piperidines and Parkinson-Disease--Secondary

The diagnosis of Parkinson's disease (PD) is clinical and is based on the identification of a combination of the cardinal motor signs of bradykinesia plus at least one of the following: rigidity, tremor or postural instability. There are many causes of parkinsonism such as drug induced parkinsonism, subcortical vascular disease, and multisystem atrophy. PD is a well characterised syndrome which represents only a part of the various causes of parkinsonism. A good response to dopaminergics is an important diagnostic criteria for PD. Pharmacotherapy for PD relies primarily on levodopa and dopamine agonists. Deep brain stimulation is increasingly used in the management of patients with severe dopa fluctuations and dyskinesias. Cholinesterase inhibitors are introduced for dementia in parkinsonism. Neuroprotective compounds, nerve growth factors such as GDNF and the implantation of dopaminergic cells are studied in clinical trials.

Topics: Aged; Amantadine; Antiparkinson Agents; Apomorphine; Botulinum Toxins; Catechols; Cholinesterase Inhibitors; Clinical Trials as Topic; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Enzyme Inhibitors; Ergot Alkaloids; Family Practice; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Piperidines

Topics: Adolescent; Adult; Aged; Basal Ganglia Diseases; Benzamides; Butyrophenones; Child; Drug-Related Side Effects and Adverse Reactions; Dystonia; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Muscle Hypertonia; Muscle Rigidity; Parkinson Disease, Secondary; Phenothiazines; Piperazines; Piperidines; Reserpine; Thioxanthenes

Dementia with Lewy bodies (DLB) is common. Symptomatic treatment can be difficult. We reviewed nine consecutive patients with DLB (mean age 77.5 [range 67 to 84] years; seven men and two women; mean duration of disease 3.7 [range 1.5 to 8.0] years) who had been treated with donepezil. Each initially received 2.5 to 5 mg per day of donepezil, and was stabilized on 5 mg per day. Donepezil was increased to 10 mg per day in five patients. The mean observation period was 12 (range 8 to 24) weeks. Target symptoms included cognition, hallucinations, parkinsonism, and functional abilities. By both cognitive testing and family reports, cognition improved in seven of nine patients, remained the same in one of nine, and fluctuated in one of nine (mean Mini-Mental State Examination change 4.4 +/- 6.3 points). Function was improved or maintained in six of nine patients and fluctuated in two of nine. Hallucinations initially worsened, then fluctuated in one patient, but improvement in frequency, duration, and content was reported in eight of nine cases. In three of nine patients, treatment with donepezil resulted in worsening of parkinsonism, which in each case responded to levodopa/carbidopa. Treatment of DLB patients with donepezil for 12 weeks most commonly improved hallucinations, and sometimes improved cognition and overall function. Treatment with donepezil was sometimes associated with worse parkinsonism.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Dementia; Donepezil; Female; Geriatric Assessment; Humans; Indans; Lewy Bodies; Male; Mental Status Schedule; Nootropic Agents; Parkinson Disease, Secondary; Piperidines

Risperidone (RIS), a new neuroleptic with 5-HT2- and dopamine D2 receptor-blocking properties, was compared with perphenazine (PER) in a double-blind, multicentre, parallel-group study in 107 chronic schizophrenics with acute exacerbation. RIS 5-15 mg or PER 16-48 mg daily was given for 8 weeks. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression. Seventy-eight patients completed the trial; there was an equal number of dropouts on both drugs. The mean daily dose at endpoint was 8.5 mg RIS and 28 mg PER. The reduction in total PANSS score to endpoint did not differ significantly, although there was a tendency in favour of RIS. The number of patients with predominantly negative symptoms who showed at least 20% reduction in total PANSS score was significantly larger in the RIS group. Furthermore, the number of patients showing at least 20% reduction in Brief Psychiatric Rating Scale (BPRS) score (BPRS being a subscale of PANSS) was significantly larger in the RIS group. The hostility cluster of BPRS improved more on RIS than on PER in the endpoint analysis. The overall prevalence of side effects was fairly similar in the two groups.

Topics: Acute Disease; Adult; Aged; Antipsychotic Agents; Denmark; Double-Blind Method; Female; Humans; Isoxazoles; Male; Middle Aged; Norway; Parkinson Disease, Secondary; Perphenazine; Piperidines; Prevalence; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

Several studies support the hypothesis of 5-HT (serotonin) involvement in the physiopathology of the extrapyramidal system. Ritanserin is a new compound with a high, selective, and long-lasting binding affinity for 5-HT2 receptors. A therapeutic effect of ritanserin has been reported in Parkinson's tremor and L-Dopa-induced dyskinesias but no effect was seen in essential tremor. In this double-blind comparative study with orphenadrine (150 mg daily p.o.) and placebo, ritanserin (30 mg daily p.o.) was administered to 36 schizophrenic outpatients who were being treated with neuroleptic drugs and who had parkinsonism. For a period of 3 weeks, the treatment was added to the antipsychotic therapy after a 7-day washout from previous antiparkinson medication. Psychopathology was rated weekly by the Brief Psychiatric Rating Scale and showed no significant changes during the trial. The Mindham Rating Scale was used to assess symptoms of parkinsonism; at week 3, ritanserin was superior to orphenadrine (p less than 0.03) and to placebo (p less than 0.01). The results confirm previous observations of the therapeutic efficacy of ritanserin on neuroleptic-induced parkinsonism, and support the hypothesis that serotonin influences extrapyramidal physiopathology.

