Biomedical subjects

L DiStefano

Publications and source records attributed to L DiStefano.

17 recordsLinked to original sources

PubMed1999

Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia.

OBJECTIVE: To determine the mechanism leading to striatal dopamine (DA) loss in dopa-responsive dystonia (DRD). BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown. METHODS: The authors sequenced GCH1 and measured levels of total biopterin (BP) and total neopterin (NP), TH, and dopa decarboxylase (DDC) proteins, and the DA and vesicular monoamine transporters (DAT, VMAT2) in autopsied brain of two patients with typical DRD. RESULTS: Patient 1 had two GCH1 mutations but Patient 2 had no mutation in the coding region of this gene. Striatal BP levels were markedly reduced (<20% of control subjects) in both patients and were also low in two conditions characterized by degeneration of nigrostriatal DA neurons (PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate), whereas brain NP concentrations were selectively decreased (<45%) in the DRD patients. In the putamen, both DRD patients had severely reduced (<3%) TH protein levels but had normal concentrations of DDC protein, DAT, and VMAT2. CONCLUSIONS: The data suggest that 1) brain BH4 is decreased substantially in dopa-responsive dystonia, 2) dopa-responsive dystonia can be distinguished from degenerative nigrostriatal dopamine deficiency disorders by the presence of reduced brain neopterin, and 3) the striatal dopamine reduction in dopa-responsive dystonia is caused by decreased TH activity due to low cofactor concentration and to actual loss of TH protein. This reduction of TH protein, which might be explained by reduced enzyme stability/expression consequent to congenital BH4 deficiency, can be expected to limit the efficacy of acute BH4 administration on dopamine biosynthesis in dopa-responsive dystonia.

Adult↗

PubMed1999

Brain choline acetyltransferase activity in chronic, human users of cocaine, methamphetamine, and heroin.

Cognitive impairment has been reported in some chronic users of psychostimulants, raising the possibility that long-term drug exposure might damage brain neuronal systems, including the cholinergic system, which are responsible for normal cognition. We measured the activity of choline acetyltransferase (ChAT), the marker enzyme for cholinergic neurones, in autopsied brain of chronic users of cocaine, methamphetamine, and, for comparison, heroin. As compared with the controls, mean ChAT levels were normal in all cortical and subcortical brain areas examined. However, the two of 12 methamphetamine users, who had the highest brain/blood drug levels at autopsy, had a severe (up to 94%) depletion of ChAT activity in cerebral cortex, striatum, and thalamus. Based on the subjects examined in the present study, our neurochemical data suggest that brain cholinergic neurone damage is unlikely to be a typical feature of chronic use of cocaine, methamphetamine, or heroin, but that exposure to very high doses of methamphetamine could impair, at least acutely, cognitive function requiring a normal nucleus basalis cholinergic neuronal system. Reduced brain ChAT might be explained in part by a hyperthermia-related mechanism as low ChAT levels have also been observed in brain of some patients with neuroleptic drug-associated hyperthermia. Studies of cognitive and brain cholinergic status in high dose users of MA are warranted.

Adult↗

PubMed1999

Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and in hereditary spinocerebellar ataxia disorders: a nonspecific change?

Controversy exists as to the clinical importance, cause, and disease specificity of the cytochrome oxidase (CO) activity reduction observed in some patients with Alzheimer's disease (AD). Although it is assumed that the enzyme is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subunits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, groups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrations of all four CO subunits were significantly decreased (-19 to -47%) in temporal and parietal cortices in the AD group but were not significantly reduced (-12 to -17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (-42 to -47%) generally exceeded that encoded by nuclear DNA (-19 to -43%). In the spinocerebellar ataxia disorders, COX I and COX II levels were significantly decreased in cerebellar cortex (-22 to -32%) but were normal or close to normal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial- and nuclear-encoded CO subunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodegenerative process.

Aged↗

PubMed1998

Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.

BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

Adolescent↗

PubMed1995

GM1 ganglioside rescues substantia nigra pars compacta neurons and increases dopamine synthesis in residual nigrostriatal dopaminergic neurons in MPTP-treated mice.

