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Biomedical subjects

C W Olanow

Publications and source records attributed to C W Olanow.

At least 109 records · Page 6Linked to original sources
PubMed1993

Infusion of iron into the rat substantia nigra: nigral pathology and dose-dependent loss of striatal dopaminergic markers.

Iron has recently been suggested to contribute to the pathogenesis of Parkinson's disease (PD) because of the finding of increased iron levels in the substantia nigra pars compacta (SNc) above those of control patients. Iron is capable of catalyzing numerous reactions which could lead to free radical formation and oxidative damage to DNA, proteins, lipid membranes, and other biological molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of increased iron, which promotes these cytotoxic reactions. To test whether excess iron could play a causative role in the degeneration of nigral neurons, we infused 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilaterally utilizing two different infusion protocols. All infusates were isosmotic and pH-balanced in a citrate-bicarbonate vehicle. Animals were decapitated at either 1 or 2 months postinfusion. Striatal tissue was assayed for biogenic amines by HPLC and the remaining brainstem was processed for histological analysis. Iron-stained coronal sections revealed 1) no left/right staining difference with vehicle infusion, 2) a dose-dependent iron accumulation in the infused SN that was restricted to the zona compacta and dorsal-most zona reticularis when the lowest iron concentration was infused, and 3) a dose-dependent reduction in SN volume. Thionine-stained sections revealed neuronal loss and accompanying reactive gliosis within an area that corresponded closely to that of increased iron staining. These degenerative changes were more extensive in animals infused via a side-by side vs. a sequential protocol. Neurochemically, there was a highly significant correlation between the amount of iron infused intranigrally and magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral striatum. These data indicate that iron infusion into the SN can cause degenerative changes within the SN and that these changes can be restricted to the SNc region when low amounts of iron are infused. The data further support the hypothesis that iron-induced degeneration may contribute to the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Orobuccal dyskinesia associated with trihexyphenidyl therapy in a patient with Parkinson's disease.

Dyskinesia is a common adverse effect complicating chronic dopaminergic therapy for Parkinson's disease. Movements are frequently choreic in nature and have been ascribed to overstimulation of "supersensitive" striatal postsynaptic dopamine receptors. Anticholinergic medications, despite some clinical efficacy in Parkinson's disease, have rarely been reported to cause dyskinesia. We report a patient with Parkinson's disease who developed orobuccal dyskinesia while being treated with trihexyphenidyl (Artane). Dyskinesia was observed following the introduction of trihexyphenidyl, resolved with its discontinuation, and reappeared with its reinstitution. Carbidopa-levodopa (Sinemet) alone did not cause dyskinesia but augmented dyskinesia associated with trihexyphenidyl.

Dyskinesia, Drug-Induced↗
PubMed1993

A rationale for monoamine oxidase inhibition as neuroprotective therapy for Parkinson's disease.

Neurons in the substantia nigra may be vulnerable to oxidant stress because (a) the metabolism of dopamine generates peroxides, which, in the presence of iron, can lead to the formation of the highly reactive hydroxyl free radical; and (b) neuromelanin within nigral neurons can bind metals such as iron and aluminum and thereby promote the site-specific formation of free radicals. Postmortem studies show increased iron, decreased glutathione, and increased lipid peroxidation in the substantia nigra of patients with Parkinson's disease (PD). Recent studies also report iron and aluminum accumulation within neuromelanin granules of patients with PD. These findings suggest that the substantia nigra in the patient with PD is in a state of oxidant stress and that antioxidant therapy might protect residual dopamine neurons and slow the natural progression of PD. Selective inhibitors of monoamine oxidase type B (MAO-B) have been chosen for study because of their capacity to interfere with the oxidative metabolism of dopamine and so diminish the likelihood that free radicals will be formed. Initial studies demonstrate that the MAO-B inhibitor L-deprenyl (selegiline) delays the development of disability in otherwise untreated patients with early Parkinson's disease. Although the mechanism responsible for these observations remains unclear, these results are consistent with the possibility that L-deprenyl provides neuroprotective effects.

Free Radicals↗
PubMed1993

A scientific rationale for protective therapy in Parkinson's disease.

The desire to introduce neuroprotective therapy for Parkinson's disease has begun to focus attention on pathogenetic mechanisms responsible for cell death. Considerable theory and some evidence have now accumulated to suggest that factors related to oxidative stress, mitochondrial bioenergetic defects, excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies acting either singularly or in combination may contribute to the development of cell death in Parkinson's disease. A better understanding of the specific pathogenetic mechanism involved in cell degeneration might provide a scientific basis for testing a putative neuroprotective therapy. This chapter reviews the theory and evidence in support of these different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease.

Antiparkinson Agents↗
PubMed1993

A radical hypothesis for neurodegeneration.

Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.

Animals↗
PubMed1993

The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses.