Topics: Adolescent; Adult; Double-Blind Method; Female; Humans; Male; Middle Aged; Orphenadrine; Parkinson Disease, Secondary; Piperidines; Psychiatric Status Rating Scales; Ritanserin; Serotonin Antagonists

A single-blind study compared the clinical efficacy of biperiden hydrochloride (Akineton, Abbott) and benzhexol (Artane, Lederle) in the treatment of neuroleptic-induced Parkinsonism. Both drugs were highly effective and all patients responded favourably to medication. No significant difference was observed between the two treatment groups when individual symptoms were examined.

Topics: Adolescent; Adult; Biperiden; Female; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Piperidines; Trihexyphenidyl

Topics: Aged; Biperiden; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Thioridazine

The influence of prodipin, a putative dopamine releasing compound, on the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the spinal liquor of 28 patients with Parkinson's disease was investigated. The patients were divided into three groups. In group 1 the combined antiparkinson therapy was interrupted, and 20 mg prodipin was infused. In group 2 and 3 the therapy was continued, while an additional 20 mg of prodipin was administered by infusion only to group 3. 4 Liquor-samples were obtained from each patient: 1 basic value and three additional samples 5, 8 and 24 hours after administration of 2 g probenecid. The base concentration of HVA was 15 ng/ml and this was not increased by probenecid in group 1; the concentration of 5-HIAA was 11.6 ng/ml and this was doubled by probenecid to 22.9 ng/ml. The HVA concentration increased to a maximum of 28.9 ng/ml during continued therapy (group 2); the elevated 5-HIAA remained unchanged. Prodipin does not cause an alteration in metabolite concentration in cases of interrupted therapy (group 1), but leads, in the case of continued therapy, to a 1.8-fold increase in HVA, and a 1.6-fold increase in 5-HIAA (group 3).

Topics: Aged; Antiparkinson Agents; Clinical Trials as Topic; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Parkinson Disease, Secondary; Phenylacetates; Piperidines; Time Factors

Topics: Adolescent; Adult; Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Biperiden; Clinical Trials as Topic; Humans; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines

Topics: Basal Ganglia Diseases; Blood Pressure; Chronic Disease; Clinical Trials as Topic; Female; Fluorobenzenes; Fluphenazine; Heart Rate; Humans; Injections, Intramuscular; Male; Parkinson Disease, Secondary; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: Adolescent; Adult; Age Factors; Aged; Child; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Movement Disorders; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Placebos; Psychotic Disorders; Sex Factors; Time Factors; Tranquilizing Agents; Trihexyphenidyl

Topics: 1-Propanol; Adult; Biperiden; Clinical Trials as Topic; Handwriting; Humans; Male; Middle Aged; Neurologic Examination; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines; Psychiatric Status Rating Scales

Janus-activated kinases (JAKs) are well known to play a physiological as well as pathological role in several disease conditions such as autoimmune disorders. The present study evaluated the therapeutic potential of CP690550 (pan-JAK inhibitor) in 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP) model of Parkinson's disease. Intrastriatal administration of MPTP (30 micromol in 2 microl) produced a significant alteration in behavioural (bar test and block test). Biochemical investigations in serum and brain homogenate revealed a significant alteration in the JAK-mediated cytokine levels. MPTP administration also showed significant imbalance of inflammatory (increased TNF-α, IL-6 and NF-κb) versus anti-inflammatory cytokines (decreased IL-10 levels). MPTP-treated brain sections revealed alteration in the tissue architecture as well as undifferentiated bodies of varying contour and lesions. Chronic administration of CP690550 (3 and 10 mg/kg, po) for 7 days significantly reversed the behavioural, biochemical and histological alterations induced by MPTP. In conclusion, the findings of the present study govern the possible therapeutic potential of CP690550 in MPTP-treated mice and thus highlight the therapeutic potential of JAK inhibitors in treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cytokines; Disease Models, Animal; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Pyrimidines

Parkinson's disease (PD) is a neurodegenerative disorder caused by selective dopaminergic neuronal loss. Rotenone is a neurotoxin that selectively destroys dopaminergic neurons, leading to PD-like symptoms. Quercetin possesses antioxidant, anti-inflammatory, and neuroprotective properties but a major drawback is its low bioavailability. Therefore, the present study was designed to evaluate the neuroprotective effect of quercetin in combination with piperine against rotenone- and iron supplement-induced model of PD. Rotenone was administered at a dose of 1.5 mg/kg through an intraperitoneal route with iron supplement at a dose of 120 μg/g in diet from day 1 to day 28. Pre-treatment with quercetin (25 and 50 mg/kg, p.o.), piperine (2.5 mg/kg, p.o.) alone, quercetin (25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg), and ropinirole (0.5 mg/kg, i.p.) was administered for 28 days 1 h prior to rotenone and iron supplement administration. All behavioral parameters were assessed on weekly basis. On the 29th day, all animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite, GSH, mitochondrial complexes I and IV), neuroinflammatory (TNF-α, IL-1β, and IL-6), and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) estimation. Quercetin treatment attenuated rotenone- and iron supplement-induced motor deficits and biochemical and neurotransmitter alterations in experimental rats. However, combination of quercetin (25 mg/kg) with piperine (2.5 mg/kg) significantly enhanced its neuroprotective effect as compared with treatment with quercetin alone. The study concluded that combination of quercetin with piperine contributed to superior antioxidant, anti-inflammatory, and neuroprotective effect against rotenone- and iron supplement-induced PD in experimental rats.