GM1 ganglioside has been shown to stimulate recovery of the damaged dopamine system under a number of different circumstances. In addition to rescue of damaged dopamine neurons, the present study assessed the ability of GM1 to enhance the synthesis of dopamine in remaining nigrostriatal neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. There was a significantly greater accumulation of L-dopa 30 min after aromatic amino acid decarboxylase inhibition with NSD-1015 (100 mg/kg) and an increase in the ratio of L-dopa to dopamine in MPTP+GM1-treated mice than in mice that received only MPTP. This effect of GM1 on dopamine synthesis was dependent upon the degree of initial damage to the nigrostriatal dopamine system. That is, the GM1 effect on dopamine synthesis could not be demonstrated in mice with greater than 95% striatal dopamine loss and 75% substantia nigra dopamine neuron loss. These results suggest that in addition to previously reported effects of GM1 on rescue and repair of dopaminergic neurons, GM1 may also have the ability to enhance dopamine synthesis in residual dopaminergic neurons. Direct effects on dopamine neurochemistry may contribute to functional improvement seen after GM1 treatment in various models of parkinsonism.

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

PubMed1995

Enhanced restoration of striatal dopamine concentrations by combined GM1 ganglioside and neurotrophic factor treatments.

Intraperitoneal injection of GM1 ganglioside or intracerebroventricular infusion of basic fibroblast growth factor (FGF-2) or epidermal growth factor (EGF) partially restored dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum of young MPTP-treated mice. Combined treatments of GM1 ganglioside with FGF-2 or EGF produced a greater restoration of striatal dopamine levels than treatments with GM1 or either of the neurotrophic factors alone. GM1 treatment, but not trophic factor treatments caused significant sparing of substantia nigra pars compacta (SNc) tyrosine hydroxylase (TH)-positive neurons. These results confirm previous findings that GM1 provides trophic support for damaged dopamine neurons and suggests that GM1, FGF-2, and EGF may also enhance dopaminergic function in residual neurons. The results also suggest that a potentially fruitful approach to treating degenerative disorders of the dopamine system may be the use of combined trophic factor therapies.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Volume transmission of dopamine over large distances may contribute to recovery from experimental parkinsonism.

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome that spontaneously recovers by 6 weeks after induction. Striatal dopamine depletions in these animals are heterogenous with more extensive damage dorsolaterally than ventromedially. Measures of extracellular dopamine levels by in vivo microdialysis showed that dopamine released from a relatively preserved ventral striatal innervation can diffuse over a distance of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribute to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reuptake inhibition, but not in normal animals without reuptake inhibition. In cats recovered from MPTP-induced parkinsonism, a greater amount of dopamine was recovered from the extracellular fluid in the dorsolateral caudate following stimulated release of dopamine from the ventromedial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmission of dopamine over large distances is possible and perhaps an important contributor to functional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to significant functional improvement.

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

PubMed1994

GM1 ganglioside treatment partially reverses the nigrostriatal dopamine defect in the weaver mutant mouse.

The weaver mutation in the mouse is a developmental disorder characterized by cerebellar atrophy as well as decreased numbers of substantia nigra dopaminergic neurons and a striatal dopamine loss. Since the nigrostriatal dopamine loss occurs postnatally, the present study was performed to determine whether early intervention with GM1 ganglioside could alter the extent of this dopamine loss. Weaver mice that received injections of GM1 ganglioside (30 mg/kg) daily, beginning at 7-10 days of age, had significantly higher striatal dopamine levels and significantly more tyrosine hydroxylase-positive substantia nigra pars compacta neurons than weaver mice that received only daily saline injections. These results show that GM1 treatment can alter at least some aspects of this inherited developmental disorder. If the weaver defect is related to a deprivation of trophic support for certain midbrain dopaminergic neurons, the presence of GM1 may be able to enhance the survival of these neurons.

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

PubMed1994

Cerebellar glutamate metabolizing enzymes in spinocerebellar ataxia type I.

We measured the levels of three glutamate metabolizing enzymes, namely, glutamate dehydrogenase (GDH), aspartate aminotransferase (AAT), and glutamine synthetase (GS) in cerebellar and occipital cortices of nine patients with dominantly-inherited olivopontocerebellar atrophy (OPCA; spinocerebellar ataxia type I). As compared with the controls, mean GDH activities in cerebellar cortex of the OPCA patients were normal whereas levels of AAT (-17%) and the glial enzyme GS (-27%) were significantly reduced. No statistically significant changes were observed in occipital cortex, a morphologically unaffected brain area. We suggest that the decreased GS levels could reflect impaired capacity of astrocytes to metabolize glutamate which might contribute to the degenerative processes in OPCA cerebellum.

Adult↗

PubMed1994

Oral administration of semisynthetic sphingolipids promotes recovery of striatal dopamine concentrations in a murine model of parkinsonism.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to young C57/B16J black mice caused a striatal dopamine depletion that could be at least partially reversed by chronic intraperitoneal administration of GM1 ganglioside. The present study shows that the semisynthetic sphingolipids LIGA 4 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-acetamide-4-t rans-octadacene) and LIGA 20 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-chloro-acetam ide-4- trans-octadacene) are also effective in at least partially reversing MPTP-induced striatal dopamine depletions in mice after oral administration. These results suggest that semisynthetic ganglioside derivatives may be superior to the parent GM1 ganglioside for human clinical use.

