Increased L-DOPA-derived dopamine following selective MAO-A or -B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation.

BACKGROUND AND PURPOSE: Selective MAO type B (MAO-B) inhibitors are effective in potentiation of the clinical effect of L-DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO-A) in rat brain. We sought to clarify the roles of MAO-A and MAO-B in deamination of DA formed from exogenous L-DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter-3 (OCT-3) inhibition by decinium-22 on extracellular DA levels following L-DOPA. EXPERIMENTAL APPROACH: Striatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6-hydroxydopamine or 5,7-dihydroxytryptamine respectively. Microdialysate DA levels after systemic L-DOPA were measured after inhibition of MAO-A or MAO-B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence. KEY RESULTS: Rasagiline increased DA extracellular levels following L-DOPA to a greater extent in double- than in single-lesioned rats (2.8- and 1.8-fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10-fold. MAO-A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO-B was localized in glia and to a small extent in MSNs. Inhibition of OCT-3 increased DA levels in the double- more than the single-lesion animals. CONCLUSIONS AND IMPLICATIONS: In striatum devoid of dopaminergic and serotonergic inputs, most deamination of L-DOPA-derived DA is mediated by MAO-A in MSN and a smaller amount by MAO-B in both MSN and glia. OCT-3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT-3 are potential future targets for anti-Parkinsonian treatments.

Vestibulocervical reflexes in idiopathic Parkinson disease.

OBJECTIVES: The mechanism of gait instability in Parkinson disease (PD) is not completely understood. We examined the saccular part of the otolith function and its possible contribution to gait difficulties in idiopathic PD. METHODS: Fifty-four PD patients (mean age 66 years, 32 men) were included. These were characterized with respect to disease severity, duration, treatment, as well as the presence of disease complications, dementia and depression. Vestibular evoked myogenic potentials (VEMP) were recorded in patients and 53 healthy controls. RESULTS: VEMP responses were recorded in all controls. Unilaterally absent VEMP responses were found in 20 (37%) of PD patients and bilaterally absent responses in four (7.4%). All patients with preserved peaks had normal latencies as compared with controls. The number of PD patients with abnormal/absent VEMP was thus significantly higher than in controls (p<0.00). There were no correlations between VEMP abnormality and disease stage, falls or medication. A correlation was found between abnormal VEMP and depression/antidepressant treatment. CONCLUSION: PD patients often have absent vestibulocollic reflexes. Further investigations are needed to elucidate the significance of this finding for postural stability and gait in this disorder.

Clinical characteristics of patients with ischemic ocular nerve palsies and lacunar brain infarcts: a retrospective comparative study.

BACKGROUND: Ischemic ocular motor nerve palsies (IOMP) and lacunar brain infarcts share a similar pathological mechanism. The clinical characteristics of patients as well as the protective role of aspirin should therefore be similar in both conditions. METHODS: The medical records of 107 consecutive patients with IOMP and 160 patients with lacunar cerebrovascular accidents (CVA) were reviewed and analyzed with respect to patient characteristics, vascular risk factors, and aspirin intake. The data on patients with and without aspirin were compared within each group as well as between both groups. RESULTS: Hyperlipidemia, smoking, high carotid stenosis (>70%) and the presence of more than one vascular risk factor in an individual patient were found to be more common in patients with lacunar brain infarcts regardless of aspirin intake. Absence of vascular risk factors was encountered more in IOMP patients. The recurrence of lacunar CVA was significantly higher than recurrence of IOMP. A history of Bell's palsy was more common in IOMP patients than in patients with lacunar CVA. Within the IOMP group, the prevalence of vascular risk factors did not differ between the aspirin and non-aspirin group. Ischemic heart disease (IHD), CVA and recurrence were found more often in the aspirin group. Within the CVA group hypertension, IHD, cardiac arrhythmia and recurrence rate were more common in the aspirin group whereas smoking was found to be more common in the non-aspirin group of patients. CONCLUSIONS: Arteriosclerosis is the main cause of lacunar CVA and IOMP. However, IOMP depends less on the presence of vascular risk factors than does lacunar CVA. Furthermore, aspirin - at least at low doses - does not seem to have a protective effect on either of these conditions, but more extensive prospective studies of homogeneous groups of patients are needed to clarify the preventive role of antiplatelet agents in IOMP.

Infectious inflammation of the CNS involves activation of mitogen-activated protein kinase and AKT proteins in CSF in humans.

The mitogen-activated protein kinases (MAPKs) and the AKT are interacting proteins that serve as transmitters of numerous extracellular signals to their intracellular targets, thereby regulating many cellular processes, such as proliferation, differentiation, development or stress responses. Whereas a large amount of information about the MAPKs/AKT participation in biological processes is available, less is known about their role in human diseases. We postulated that the MAPKs/AKT could be involved in inflammatory processes of the central nervous system (CNS) in humans and we investigated the CSF of 12 patients with viral infection of the CNS for the presence of the distinct components of these cascades. The cerebrospinal fluid (CSF) of 18 individuals who underwent a lumbar puncture for diagnostic purposes served as controls. Six patients with inflammatory disease of the CNS revealed the presence of activated ERK. In five patients p38MAPK was detected, in three in its activated form. The activity of AKT could be demonstrated in four patients. JNK was not found. None of the control patients showed the presence of MAPK enzymes. The mean CSF cellularity was higher in MAPK-positive than in MAPKnegative patients. There was no difference in mean age or gender between the patients and controls, or between the MAPK- and AKT-positive or -negative patients. Our work demonstrates that the MAPK and AKT cascades might participate in inflammatory processes of the CNS. As selective inhibitors of the MAPKs are available, their application in the future might reduce an inappropriate inflammatory response and thus limit brain damage in severe cases of meningoencephalitis.