Topics: Alkaloids; Benzodioxoles; Corpus Striatum; Dietary Supplements; Drug Synergism; Electron Transport Complex I; Electron Transport Complex IV; Glutathione; Indoles; Interleukin-1beta; Interleukin-6; Iron; Lipid Peroxidation; Neuroprotective Agents; Neurotransmitter Agents; Nitrites; Parkinson Disease, Secondary; Piperidines; Polyunsaturated Alkamides; Quercetin; Rotenone; Tumor Necrosis Factor-alpha

Pridopidine is a small molecule in clinical development for the treatment of Huntington's disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.

Topics: Animals; Dopaminergic Neurons; Female; Male; Mice; Motor Skills; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Receptors, sigma; Sigma-1 Receptor; Substantia Nigra

Recently, the biased and highly selective 5-HT

Topics: Animals; Basal Ganglia; Brain Waves; Cerebral Cortex; Disease Models, Animal; Dyskinesias; Electric Stimulation; Evoked Potentials; Female; Levodopa; Neural Pathways; Parkinson Disease, Secondary; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Thalamus

Ghrelin is a peptide produced in the gut with a wide range of physiological functions. Recent studies have suggested it may have potential as a neuroprotective agent in models of Parkinson's disease, reducing the impact of toxic challenges on the survival of nigral dopaminergic neurons. The presence of the ghrelin receptor (GHSR1a) on the dopaminergic neurons of the substantia nigra raises the possibility that a potential application for this property of ghrelin may be as an adjunctive neuroprotective agent to enhance and support the survival and integration of dopaminergic cells transplanted into the striatum. Thus far, inconsistent outcomes in clinical trials for fetal cell transplantation have been linked to low rates of cell survival which we hypothesize could be ameliorated by the presence of ghrelin. To explore this, we confirmed the expression of the GHSR1a and related enzymes on e14 ventral mesencephalon. To determine a functional effect, five groups of female Sprague-Dawley rats received a unilateral 6-OHDA lesion to the medial forebrain bundle and four received an intrastriatal graft of e14 ventral mesencephalic cells. Grafted rats received saline; acyl-ghrelin (10 µg/kg); acyl-ghrelin (50 µg/kg) or the ghrelin agonist JMV-2894 (160 µg/kg) i.p. for 8 weeks. An effect of ghrelin at low dose on hippocampal neurogenesis indicated blood-brain barrier penetrance and attainment of biologically relevant levels but neither acyl-ghrelin nor JMV-2894 improved graft survival or efficacy.

Topics: Animals; Cell Survival; Dopaminergic Neurons; Female; Ghrelin; Indoles; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Triazoles

Parkinson's disease (PD) is the second most common progressive neurodegenerative movement disorder. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate‑limiting step in the nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in mammals, is a substrate for NAD+‑dependent enzymes, such as sirtuin 1 (SIRT1), and contributes to cell fate decisions. However, the role of NAMPT in PD has remained to be fully elucidated. In the present study, PC12 cells were treated with the neurotoxin 6-hydroxydopamine (6‑OHDA) to establish an in vitro model of PD, following which an obvious inhibitory effect on the levels of NAMPT and NAD+ as well as the NAD+/NADH ratio was detected. In addition, pre‑incubation with FK866, a highly specific NAMPT inhibitor, enhanced the inhibitory effects of 6‑OHDA on the viability of PC12, while pre‑incubation with nicotinamide mononucleotide (NMN), am enzymatic product of NAMPT, had the opposite effect. Furthermore, it was revealed that NMN markedly attenuated 6‑OHDA‑induced decreases in superoxide dismutase activity and glutathione levels, as well as 6‑OHDA‑induced increases in malondialdehyde and lactate dehydrogenase in PC12 cells. Furthermore, 6‑OHDA significantly reduced SIRT1 activity in PC12 cells, which was inhibited by NMN. The pharmacological activator resveratrol also significantly inhibited 6‑OHDA‑mediated decreases in PC12 cell viability while reversing 6‑OHDA‑induced decreases in SIRT1 levels. The results of the present study suggested that NMT protected against 6‑OHDA‑induced decreases in PC12 cell viability, and that SIRT1 activation had a role in this process. Treatment with NMN to activate SIRT1 may represent a novel therapeutic strategy for treating PD.

