Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study.

Objective: This study aimed to assess potential efficacy and safety of dextromethorphan/quinidine (DMQ) in prophylactic treatment of migraine in patients with multiple sclerosis (MS) with superimposed pseudobulbar affect (PBA).

Methods: Multiple sclerosis patients with superimposed PBA and comorbid migraine were enrolled into this open-label observational study at the University of Southern California Comprehensive MS Center. The baseline characteristics included, among other data, frequency and severity of acute migraine attacks and use of migraine relievers.

CD4 cell response to interval therapy with natalizumab.

Natalizumab treatment alters peripheral CD4 cells counts in multiple sclerosis (MS) patients, providing a way to monitor the pharmacodynamic effects of the drug. The study was undertaken to assess whether CD4 cell counts correlate with different phases of natalizumab treatment of relapsing MS patients, including during a 12-week planned treatment interruption, and whether that might provide insights on lymphocyte trafficking. Clinical outcomes, MRI data, and CD4 cell counts were assessed at baseline prior to initiating natalizumab, while on regular dosing, at the end of the 12-week extended dosing interval, and at the time of reinitiation of natalizumab.

Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson's disease.

Background: Preladenant is a selective adenosine A₂A receptor antagonist under investigation for Parkinson's disease treatment.

Methods: A phase 2 36-week open-label follow-up of a double-blind study using preladenant 5 mg twice a day as a levodopa adjunct in 140 subjects with fluctuating Parkinson's disease was conducted. The primary end point was adverse event (AE) assessment.

Caffeine consumption and risk of dyskinesia in CALM-PD.

Background: Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia.

Methods: We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa.

Results: For subjects who consumed >12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.

Memory, mood, dopamine, and serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson's disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning.

Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury.

Studies have suggested that there are beneficial effects of exercise in patients with Parkinson's disease, but the underlying molecular mechanisms responsible for these effects are poorly understood. Studies in rodent models provide a means to examine the effects of exercise on dopaminergic neurotransmission. Using intensive treadmill exercise, we determined changes in striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse.

The selective kappa-opioid receptor agonist U50,488 reduces L-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates.

Several lines of evidence demonstrate that the striatal enkephalinergic system may be involved in the development of LIDs. Preproenkephalin-B (PPE-B) transcript levels are elevated with LIDs and there are also declines in kappa-opioid and other opioid receptors in different regions of the basal ganglia. If reduced kappa-opioid receptors are linked to LIDs, it is possible that drugs that stimulate this subtype may decrease dyskinesias.

The Webcam system: a simple, automated, computer-based video system for quantitative measurement of movement in nonhuman primates.

Investigations using models of neurologic disease frequently involve quantifying animal motor activity. We developed a simple method for measuring motor activity using a computer-based video system (the Webcam system) consisting of an inexpensive video camera connected to a personal computer running customized software. Images of the animals are captured at half-second intervals and movement is quantified as the number of pixel changes between consecutive images.

Enhanced striatal opioid receptor-mediated G-protein activation in L-DOPA-treated dyskinetic monkeys.

Long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease leads to dyskinesias in the majority of patients. The underlying molecular mechanisms for L-DOPA-induced dyskinesias (LIDs) are currently unclear. However, the findings that there are alterations in opioid peptide mRNA and protein expression and that opioid ligands modulate dyskinesias suggest that the opioid system may be involved.

Dyskinesias in normal squirrel monkeys induced by nomifensine and levodopa.

The mechanisms underlying levodopa-induced dyskinesias are unclear. They might involve impairment of the buffering capacity for dopamine, resulting from loss of nigral dopaminergic cells and the subsequent degeneration of their terminals in striatum. This study investigated the role of striatal buffering in the development of dyskinesias.

Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys.

Although l-3,4-dihydroxyphenylalanine (L-dopa) is one of the most effective therapies for Parkinson's disease, continued treatment may result in excessive involuntary movements known as L-dopa-induced dyskinesias (LIDs). Because LIDs can become dose-limiting, there is great interest in finding ways to ameliorate or prevent this troubling side effect of L-dopa therapy. It was recently reported that the D3 receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] reduces LIDs without diminishing antiparkinsonian effects of L-dopa in macaques.

Imaging and therapeutics: the role of neuronal transport in the regional specificity of L-DOPA accumulation in brain.

Purpose: To investigate the in vitro regional accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) in brain tissue.

Procedure: Neuronal membrane transport of L-DOPA was investigated in rat and squirrel monkey brain tissue. The kinetics of L-DOPA regional transport was characterized, and the effect of amino acids on transport was evaluated using isolated nerve terminals from striatum and cerebral cortex.

The hyperkinetic abnormal movements scale: a tool for measuring levodopa-induced abnormal movements in squirrel monkeys.

The Hyperkinetic Abnormal Movements Scale (HAMS) was developed based on extensive observation of normal and abnormal movements in squirrel monkeys. The observations of abnormal movements were performed using animals that had undergone prior lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that subsequently developed levodopa-induced abnormal movements. Specific and easily observable changes in behavior were used to delineate the boundaries between each rating level of the scale.

Novel observations with FDOPA-PET imaging after early nigrostriatal damage.