Body packer: cocaine intoxication, causing death, masked by concomitant administration of major tranquilizers.

Cocaine, derived from the leaves of the shrub Erythroxylon coca, which grows on the slopes of the Andes, remains one of the most widely abused illicit drugs (Johnson et al., 1993). Its abuse appears to be increasing and as a result, so is its trafficking across borders, with ever-increasing sophistication of concealment (Rouse, 1992). Over the past few years, cases of cocaine intoxication have been reported, resulting from ruptured packets of cocaine that have been swallowed, or inserted into the vagina or rectum by couriers (drug smugglers), so called 'body packers' or 'mules' (Westli and Mittleman, 1981; Ricaurte and Langston, 1995). Cocaine is a powerful sympathomimetic and central nervous system stimulant, an overdose of which causes primarily cardiac, neurological and psychiatric effects (Ricaurte and Langston, 1995). Acute toxicity is dose-related and is characterized in the first place by its sympathomimetic effects, which include tachycardia, hypertension and hyperthermia arrythmias, followed by seizures. Brainstem depression and cardio-respiratory collapse, stroke, coma, intracranial vasculitis, myocardial infarction and sudden death have all been reported in cocaine abuse (Ricaurte and Langston, 1995). We present a fatal case with neurological and psychiatric symptoms, but without the usual cardiac and systemic signs.

Long-term tolerability and efficacy of cabergoline, a new long-acting dopamine agonist, in Parkinson's disease.

Motor fluctuations constitute a severe complication of chronic levodopa therapy. The addition of dopamine agonists may partially alleviate these responses; however, due to the short half-life of these drugs, several daily doses are required. Cabergoline is a new dopamine agonist with a long half-life and can be given in a single daily dose. Seventeen patients with severe fluctuations were treated with cabergoline, seven of them for > 1 year (up to 39 months). The motor status ameliorated and the percentage of "off" hours significantly decreased in the first year and did not increase significantly later during long-term follow-up. Cabergoline is a promising treatment for parkinsonian patients with motor fluctuations.

Effects of a single intravenous dose of scopolamine on the quantitative EEG in Alzheimer's disease patients and age-matched controls.

Quantitative EEG (qEEG) was evaluated in Alzheimer's disease (AD) patients and age-matched controls following the administration of a single acute intravenous dose of scopolamine. Eleven AD patients and 8 cognitively intact age-matched controls underwent qEEG in baseline conditions, following double-blind intravenous administration of 0.5 mg scopolamine or placebo. At baseline, AD patients had significantly decreased absolute and relative alpha and increased relative theta amplitudes. In both groups, scopolamine administration was followed by a decrease in absolute and relative alpha amplitude, and increase in the absolute and relative delta activity. The increase in the absolute and relative delta amplitude by scopolamine was significantly more prominent in the controls; the decrease of alpha activity, while larger in controls, was not statistically different from AD. We conclude that scopolamine affects the change in delta amplitude differently in AD patients and controls, probably reflecting the reduced cholinergic tone in AD.

Electrophysiologic features in patients with chronic neurolathyrism.

Neurolathyrism is a toxic nutritional disorder induced by the ingestion of the chick-pea "lathyrus sativus" and characterized by a pure motor spastic paraparesis. Eight patients with long-standing disease underwent nerve conduction and electromyographic studies. Two of them (25%) showed electrophysiological signs of lower motor neuron disease in their lower limbs. Subclinical affection of the anterior horn cells occurs probably more frequently than expected in chronic neurolathyrism.

Generalized epileptic seizures as the presenting symptom of lacunar infarction in the brain.

Five elderly hypertensive patients presented with grand mal seizures and had computed tomographic (CT) findings consistent with lacunar infarction. Three of them had also a recent hemiparesis, contralateral to the side of the CT findings. Follow-up CT scans supported the diagnosis of lacunar infarction. Contrary to the accepted opinion, generalized epileptic seizures may be the presenting symptom of lacunar brain infarction.

Herpes encephalitis during pregnancy: failure of acyclovir and adenine arabinoside to prevent neonatal herpes.

A gravid woman with herpes Type II encephalitis delivered an infant with herpes neonatorum despite therapy with acyclovir. Acyclovir was not measurable in the baby's serum 10 h after birth. The viral isolate was sensitive to acyclovir in vitro, and the neonatal infection responded to treatment with the drug. Prenatal antiviral therapy may be ineffective in preventing intrauterine herpesvirus infection.

Long-term effects of L-deprenyl in chronic levodopa treated parkinsonian patients.

In a previous communication the results of a three months clinical trial with the co-administration of the Beta-type Monoamineoxydase (MAO)-inhibitor L-deprenyl in long-term levodopa treated Parkinsonian patients were reported. In view of the favourable effects observed in this study, as well as in others, L-deprenyl was continued in this patient group and given to other patients, found suitable, for periods of four years and more. In the 29 patients reported here, special attention was addressed to fluctuating manifestations of chronic levodopa therapy. Apart from a considerable subjective improvement, L-deprenyl effected an objective improvement in the overall disability score as well as an appreciable reduction of "on-off" phenomena in the great majority of the patients. Dyskinesias appeared in 4 of the patients and increased mildly in another ten. Untoward effects of L-deprenyl were not serious, mostly transitory, and none was prohibitive. In 13 of the 29 patients (44.83%) the levodopa dose could be reduced by 26.5% +/- 0.46, while in two patients it was raised from 250 mgm to 462.5 mgm daily. The present and previous clinical studies show that L-deprenyl is a valuable adjunctive agent for the long-term levodopa treated parkinsonian patient.