Topics: Acrylamides; Animals; Cell Survival; Cytokines; L-Lactate Dehydrogenase; Malondialdehyde; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Oxidopamine; Parkinson Disease, Secondary; PC12 Cells; Piperidines; Rats; Sirtuin 1

Parkinson's disease (PD) is the second most common neurodegenerative disorder, but there are few treatments currently available. The autophagy pathway plays an important role in the pathogenesis of PD; modulating this pathway is considered to be a promising treatment strategy. Piperine (PIP) is a Chinese medicine with anti-inflammatory and antioxidant effects. The present study investigated the neuroprotective effects of PIP on rotenone-induced neurotoxicity in SK-N-SH cells, primary rat cortical neurons, and in a mouse model. Mice were administered rotenone (10mg/kg) for 6 weeks; PIP (25mg/kg, 50mg/kg) was subsequently administered for 4 weeks. We found that PIP treatment attenuated rotenone-induced motor deficits, and rescued the loss of dopaminergic neurons in the substantia nigra. PIP increased cell viability and restored mitochondrial functioning in SK-N-SH cells and primary neurons. In addition, PIP induced autophagy by inhibiting mammalian target of rapamycin complex 1(mTORC1) via activation of protein phosphotase 2A (PP2A). However, inhibiting PP2A activity with okadaic acid reduced these protective effects, suggesting that PP2A is a target of PIP. These findings demonstrate that PIP exerts neuroprotective effects in PD models via induction of autophagy, and may be an effective agent for PD treatment.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Autophagy; Benzodioxoles; Cell Survival; Dopaminergic Neurons; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Parkinson Disease, Secondary; Piperidines; Polyunsaturated Alkamides; Protein Phosphatase 2; Rats; Rotenone; Substantia Nigra

Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/- and σ1R-/-) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/- or σ1R-/- mice (MPTP-σ1R+/- or MPTP-σ1R-/- mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/- mice treated with the σ1R agonist PRE084 or MPTP-σ1R-/- mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/- mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/- mice or σ1R-/- mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R-/- mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R-/- mice. The number of activated astrocytes in MPTP-σ1R-/- mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anisoles; Astrocytes; Cell Death; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Morpholines; Neuroprotective Agents; Parkinson Disease, Secondary; Pars Compacta; Phenols; Phosphorylation; Piperidines; Propylamines; Psychomotor Performance; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sigma-1 Receptor; Signal Transduction; Vesicular Monoamine Transport Proteins

Clinical observations have suggested that antagonism of 5-HT2A receptors may benefit patients with parkinsonian symptomatology. The mechanism of the antiparkinsonian effects of 5-HT2A receptor antagonists has not been fully elucidated. We have shown that the selective 5-HT2A receptor antagonist M100907 [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol] improved motor impairments in mice treated with the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In Parkinson's disease (PD) patients and animal models of parkinsonism dopamine denervation is associated with increased cortico-striatal glutamatergic transmission. We hypothesized that 5-HT2A receptor antagonists may exert their antiparkinsonian effects by decreasing striatal glutamate. Here, using in vivo microdialysis, we have shown an increased basal level of extracellular striatal glutamate when measured 3weeks after MPTP administration. The local administration of M100907 to the striatum significantly decreased striatal extracellular glutamate levels in MPTP-treated and saline treated mice. Basal extracellular serotonin (5-HT) levels were also elevated, whereas dopamine (DA) levels were significantly reduced in the striatum of MPTP-treated mice. Infusion of M100907 into the striatum produced no effect on dopamine or 5-HT levels. Local application of tetrodotoxin suppressed glutamate, 5-HT and DA concentrations in striatal dialysates in the presence or absence of M100907. The striatal expression of the glutamate transporter GLT1 was unchanged. However, there was an upregulation of the expression of 5-HT2A receptors in the striatum of MPTP-treated animals. Our data provide further evidence of enhanced glutamatergic neurotransmission in parkinsonism and demonstrate that blocking 5-HT2A receptors in the striatum will normalize glutamatergic neurotransmission.

Topics: Animals; Extracellular Space; Fluorobenzenes; Glutamic Acid; Male; Mice; Mice, Inbred C57BL; Microdialysis; MPTP Poisoning; Neostriatum; Parkinson Disease, Secondary; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Synaptosomes

In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients.

Topics: Adenosine A2 Receptor Antagonists; Analysis of Variance; Animals; Benzothiazoles; Drug Therapy, Combination; Levodopa; Mass Spectrometry; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Purines; Pyrimidines; Rats; Receptors, N-Methyl-D-Aspartate; Triazoles

Neuroinflammation and blood brain barrier (BBB) dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 µg/2 µL) or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 µL at 50 nM) or L-333,060 (2 µL at 100 nM), administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

Topics: Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Cells; Dopaminergic Neurons; Inflammation; Male; Motor Activity; Neurokinin-1 Receptor Antagonists; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Substance P; Substantia Nigra; Tryptophan

Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Male; Motor Activity; MPTP Poisoning; Parkinson Disease, Secondary; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Thiazoles

Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anti-Dyskinesia Agents; Antiparkinson Agents; Benzoxazoles; Denervation; Dopamine; Dopamine Agents; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Female; Image Processing, Computer-Assisted; In Situ Hybridization; Levodopa; Macaca fascicularis; Motor Activity; Neuroprotective Agents; Oligonucleotide Probes; Ovariectomy; Parkinson Disease, Secondary; Piperidines; Pyrimidines; Receptor, Adenosine A2A; Receptors, N-Methyl-D-Aspartate; Triazoles

