The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis

BACKGROUND: The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival. METHODS/PRINCIPAL FINDINGS: A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p=0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra. CONCLUSIONS: The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the "catecholaldehyde hypothesis" as an important link for the etiology of sporadic PD

The use of Traditional Medicine by Ghanaians in Canada

Peer reviewedPublisher PD

Both Stereoselective (R)- and (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline Enantiomers Protect Striatal Terminals Against Rotenone-Induced Suppression of Dopamine Release

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is present in the human and rodent brain as a mixture of stereospecific (R)- and (S)-1MeTIQ enantiomers. The racemate, (R,S)-1MeTIQ, exhibits neuroprotective activity as shown in the earlier study by the authors, and In addition, it was suggested to play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. In this article, we investigated the influence of stereospecific enantiomers of 1MeTIQ, (R)- and (S)-1MeTIQ (50 mg/kg i.p.) on rotenone-induced (3 mg/kg s.c.) behavioral and neurochemical changes in the rat. In behavioral study, in order to record dynamic motor function of rats, we measured locomotor activity using automated locomotor activity boxes. In biochemical studies, we analyzed in rat striatum the concentration of dopamine (DA) and its metabolites: intraneuronal DOPAC, extraneuronal 3-MT, and final HVA using HPLC with electrochemical detection. Otherwise, DA release was estimated by in vivo microdialysis study. The behavioral study has demonstrated that both acute and repeated (3 times) rotenone administration unimportantly depressed a basic locomotor activity in rat. (R)- and (S)-1MeTIQ stereoisomers (50 mg/kg i.p.) produced a modest behavioral activation both in naïve and rotenone-treated rats. The data from ex vivo neurochemical experiments have shown stereospecificity of 1MeTIQ enantiomers in respect of their effects on DA catabolism. (R)-1MeTIQ significantly increased both the level of the final DA metabolite, HVA (by about 70%), and the rate of DA metabolism (by 50%). In contrast to that, (S)-1MeTIQ significantly depressed DOPAC, HVA levels (by 60 and 40%, respectively), and attenuated the rate of DA metabolism (by about 60%). On the other hand, both the enantiomers increased the concentrations of DA and its extraneuronal metabolite, 3-MT in rat striatum. In vivo microdialysis study has shown that repeated but not acute administration of rotenone produced a deep and significant functional impairment of striatal DA release. Both (R)- and (S)- stereospecific enantiomers of 1MeTIQ antagonized rotenone-induced suppression of DA release; however, the effect of (R)-1MeTIQ was more strongly expressed in microdialysis study. In conclusion, we suggest that both chiral isomers of 1MeTIQ offer neuroprotection against rotenone-induced disturbances in the function of dopaminergic neurons and (R,S)-1MeTIQ will be useful as a drug with marked neuroprotective activity in the brain

MAO-inhibitors in Parkinson's Disease

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD

Cardiovascular risk and autonomic changes during high and low affect provocations