We monitored the motor response and plasma and ventricular CSF (CSFv) concentrations of L-dopa during IV infusions of L-dopa in two patients with advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but lagged behind, those in plasma. In the fasting state, the duration, but not the magnitude, of the motor response was greater with increasing plasma and CSFv levels of L-dopa. During IV infusions of L-dopa following oral administration of phenylalanine, a large neutral amino acid that shares a transport system into the brain with L-dopa, the duration of the motor response was markedly attenuated despite undiminished CSFv levels of L-dopa. These observations suggest that either L-dopa entry into CSFv and the brain are differentially affected by phenylalanine or that phenylalanine affects other steps in the motor response. These observations demonstrate that, except in the fasting state, L-dopa in CSFv is not a reliable predictor of motor response.

Amino Acids↗
PubMed1992

Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study.

The Laser Microprobe Mass Analyzer (LAMMA) is a sensitive instrument for identifying and localizing trace elements in tissue samples. Using LAMMA, we have examined melanin-containing neurons of the substantia nigra in patients with Parkinson's disease (PD) and controls. We found that iron significantly accumulates within neuromelanin granules of patients with PD compared to controls. Increased aluminum was found in the neuromelanin granules of 2 of 3 PD cases but in no controls. The accumulation of iron and aluminum, which are known to promote oxidant stress, may account for the selective degeneration of neuromelanin-containing neurons in PD.

Aluminum↗
PubMed1992

An introduction to the free radical hypothesis in Parkinson's disease.

Iron-induced oxidant stress has been implicated in the pathogenesis of Parkinson's disease. An increasing body of evidence now indicates that in Parkinson's disease the environment within the substantia nigra is conducive to the formation of cytotoxic free radicals and cell degeneration. Dopamine neurons may be particularly vulnerable because of the oxidative metabolism of dopamine and the potential of neuromelanin to promote the site-specific accumulation and reduction of iron. This hypothesis has attracted considerable attention because it opens the way for employing antioxidant strategies as possible neuroprotective treatment for Parkinson's disease. Although the concept is appealing, free radicals have not yet been proven to play a role in Parkinson's disease, and many important issues remain to be resolved before the oxidative hypothesis can ultimately be confirmed or refuted.

Animals↗
PubMed1992

Iron induces degeneration of nigrostriatal neurons.

Parkinson's-diseased (PD) brains have been reported to contain increased quantities of iron within the zona compacta of the substantia nigra (SN). To test whether excess iron in the SN could cause a PD-like loss of dopaminergic neurons, various concentrations of iron were infused unilaterally within the SN of adult male rats. At 1-2 months post-infusion, examination of thionine and iron stained brain sections from animals infused with low concentration iron revealed: (1) iron diffusion limited to and concentrated within the infused SN and (2) a selective degeneration of neurons within zona compacta of SN. Infusion of higher iron concentrations induced near complete neuronal losses in zona compacta, as well as neuronal degeneration within zona reticularis and areas immediately adjacent to the SN. Striatal dopamine and its catabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced in a dose-dependent fashion, with over 80% depletions observed at the highest iron concentration infused. These data indicated that neurons within zona compacta of SN are sensitive to infusions of low iron concentrations. The data support the notion that iron in zona compacta of the SN could act as an endotoxin in the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Early therapy for Parkinson's disease.

The management of patients with early Parkinson's disease should now take into account the possibility that MAO-B inhibitors may provide neuroprotective therapy, that dopamine undergoes oxidative metabolism and has the potential to generate cytotoxic free radicals, and that the early employment of drugs which provide sustained central dopamine agonism may delay the development of adverse effects associated with chronic levodopa therapy. The aim of treatment for patients with early Parkinson's disease is to utilize strategies designed to address these issues without compromising clinical control. These approaches are reviewed.

Antiparkinson Agents↗
PubMed1992

A rationale for dopamine agonists as primary therapy for Parkinson's disease.

Levodopa is the most potent symptomatic treatment for Parkinson's disease but adverse reactions are common and the initial response is not maintained. Further there is recent evidence that suggests that free radicals generated from the oxidative metabolism of dopamine may contribute to the pathogenesis of Parkinson's disease. This raises the possibility that levodopa therapy by way of its conversion to dopamine may promote free radical formation and accelerate the rate of neuronal damage. Levodopa sparing strategies designed to minimize the cumulative levodopa dosage employed over the course of the disease seem a rational way to treat Parkinson patients in face of current information. Such a strategy would include the use of dopamine agonists as primary symptomatic therapy, the introduction of levodopa as an adjunct when dopamine agonists can no longer sufficiently provide satisfactory clinical control and the use of the lowest dose of levodopa that will provide satisfactory clinical control. In this way symptomatic control is not compromised on theoretical grounds, but the cumulative levodopa dose is minimized in an effort to reduce the likelihood of free radical formation with their potential adverse consequences on disease progression.