Sensitization of NMDA receptors containing the NR2B subunit has been increasingly associated with various forms of synaptic plasticity, including those implicated in the pathogenesis of extrapyramidal motor dysfunction. To determine whether activation of NR2B containing receptors contributes to the development and maintenance of levodopa-induced response changes in parkinsonian animals, we evaluated the effects of the selective NR2B antagonist CP-101,606 on these response alterations in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Three weeks of twice-daily levodopa treatment decreased the duration of the rotational response to acute levodopa challenge. The response alteration was associated with an increase in GluR1 (S831) phosphorylation in medium spiny neurons of the dorsolateral striatum. Both the attenuated rotational response and augmented GluR1 phosphorylation were decreased by CP-101,606 treatment. These CP-101,606 effects were observed when the compound was administered either at the end of chronic levodopa treatment (ameliorative effect) or together with the twice-daily levodopa treatment for 3 weeks (preventive effect). Furthermore, concurrent administration of CP-101,606 with levodopa potentiated the ability of levodopa challenge to reverse the 6-OHDA lesion-induced contralateral forelimb movement deficit as measured in a drag test. These results suggest that activation of NR2B subunit containing NMDA receptors contributes to both the development and maintenance of levodopa-induced motor response alterations, through a mechanism that involves an increase in GluR1 phosphorylation in striatal spiny neurons.

Topics: Animals; Excitatory Amino Acid Antagonists; Functional Laterality; Levodopa; Locomotion; Male; Neostriatum; Oxidopamine; Parkinson Disease, Secondary; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Rotation; Serine; Stereotyped Behavior; Sympathectomy, Chemical

Treatments for Parkinson's disease based on replacement of lost dopamine have several problems. Following loss of dopamine, enhanced N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the striatum is thought to be part of the cascade of events leading to the generation of parkinsonian symptoms. We determined the localisation and pharmacological characteristics of NMDA receptors that play a role in generating parkinsonian symptoms within the striatum. Rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and cannulae implanted bilaterally to allow injection of a range of NMDA receptor antagonists at different striatal sites. When injected rostrally into the dopamine-depleted striatum, the glycine site partial agonist, (+)-HA-966 (44-400 nmol) caused a dose-dependent contraversive rotational response consistent with an antiparkinsonian action. (+)-HA-966 (400 nmol) had no effect when infused into more caudal regions of the dopamine-depleted striatum, or following injection into any striatal region on the dopamine-intact side. To determine the pharmacological profile of NMDA receptors involved in inducing parkinsonism in 6-OHDA-lesioned rats, a range of NMDA receptor antagonists was infused directly into the rostral striatum. Ifenprodil (100 nmol) and 7-chlorokynurenate (37 nmol), but not MK-801 (15 nmol) or D-APV (25 nmol) elicited a dramatic rotational response when injected into the dopamine-depleted striatum. This pharmacological profile is not consistent with an effect mediated via blocking NR2B-containing NMDA receptors. The effect of intrastriatal injection of ifenprodil was increased in animals previously treated with levodopa (L-dopa) methyl ester. This was seen as an increase in on-time and in peak rotational response. We propose that stimulation of NR2B-containing NMDA receptors in the rostral striatum underlies the generation of parkinsonian symptoms. These studies are in line with previous findings suggesting that administration of NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients, when given de novo and following L-dopa treatment.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Levodopa; Male; Microinjections; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

PNU-96391A is a weak dopamine (DA) D(2) receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle. Repeated twice daily treatment with L-DOPA and the decarboxylase inhibitor benserazide (15 and 5 mg/kg, IP, respectively), or quinpirole (D(2)/D(3) agonist, 0.1 mg/kg, SC) increased the contralateral rotations measured on day 7 and 14 as compared to day 1. PNU-96391A (10-60 mg/kg, SC, bid.) antagonized the development of behavioral sensitization induced by both agonists. The basal activity of L-DOPA was not affected while a reduction of quinpirole-induced rotations was observed after 30-60 mg/kg, SC of PNU-96391A. Neurochemical analyses confirmed >99 % reductions of striatal DA levels, unilaterally. Concomitant treatment with PNU-96391A and L-DOPA did not affect plasma levels of PNU-96391A indicating that the effects observed are not related to pharmacokinetic interactions. These results suggest that PNU-96391A could be therapeutically useful to prevent the development of behavioral sensitization induced by DA agonists.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain Chemistry; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Homovanillic Acid; Levodopa; Male; Medial Forebrain Bundle; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Quinpirole; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Sympathectomy, Chemical; Sympatholytics

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.

Topics: Animals; Autoradiography; Callithrix; Caudate Nucleus; Corpus Striatum; Disease Models, Animal; Dopamine Agents; Drug Administration Schedule; Drug Therapy, Combination; Enkephalins; Female; In Situ Hybridization; Injections, Subcutaneous; Levodopa; Ligands; Male; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Protein Precursors; Putamen; RNA, Messenger; Tritium

To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias.. Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined.. The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa.. CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05).. AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzodiazepines; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Female; Levodopa; Macaca fascicularis; Male; Motor Activity; Parkinson Disease, Secondary; Piperidines; Receptors, AMPA; Severity of Illness Index