Does having a positive family history of essential hypertension predispose one to greater cardiovascular reactivity? Could reactivity be assessed with stress tasks that have greater external validity than traditional laboratory stressors? To answer these questions? 2b subjects with parental history of essential hypertension and 3b subjects without) were induced to converse with an experimenter on (a) a neutral topic (the weather)? and (b) an affective topic (a frustrating person or event). The topics were selected from a Iist of 2b because they had been rated by undergraduates as being the least and most arousing topics to talk about with a stranger in an experimental situation. The ratings yielded no interactions of sex of experimenter with sex of the subject. Subjects also performed a mental arithmetic task which is a standard laboratory stressor. The order of task presentation was randomly assigned within groups but matched across groups and sex to control sequence effects. For each subject? a 15-minute base I ine period was al lowed before each task. Readings of blood pressure? heart rate and rate of respiration were made at minute one? three? and five of each task phase. Each conversation task consisted of five minutes of talking followed by Iistening for five minutes to the experimenter. The tasks were separated by five-minute intervals to allow return to baseline levels. Results indicated that compared to individuals without parental history of hyper tension? individuals with parental history displayed higher levels of blood pressure (but not heart rate and rate of respiration) whether talking or listening. When peak values were considered; positive parental history subjects showed greater reactivity to the affective topic on diastolic blood pressure. The results also indicated that the three kinds of stressors yielded different levels of physiological responses with the math task and talk phase of the affect task yielding higher levels of blood pressure and heart rate than talk about the weather. The difference between the math and affective tasks was not significant on systolic blood pressure? but math yielded higher responses on heart rate and lower responses on diastolic blood pressure than talking about a frustrating event or person. These results suggest that a more generalizabIe stress stimulus such as an affect-laden conversation? can be reasonably standardized across subjects and elicits an aIpha-adrenergic vaso-constrictive response? a response more readily given by individuals with positive parental history than individuals without. The results also suggest that individuals with positive parental history of hypertension have higher blood pressure levels than individuals without. With respect to the similarity of the findings of this study? with those of other studies which have used older populations? it is proposed that these results are generalizable to older populations and provide evidence that a positive family history of essential hypertension may be considered a risk factor for later cardiovascular disease.Arts, Faculty ofPsychology, Department ofGraduat

The making of famous and glamorous artists : the role of FILE megazine in the work of General Idea

textFrom 1972 until 1989, the artist trio General Idea produced FILE Megazine. The first eight issues of FILE, published from 1972 – 1975, are the focus of this thesis. They stand apart from the later issues because their covers hijacked the look and iconic logo of Life magazine. The red rectangle with white block letters attracted the attention of Time Inc. and resulted in a lawsuit. Rather than fight the corporate giant, General Idea changed their logo after the autumn 1975 issue. FILE, like many artists’ magazines, is typically discussed in idealistic language that privileges the subversive or democratic intentions of the publication while neglecting its significance as a device for the promotion of community and collaboration. I argue that General Idea envisioned FILE as a utopian project intended to produce the world they sought to live in. Authors frequently employ FILE as a tool to discuss General Idea’s work, focusing on it as a mirror or archive of a larger project and emphasizing FILE’s humorous, bawdy, and irreverent aspects. In this thesis, I situate FILE in terms of its historical, art historical, and theoretical frameworks. I pay particular attention to General Idea’s early involvement in the mail art network, FILE’s relationship to 1960s and 1970s artists’ magazines and magazine art, the contemporaneous social and political climate in Canada, and General Idea’s investigation and employment of theoretical frameworks culled from Marshall McLuhan’s text The Medium is the Message and Roland Barthes’ book Mythologies.Art Histor

Causal beliefs of mental disorders and treatment preferences in Ghana

The present study investigated the association between social change and personality, causal beliefs, and treatment style and goal preferences of 375 Ghanaian teachers. The index of social change (ISC) was conceptualized as the average percentile rank of the individual's income and levels of education and acculturation. The self-report measures (greatly modified after two pilot studies), were subscales of the Suinn\Lew Acculturation Scale, the Depressive Experiences Questionnaire (dependency), the Sociotropy-Autonomy Scale (autonomy), the Symptom Checklist '90 (paranoid ideation), the Spheres of Control Scale, and the Cognitive Somatic Anxiety Questionnaire. Respondents also completed a questionnaire on causal beliefs and treatment preferences pertaining to mental disorders. Results indicated that beliefs and treatment preferences were affected by the index of social change (ISC) and were specific to type of disorder. High ISC teachers endorsed significantly higher ratings on belief in an internal cause for Depression and Dependent Personality Disorder, and indicated greater preference for participation in treatment than lower ISC teachers. Contrary to prediction, lower ISC teachers indicated a greater preference for individual goals in treatment for Depression and Schizophrenia. High ISC teachers also reported greater perception of interpersonal control and emotional support, but less dependency, and interpersonal sensitivity than lower ISC teachers. Little support was found for the commonly observed somatization of distress among non-Western peoples. Explanations [Page III missing from original thesis abstract]Arts, Faculty ofPsychology, Department ofGraduat