal dopamine D1 and D2 receptors are a reflection of striatal cell loss induced by the hypoxic-ischemic injury. The absence of changes in [3H]mazindol binding or dopamine levels in the lesioned caudate-putamen indicates that the dopaminergic presynaptic structures are preserved.

Animals↗

PubMed1991

Effect of unilateral perinatal hypoxic-ischemic brain injury in the rat on striatal muscarinic cholinergic receptors and high-affinity choline uptake sites: a quantitative autoradiographic study.

The binding characteristics and distribution of M1 and M2 muscarinic cholinergic receptors and high-affinity choline uptake sites were studied in the striatum of the rat at 3-4 and 9-12 weeks of age after exposure to unilateral perinatal hypoxic-ischemic brain injury. High-affinity choline uptake sites were labeled with [3H]hemicholinium-3, M1 receptors with [3H]pirenzepine, and M2 receptors with [3H]AF-DX 116. Saturation experiments revealed a significant decrease in the maximal binding capacity (Bmax) for [3H]pirenzepine-labeled M1 receptors in the lesioned caudate/putamen complex in immature rats with moderate brain injury, in comparison with controls. In contrast, the Bmax value for [3H]hemicholinium-3-labeled high-affinity choline uptake sites was significantly increased. No changes in dissociation constants (KD) were observed. These changes were most pronounced in the dorsolateral region of striatum. Striatal regional distribution of [3H]AF-DX 116 was not affected. In mature rats, binding of [3H]pirenzepine returned to control values, whereas [3H]hemicholinium binding showed a persistent increase (23%). The increase in [3H]hemicholinium-3 binding, as a specific marker of cholinergic nerve terminals, is consistent with our prior morphologic studies demonstrating relative preservation of cholinergic neurons and neuropil, and supports the concept that striatal cholinergic systems are resistant to hypoxic-ischemic injury.

Aging↗

PubMed1991

Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease.

We evaluated whether patients with young-onset Parkinson's disease (PD) (onset between 21 and 40 years) develop levodopa-induced dyskinesias and motor response fluctuations more frequently and earlier than patients with older-onset PD (onset after 40 years) by determining the period from levodopa introduction to development of dyskinesias or fluctuations in 25 young-onset (mean age at onset, 33.54 years) and in 25 matched older-onset PD patients (mean age at onset, 55.76 years). Young-onset PD patients had significantly higher frequency for both dyskinesias and fluctuations after both 3 and 5 years of levodopa. Young-onset PD patients also developed both levodopa-induced dyskinesias and fluctuations earlier than older-onset PD patients. We suggest that the introduction of levodopa therapy in patients with young onset PD should be postponed as long as possible.

Adult↗

PubMed1991

Unilateral MPTP-induced parkinsonism in monkeys. A quantitative autoradiographic study of dopamine D1 and D2 receptors and re-uptake sites.

The cynomolgus monkeys received a unilateral intracarotid injection of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in order to induce a chronic model of hemi-parkinsonism. The procedure was well tolerated by the animals. Unilateral injection of MPTP caused rigidity and bradykinesia of the contralateral limbs, but the animals were able to eat and drink without levodopa therapy. During spontaneous motor activity, animals rotated toward the lesioned side whereas systemic apomorphine injection stimulated circling toward the normal non-lesioned side. Twelve weeks after MPTP injection, we found a marked reduction in striatal and nigral [3H]-mazindol binding on the MPTP-injected side which is indicative of a loss in both dopaminergic nerve terminals and cell bodies. The unilateral dopaminergic denervation was associated with an ipsilateral increase in striatal and a reduction in nigral [3H]-spiperone-labelled D2 dopamine receptors; these changes are consistent with the known localization of the D2 receptors on striatal dopaminergic nerve terminals and on nigral dopaminergic cell bodies. In contrast, no changes in [3H]-SCH 23390-labelled D1 dopamine receptors were observed at the level of either the striatum or the substantia nigra. This study describes a well tolerated procedure which induces a clinical and morphological hemi-parkinsonian syndrome. This animal model may be useful in the studies of new antiparkinsonian drugs, for testing the functional efficacy of brain tissue implants and in the understanding of the physiopathogenesis of levodopa-induced dyskinesias.

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

PubMed1990

Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat.

We examined the status of dopamine (DA) D1 and D2 receptors by using [3H]SCH 23390 and [3H]spiperone binding, respectively, and DA uptake sites by using [3H]mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher [3H]SCH 23390 and [3H]spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in [3H]mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal [3H]spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

Animals↗

PubMed1990

Quantitative autoradiographic distribution of [3H]mazindol-labeled dopamine uptake sites in the brains of superoxide dismutase transgenic mice.

Superoxide dismutase (SOD) is an important enzyme which is involved in the dismutation of the toxic radical, superoxide anion. The activity of CuZnSOD is increased in patients who suffer from Down's Syndrome, Alzheimer's disease, and in Parkinson's disease. In order to evaluate the contribution of this enzyme to the neuropathology of these neurodegenerative diseases, transgenic mice have been constructed which express the human CuZnSOD gene. As a first step towards exploring these issues, we have carried out an autoradiographic binding study of the distribution of the catecholaminergic uptake blocker mazindol in the brain of these transgenic mice and of their littermates. Desmethylimipramine (DMI)-insensitive [3H]mazindol binding sites which correspond to dopamine uptake sites were located in the striatum, the nucleus accumbens, the olfactory tubercle and in the substantia nigra. Within the striatum, there was a lateromedial gradient, with higher concentration of dopamine uptake sites being found laterally. These findings suggest that subregions of the basal ganglia may be more susceptible to the deleterious effects of dopaminotoxic drugs which are taken up into the dopaminergic neurons via these uptake sites. Saturation experiments revealed no differences in the characteristics of [3H]mazindol binding sites between the two groups of mice. Thus, increased activity of SOD is not associated with diffuse changes in the molecular structures of receptors in mice brain.

Animals↗

PubMed1990

Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiologic features.

We evaluated 11 patients with hemiparkinson-hemiatrophy syndrome, 6 with body and contralateral cerebral hemispheric hemiatrophy, 4 with only body hemiatrophy, and 1 with just brain hemiatrophy. The mean age of symptom onset was 38.1 years (range, 18 to 54) with 5.2 +/- 3.1 (mean +/- SD) years of illness until the last follow-up visit. The presenting symptom was unilateral tremor in 6 patients, hand dystonia in 2, bradykinesia in 2, and abnormal gait in 1 patient. Three patients had a good response to levodopa, 4 had moderate response, and 2 patients had a poor response. During a mean follow-up period of 1.7 years (range, 4 months to 5 years), the Hoehn and Yahr score changed in only 3 patients: 2 gained 1.5 points and 1 gained 3 points over 2.5 years. We discuss the association between hemiparkinsonism-body hemiatrophy and contralateral hemispheric hemiatrophy, and raise the possibility of early childhood brain insult with delayed-onset parkinsonism.

Adolescent↗

PubMed1990

[Not Available].

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Ethics, Medical↗

PubMed1988

Hemiballismus: changes in cerebrospinal fluid.

Concentrations of serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxy-phenylacetic acid (DOPAC), were measured in the samples of cerebrospinal fluid of 5 patients with acute hemiballismus. The only significant change was the increased content of HVA compared to controls. This finding support the hypothesis on the increased dopamine turnover in hemiballismus and provide a rational basis for the present treatment with antidopaminergic agents.

3,4-Dihydroxyphenylacetic Acid↗