In the setting of nigrostriatal dopamine depletion, glutamatergic pathways to the striatum and basal ganglia output nuclei become overactive. Systemically administered glutamate receptor antagonists may have direct antiparkinsonian actions in rodents, but there is little evidence for this in primates. Glutamate antagonists may also potentiate conventional dopaminergic therapies; however, there is concern that broad spectrum, nonselective antagonists may have unwanted side-effects. Because subunit-selective antagonists may avoid these liabilities, we have examined the antiparkinsonian effects of a selective antagonist of the NR2B subunit of the NMDA receptor. In rats, CP-101,606 decreased haloperidol-induced catalepsy with an ED(50) of about 0.5 mg/kg. In MPTP-treated monkeys, CP-101,606 (1 mg/kg) reduced parkinsonian motor symptoms by 20%. At a dose of 0.05 mg/kg, CP-101,606 markedly potentiated the effect of a submaximal dose of levodopa, reducing motor symptoms by about 50% compared to vehicle and by about 30% compared to levodopa alone. No side-effects were apparent at any dose of CP-101,606. We conclude that CP-101,606 has direct antiparkinsonian actions in both rodents and monkeys and it synergistically potentiates levodopa in MPTP-treated monkeys. Clinical evaluation of selective NR2B antagonists may be warranted in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Catalepsy; Dopamine Agents; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Haloperidol; Levodopa; Macaca mulatta; Male; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Inbred F344; Reaction Time; Receptors, N-Methyl-D-Aspartate

Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally.

Topics: Animals; Benzimidazoles; Electrophysiology; Excitatory Amino Acid Antagonists; Hydantoins; Hydrogen Bonding; Male; Neuroprotective Agents; Oocytes; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Sympatholytics; Xenopus

Tinuvin 123, a compound used in the manufacture of plastics, has recently been suggested to possibly cause Parkinson's disease (PD). Herein, we revisited this issue by assessing the effect of Tinuvin 123 on dopaminergic neurons of the substantia nigra following its stereotaxic injection in the rat. Twenty-one days post unilateral stereotaxic injection of Tinuvin 123, systemic injection of both apomorphine and amphetamine caused rotations toward the side of the lesion in these rats. Tinuvin 123 produced a small to moderate dose-dependent reduction in striatal levels of dopamine and metabolites on the side of the lesion. This compound also produced dramatic cell loss in the substantia nigra on the side of the lesion. However, the loss of cells lacked the phenotypic specificity for tyrosine hydroxylase (TH)-positive neurons that is expected with a dopaminergic neurotoxin. Indeed, aside from a robust glial reaction, both TH-positive and glutamic acid dehydrogenase (GAD)-positive neurons were destroyed, and near the site of the injection, there was complete tissue destruction. This study indicates that, using this mode of injection, Tinuvin 123 exerts a dramatic tissue toxicity without any evidence of specificity for dopaminergic neurons. Thus, our data argues against a role for Tinuvin 123 as an environmental toxin causing a clinical condition characterized by the selective loss of dopaminergic neurons as seen in PD.

Topics: Animals; Astrocytes; Behavior, Animal; Calcium Channel Blockers; Decanoic Acids; Dopamine; Environmental Pollutants; Functional Laterality; gamma-Aminobutyric Acid; Glial Fibrillary Acidic Protein; Glutamate Decarboxylase; Male; Movement; Neostriatum; Nerve Degeneration; Neural Pathways; Neurons; Neurotoxins; Occupational Exposure; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; Survival Rate; Tyrosine 3-Monooxygenase

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Callithrix; Dopamine Agents; Excitatory Amino Acid Antagonists; Levodopa; Motor Activity; Parkinson Disease; Parkinson Disease, Secondary; Piperidines

Current symptomatic treatment for Parkinson's disease is based largely on dopamine-replacing agents. The fact that long-term treatment with these drugs is characterized by many side effects has lead to widespread interest in nondopaminergic therapies. To date, however, it has proved difficult to devise a nondopaminergic therapy with significant antiparkinsonian efficacy when administered as monotherapy. Overactivity of the striatolateral pallidal pathway, the "indirect" striatal output pathway, is thought be responsible for the generation of parkinsonian symptoms. Indeed, it has been suggested that selective reduction in the activity of the "indirect" pathway may be achieved by blockade of NR2B-containing NMDA receptors. In the present study, we demonstrate that selective blockade of NR2B-containing NMDA receptors with the polyamine antagonists ifenprodil and eliprodil causes a significant increase in locomotor activity in the reserpine-treated rat model of Parkinson's disease (30 mg/kg ifenprodil, 221.2 +/- 54 mobile counts compared to vehicle, 19.6 +/- 6.87, P < 0.001). Additionally, we show that, subsequent to dopamine depletion, the ability of ifenprodil to bind to the polyamine site and inhibit binding of the NMDA channel blocker [3H] MK-801 is increased fourfold (IC50 3.7 +/- 0.4 microM compared to vehicle, IC50 14.3 +/- 2.34 microM, P < 0.01). We suggest that ifenprodil selectively targets the polyamine site on overactive NR2B-containing NMDA receptors. Thus, we propose that NR2B-selective NMDA receptor antagonists may prove useful in the treatment of Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Binding, Competitive; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reserpine

A series of conformationally restricted analogues of nicotine has been synthesized and evaluated as agonists of neuronal acetylcholine receptors. Compound 2 (SIB-1663), which selectively activated human recombinant alpha 2 beta 4 and alpha 4 beta 4 nAChRs, was shown to be active in animal models of Parkinson's disease and pain.