Dopamine Agents↗
PubMed1992

Magnetic resonance imaging in parkinsonism.

MRI is a relatively simple, safe, in vivo technique that has proved to be of great value in differentiating patients with Parkinson's disease from those with atypical parkinsonism, and it is the first laboratory marker to be able to do so. By permitting the in vivo detection of increased iron in the nigra and striatum of patients with parkinsonism, MRI may also have provided a clue into the mechanism of cell death in neurodegenerative disorders. Finally it is conceivable that MRI scanning may serve as a screening tool that permits the early recognition of pathologic iron accumulation before the development of clinical symptoms. This is reasonable to anticipate for patients with atypical parkinsonism in whom large quantities of iron appear to accumulate in the putamen early in the disease. It is possible that with some refinement, abnormalities in the nigra may be detected on MRI with a higher level of certainty. In an era in which we may be able to provide neuroprotective therapy, MRI might be an important technique for defining a population of patients at risk for the development of Parkinson's disease who might benefit from presymptomatic therapy.

Brain↗
PubMed1992

Does selegiline monotherapy in Parkinson's disease act by symptomatic or protective mechanisms?

Selegiline monotherapy has been clearly demonstrated to delay the development of disability in early, otherwise untreated Parkinson's disease patients. It remains uncertain, however, whether this benefit is due to protective effects on residual neurons or to symptomatic effects that mask the detection of underlying disability. This paper examines the evidence and theory supporting the hypotheses that selegiline acts by protective or symptomatic mechanisms and considers what future studies might help clarify these issues.

Double-Blind Method↗
PubMed1991

Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson's disease.

We studied the pharmacokinetics of levodopa and its metabolites in plasma and ventricular cerebrospinal fluid in 4 parkinsonian patients with indwelling Ommaya reservoirs placed at the time of previous adrenal-medullary to caudate nucleus transplantation. Cerebrospinal fluid levodopa levels were 11.9% of those in plasma. Motor performance and dyskinesia correlated more closely with the time course of the appearance of levodopa in the ventricular cerebrospinal fluid than with the plasma levodopa concentration and did not correlate with plasma 3-O-methyldopa or cerebrospinal fluid 3-O-methyldopa or homovanillic acid. Our data confirm that the wearing off of the levodopa effect in patients with advanced Parkinson's disease is a function of drug concentration in the central nervous system.

Aged↗
PubMed1991

Development of dopaminergic neurons in the human substantia nigra.

A series of 29 human embryonic brains were examined in order to characterize the ontogeny of dopaminergic neurons within the developing substantia nigra. Embryos from Postconception Weeks 4.0 to 11.2 (last menstrual period 6.0-13.2) were studied. Immunohistochemical staining was performed using a polyclonal antibody to tyrosine hydroxylase. Tyrosine hydroxylase-like immunoreactivity was first seen in cells of the ventral mesencephalon at 6.5 weeks adjacent to the ventricular zone. Ventral migration of TH-positive cells began at 6.7 weeks. Neural process extension was first identified in tyrosine hydroxylase-positive neurons at 8.0 weeks. The ascending nigrostriatal bundle was also first demonstrated at 8.0 weeks. Tyrosine hydroxylase containing neurites were seen initially in the developing putamen at 9.0 weeks. Only a few tyrosine hydroxylase-positive cells remained adjacent to the ventricular zone at Week 10.0 and all had disappeared from the ventricular zone by 11.2 weeks. At this latter stage, a large number of dopaminergic cells had elaborated neural processes. The sequence of developmental events of human mesencephalic dopaminergic neurons is similar to the equivalent period of ontogeny in other mammals. The duration of the developmental period is, however, significantly protracted.

Dopamine↗
PubMed1991

An open multicenter trial of Sinemet CR in levodopa-naive Parkinson's disease patients.

It has been proposed that initiation of anti-Parkinson therapy with continuous release formulations of Sinemet might prevent or delay the development of adverse effects associated with chronic levodopa therapy employed in standard formulations. In anticipation of a prospective study comparing Sinemet to Sinemet CR in previously untreated Parkinson's disease patients, we evaluated Sinemet CR as primary therapy in 45 levodopa-naive Parkinson's disease patients in a 12 week, open-label, multi-center study. At the conclusion of the study, optimal results were obtained with levodopa administered as Sinemet CR in a total daily dose of 497 mg divided into 2.4 doses per day. Statistically significant improvement compared to baseline was observed for total Parkinson's score as well as each of rigidity, tremor, bradykinesia, gait and postural stability. Statistically significant improvement was also noted in total disability as well as in each of its components. Adverse experiences were mild and transient and no significant laboratory abnormalities were encountered. We conclude that a daily dose of 1 to 1.5 tablets b.i.d. of Sinemet CR as primary therapy for patients with Parkinson's disease is well tolerated and provides effective therapy.

Aged↗