Striatal 6-[18F]fluoro-L-DOPA (FDOPA) kinetic rate constants were measured by positron emission tomography (PET) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. After scanning, stereological counts of dopaminergic neurons were done in substantia nigra, and dopamine (DA) and metabolite concentrations were determined in the caudate, putamen, and substantia nigra. Graded doses of MPTP produced animals with mild to moderate reductions (10-35%) in dopaminergic neurons, where the percent of cell loss was proportional to the amount of MPTP given.

Levodopa induces dyskinesias in normal squirrel monkeys.

This study assessed whether or not levodopa induces dyskinesias in normal (ie, unlesioned) squirrel monkeys. All six animals treated twice daily with levodopa (15 mg/kg with carbidopa by oral gavage) for two weeks developed choreoathetoid dyskinesias, whereas none of the vehicle-treated animals displayed any abnormal movements. These dyskinesias did not merely reflect a generalized motor activation as locomotion was actually suppressed.

Effects of wild-type and mutated copper/zinc superoxide dismutase on neuronal survival and L-DOPA-induced toxicity in postnatal midbrain culture.

Mutations in the free radical-scavenging enzyme copper/zinc superoxide dismutase (Cu/Zn-SOD) are associated with neuronal death in humans and mice. Here, we examine the effects of human wild-type (WT SOD) and mutant (Gly93 --> Ala; G93A) Cu/Zn-SOD enzyme on the fate of postnatal midbrain neurons. One-week-old cultures from transgenic mice expressing WT SOD enzyme had significantly more midbrain neurons and fewer necrotic and apoptotic neurons than nontransgenic cultures.

Systemic and intrastriatal theophylline have opposite effects on dopamine and dopamine metabolites measured by intrastriatal microdialysis in the rat.

Using a model of intrastriatal microdialysis, we studied the effect of theophylline, an A1 and A2A adenosine receptor antagonist on striatal dopamine (DA) and DA metabolites. Systemic administration of theophylline (10 and 50 mg/kg) significantly reduced striatal extracellular (EC) levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy-phenylacetic acid (HVA). Intrastriatal administration of theophylline (10(-2) M) significantly increased DA and its metabolites (DA1 + 120%; DOPAC, +28%; HVA, +30%).

Neuroleptics up-regulate adenosine A2a receptors in rat striatum: implications for the mechanism and the treatment of tardive dyskinesia.

Neuroleptics, which are potent dopamine receptor antagonists, are used to treat psychosis. In the striatum, dopamine subtype-2 (D2) receptors interact with high-affinity adenosine subtype-2 (A2a) receptors. To examine the effect of various neuroleptics on the major subtypes of striatal dopamine and adenosine receptors, rats received 28 daily intraperitoneal injections of these drugs.

Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine.

Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.

Quantitative assessment of quinolinic acid-induced striatal toxicity in rats using radioligand binding assays.

To validate specific, sensitive and quantitative markers of the rat model of Huntington's disease produced by the intrastriatal injection of quinolinic acid, we used striatal homogenate binding assays for [3H]MK-801-labelled N-methyl-D-aspartate receptors, [3H]SCH 23390-labelled D1 and [3H]sulpiride-labelled D2 dopamine receptors, [3H]CGS 21680-labelled adenosine A2 receptors, [3H]GBR 12935-labelled dopamine uptake sites, [3H]hemicholinium-3-labelled high affinity choline uptake sites and [3H]PK 11195-labelled glial cells, in 3 groups of rats: 1) lesioned only, 2) pretreated with MK-801, an antagonist of the N-methyl-D-aspartate receptor, to assess the non-N-methyl-D-aspartate-mediated toxicity of quinolinic acid, and 3) pretreated with MK-801 plus scopolamine, an anticholinergic drug that prevents MK-801 neuronal toxicity. [3H]MK-801 and [3H]PK 11195 are sensitive markers of quinolinic acid toxicity. In addition, [3H]SCH 23390, [3H]CGS 21680 and [3H]hemicholinium-3, are found to be specific markers of quinolinic acid-induced toxicity on striatonigral and striatopallidal projecting neurons, and on large interneurons, respectively.

L-dihydroxyphenylalanine-induced asymmetric changes in striatal uric acid peak: determination by in vivo electrochemical detection in rats with unilateral nigrostriatal lesions.

Rats were unilaterally lesioned with 6-hydroxydopamine to destroy the nigrostriatal pathway. Following injection with 25 mg/kg L-dopa, circling behavior away from the lesioned side was monitored. Concurrently, in vivo electrochemical detection was used to compare changes in striatal extracellular levels of ascorbic acid (Peak 1) and uric acid (Peak 2) on the lesioned and unlesioned sides.

Direct evidence of acute, massive striatal dopamine release in gerbils with unilateral strokes.

Dopamine release into the extracellular space was measured with in vivo electrochemical detection in the ipsilateral and contralateral striata in Mongolian gerbils that suffered a stroke after acute unilateral carotid artery ligations. A sevenfold increase in the dopamine signal occurred within 15 minutes of carotid ligation in the ischemic side, while the unlesioned side had no significant change. Increased extracellular levels of dopamine persisted throughout the 3-hour recording period.

Caffeine stimulates beta-endorphin release in blood but not in cerebrospinal fluid.

Plasma beta-endorphin and prolactin profiles were obtained from groups of unstressed, adult male rats. The infusion of caffeine (20 mg/kg) via a chronic, indwelling intra-atrial cannula results in a prompt and sustained (2-2.5 h) rise In plasma beta-endorphin levels.