Topics: Anabasine; Animals; Antiparkinson Agents; Calcium; Cell Line; Cholinergic Agonists; Drug Design; Humans; Macromolecular Substances; Molecular Conformation; Neurons; Nicotine; Parkinson Disease, Secondary; Piperidines; Pyridines; Recombinant Proteins; Structure-Activity Relationship; Transfection

We have studied the effects of two D2 dopamine receptor-selective compounds, (-)-OSU 6162 and raclopride, on levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmosets (Callithrix jacchus). Three monkeys developed a severe parkinsonian syndrome following administration of MPTP. In response to daily levodopa treatment the animals developed reproducible and idiosyncratic peak-dose dyskinesias. Pretreatment with (-)-OSU 6162 and raclopride, in doses increased by multiples of three, both dose-dependently relieved the levodopa-induced dyskinesias. However, in contrast to when raclopride pretreatment was given, (-)-OSU 6162 pretreatment did not induce akinesia. Our investigation suggests that (-)-OSU 6162 may be useful an an adjuvant treatment to levodopa in advanced Parkinson's disease to selectively combat levodopa-induced dyskinesias without affecting the antiparkinsonian response.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callithrix; Carbidopa; Dopamine Antagonists; Levodopa; Male; Motor Activity; Parkinson Disease, Secondary; Piperidines; Posture; Raclopride; Salicylamides

The effects of the synthetic cannabinoid receptor agonist WIN 55,212-2 on dopamine receptor-mediated alleviation of akinesia were evaluated in the reserpine-treated rat model of parkinsonism. The dopamine D2 receptor agonist quinpirole (0.1 mg/kg, ip) caused a significant alleviation of the akinesia. This effect was significantly reduced by coinjection with the cannabinoid receptor agonist WIN 55,212-2 (0.1 and 0.3 mg/kg). The simultaneous administration of the cannabinoid receptor antagonist SR 141716A (3 mg/kg, ip) with quinpirole and WIN 55,212-2 blocked the effect of WIN 55,212-2 on quinpirole-induced alleviation of akinesia. The selective dopamine D1 receptor agonist chloro-APB (SKF82958, 0.1 mg/kg) alleviated akinesia in a significant manner. WIN 55,212-2 (0.1-1 mg/kg, ip) did not affect the antiakinetic effect of chloro-APB. Combined injection of both D1 and D2 dopamine receptor agonists (both at either 0.1 or 0.02 mg/kg) resulted in a marked synergism of the antiakinetic effect. WIN 55,212-2 (0.1-1 mg/kg) significantly reduced the antiakinetic effect of combined injections of quinpirole and chloro-APB at both 0.1 and 0.02 mg/kg. The effect of 0.3 mg/kg WIN 55,212-2 on combined D1 and D2 agonist-induced locomotion (0.02 mg/kg) was blocked by SR 141761A (3 mg/kg). Neither WIN 55,212-2 alone (0.1 and 0.3 mg/kg) nor SR 141716A (3 and 30 mg/kg) alone had an antiparkinsonian effect. These results suggest that cannabinoids may modulate neurotransmission in the pathway linking the striatum indirectly to basal ganglia outputs via the lateral globus pallidus and the subthalamic nucleus.

Topics: Animals; Basal Ganglia; Benzazepines; Benzoxazines; Dopamine Agonists; gamma-Aminobutyric Acid; Locomotion; Male; Morpholines; Naphthalenes; Nerve Tissue Proteins; Parkinson Disease, Secondary; Piperidines; Pyrazoles; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Drug; Reserpine; Rimonabant

While unproved, environmental toxins of industrial and or agricultural origin represent an attractive theory to explain the increasing incidence of degenerative diseases of the nervous system such as Parkinson's disease (PD). We have examined several chemicals utilized in an area of Israel previously demonstrated to contain a statistically greater than average number of people with Parkinson's disease. One of these agents, a light stabilizer employed universally in the production of polyolifins used in plastics, depleted primary mesencephalic cultures of dopamine neurons, and produced a dopamine-specific lesion of the substantia nigra pars compacta when injected stereotactically into the ventral midbrain of adult rats. The observed effects were dose-dependent. These findings represent a potentially significant development in the search for industrial/environmental causes of neurodegenerative disease.

Topics: Animals; Decanoic Acids; Dopamine; Dose-Response Relationship, Drug; Environmental Pollutants; Fetus; Industry; Mesencephalon; Neurons; Parkinson Disease, Secondary; Piperidines; Rats

Cisapride, a substituted piperidinyl benzamide that is chemically related to metoclopramide, is a prokinetic agent that facilitates motility of the gastrointestinal tract (1). The mechanism by which cisapride exerts its actions is not clear. It enhances acetylcholine release in the myenteric plexus of the gut, and evidence exists that it has an agonistic action on a serotonin receptor, probably the 5-HT4 receptor (2). The drug is well tolerated, and no central nervous system side effects have been reported. We describe two patients with parkinsonism who experienced aggravation of tremor while on therapy with cisapride.