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

PubMed1993

LIGA 20 increases striatal dopamine levels in aged MPTP-treated mice refractory to GM1 ganglioside treatment.

Administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to aged (12 months) C57 black mice results in a striatal dopamine depletion that can be partially reversed only by long-term (i.e. 8 weeks) intraperitoneal administration of GM1 ganglioside. The present study shows that the semi-synthetic sphingolipid LIGA 20 (II3Neu5AcGgOse4-2-d-erythro-1,3-dihydroxy-2-dichloro-acetrylam ide-4- transoctadene) can partially reverse MPTP-induced striatal dopamine depletions in aged mice after being administered orally for only 4 weeks. GM1 ganglioside administered for 4 weeks had no effect on striatal dopamine levels. These results suggest that LIGA 20 is more potent than the parent GM1 ganglioside and may exert effects on the damaged nervous system under conditions in which GM1 is ineffective.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Long-term changes in regional brain cytochrome oxidase activity induced by electroconvulsive treatment in rats.

Quantitative cytochrome oxidase (CO) histochemistry was used to examine brain regional metabolic effects of electroconvulsive shock-induced seizures (ECS). Rats receive a course of either eight ECS or control treatments and were sacrificed either 24 h or 28 days after the last session. Regional CO activity (mumol/gT/min) was quantitated throughout the brain using internally calibrated standards. Twenty-four hours after the last ECS session there was no significant difference between ECS- and sham-treated brains in any of the 99 brain regions examined. In contrast, 28 days after the last session, ECS brains showed significant increases in CO activity in the interpeduncular nucleus (+20%), bed nucleus of the stria terminalis (+25%), dorsomedial hypothalamus (+20%), ventromedial hypothalamus (+12%), mammillary nucleus (+14%), pontine nucleus (+16%), basolateral amygdala (+14%), medial amygdala (+12%), piriform cortex (+12%) and ventromedial thalamus (+9%). These results suggest that ECS induces localized increases in brain CO activity which are long-lasting and may develop independently of additional stimulation. The fact that CO changes were predominantly in limbic areas suggests that they may be relevant to the antidepressant effects of ECS.

Animals↗

PubMed1993

Reduced cerebral cortical but elevated striatal concentration of somatostatin-like immunoreactivity in dominantly inherited olivopontocerebellar atrophy.

Somatostatin-like immunoreactivity (SLI) was measured in the brains of nine patients with dominantly inherited olivopontocerebellar atrophy (OPCA), who all had a marked deficit of the cholinergic marker choline-acetyltransferase (ChAT) in the cerebral cortex and striatum. Mean concentrations of SLI in OPCA were significantly reduced by 42-58% in parietal and occipital cortices and frontal cortical eye fields, but were normal in other cortical areas, including two subdivisions of the temporal cortex which show marked depletions of both SLI and ChAT in Alzheimer's disease. This dissociation of SLI and ChAT indicates that a cortical cholinergic deficit does not invariably lead to reduction of somatostatin. In the caudate nucleus, the region of OPCA brain having the most severe ChAT deficit (-81%), SLI levels were significantly elevated by 46% and were negatively and significantly correlated with ChAT activities (r = -0.66). The SLI alterations could be due to abnormal somatostatin metabolism or release, or an increased number of somatostatin-containing neurons and could contribute to the brain dysfunction of OPCA.

Adult↗

PubMed1992

Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment.

A parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.

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

PubMed1992

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Adult↗

PubMed1989

Non-Alzheimer-type pattern of brain cholineacetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy.

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.

Adult↗

PubMed1989

Down's syndrome individuals begin life with normal levels of brain cholinergic markers.

We measured the activities of the cholinergic marker enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in autopsied brains of seven infants (age range 3 months to 1 year) with Down's syndrome (DS), a disorder in which virtually all individuals will develop by middle age the neuropathological changes of Alzheimer's disease accompanied by a marked brain cholinergic reduction. When compared with age-matched controls cholinergic enzyme activity was normal in all brain regions of the individuals with infant DS with the exception of above-normal activity in the putamen (ChAT) and the occipital cortex (AChE). Our neurochemical observations suggest that DS individuals begin life with a normal complement of brain cholinergic neurons. This opens the possibility of early therapeutic intervention to prevent the development of brain cholinergic changes in patients with DS.

Acetylcholinesterase↗