Topics: Aged; Anti-Ulcer Agents; Cisapride; Female; Humans; Parkinson Disease, Secondary; Piperidines; Tremor

We report one case of parkinsonism induced by cisapride and one case of Parkinson's disease whose symptoms were worsened by cisapride. Case 1. A 75-year-old female who had suffered from constipation and loss of appetite, was treated with cisapride for her gastro-intestinal symptoms. One year later, she developed progressive parkinsonian gait, cogwheel rigidity She showed parkinsonian gait, cogwheel rigidity and slowness in motion. Two months after cisapride was discontinued, her parkinsonism and depression disappeared. Case 2. A 66-year-old female with Parkinson's disease was given cisapride for constipation. Two months after starting cisapride, her akinesia and rigidity deteriorated gradually, and she became bed-ridden with dysphagia and dyspnea. After cisapride was discontinued, her parkinsonian symptoms improved gradually, and she became ambulant three months later. Cisapride is a benzamide derivative with a prokinetic action. Experimental studies have revealed that it has indirect cholinomimetic effects and potentially stimulates the gastrointestinal motor activity without blocking dopamine receptors or activating muscarinic cholinergic receptors. However, the present cases showed that cisapride could be a dopamine receptor blocker, and either induce or worsen parkinsonism. Therefore, cisapride should be avoided or very carefully used in parkinsonian patients and old people.

Topics: Aged; Cisapride; Female; Humans; Parkinson Disease, Secondary; Piperidines

The study attempted to verify whether activation of locus coeruleus neurons by alpha 2 antagonists might improve parkinsonian signs. Treatment with the racemic alpha 2 antagonist R 47 243 of a monkey with MPTP-induced parkinsonian signs normalized blink rate, reduced resting tremor, and improved several other parkinsonian signs. In a second experiment, the (-)-isomer R 62 651 produced a gradual change in tremor which was the inverse of the mannner in which tremor had become installed as the result of progression earlier upon the MPTP challenge. It is proposed that further research be conducted to determine whether alpha 2 antagonists may beneficially influence the progression of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adrenergic alpha-Antagonists; Animals; Blinking; Locus Coeruleus; Macaca fascicularis; Neurons; Parkinson Disease, Secondary; Piperidines; Thiazoles; Tremor

We recently demonstrated that when different drugs (mainly used for the treatment of Parkinson's disease) are administered in combination they interfere with the availability of bromocriptine in the brain of rats (striatum and hypothalamus). In the present study performed with parkinsonian patients, we measured plasma levels of bromocriptine (RIA) over 4 h after giving orally 5 mg bromocriptine alone; together with levodopa 250 mg plus 25 mg DCI (10 patients); with 100 mg amantadine HCl (5 patients) and with biperiden 5 mg (5 patients). Amantadine and biperiden did not interfere with the pharmacokinetics of bromocriptine. However, levodopa significantly diminished plasma levels (a mean increment of 1.78 mg +/- 0.30 vs 0.92 +/- 0.18 mg/ml). We postulate that levodopa may interfere with the metabolism of bromocriptine in the liver. Although we did not observe substantial clinical differences among the patients (Webster scale), this study supports our previous findings and suggests that one of the advantages of combined treatment may result from a modification of the plasma levels of bromocriptine by levodopa. A "smoothing" of the plasma bromocriptine curve possibly avoids sudden oscillations of the drug availability and enables a more "stable" penetrability of the medication into the central nervous system.

Topics: Administration, Oral; Aged; Amantadine; Biperiden; Bromocriptine; Drug Combinations; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease, Secondary; Piperidines

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Binding, Competitive; Humans; Parkinson Disease, Secondary; Piperidines; Pyridines; Rats; Receptors, Drug

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Biperiden; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Valproic Acid

Topics: Adult; Aged; Biperiden; Delayed-Action Preparations; Drug Evaluation; Female; Humans; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Syndrome

In a 78-year-old woman receiving perhexiline maleate for intractable angina pectoris, a syndrome of parkinsonism and peripheral neuropathy developed. The neuropathy was confirmed by electromyographic and nerve conduction studies. The parkinsonism and peripheral neuropathy disappeared when perhexiline maleate was discontinued.

Topics: Aged; Angina Pectoris; Female; Humans; Parkinson Disease, Secondary; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Lisuride is a soluble ergolene derivative with endocrine effects similar to but more potent than those of bromocriptine. In nine subjects with idiopathic, postencephalitic, or drug-induced parkinsonism, lisuride at a dosage of 0.05 to 0.15 mg intravenously caused an immediate improvement in tremor, rigidity, akinesia, and postural deformity, but also caused chorea and orofacial dyskinesia. Improvement lasted 2 to 3 hours. Lisuride had little or no effect in a single patient with progressively supranuclear palsy. Oral lisuride therapy, 0.8 to 4.8 mg daily, had similar effects but occasionally caused reduced awareness and hallucinations.

Topics: Administration, Oral; Aged; Benzimidazoles; Chorea; Domperidone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Growth Hormone; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Paralysis; Parkinson Disease; Parkinson Disease, Postencephalitic; Parkinson Disease, Secondary; Piperidines; Prolactin

Topics: Brain Diseases; Cerebellum; Female; Humans; Iatrogenic Disease; Middle Aged; Parkinson Disease, Secondary; Perhexiline; Piperidines; Polyradiculopathy; Retinal Hemorrhage

Topics: Aged; Angina Pectoris; Humans; Male; Maleates; Paresthesia; Parkinson Disease, Secondary; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Delayed-Action Preparations; Humans; Parkinson Disease, Secondary; Penfluridol; Piperidines; Schizophrenia

Topics: Adult; Aged; Aniline Compounds; Antiparkinson Agents; Female; Humans; Indoles; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Piperidines

Topics: Adolescent; Adult; Atropine; Female; Humans; Male; Middle Aged; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines; Schizophrenia; Xanthenes