Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aripiprazole is the newest atypical antipsychotic (AA) drug to be released in the US. It is the only AA that is a partial agonist at the D2 and 5HT1a receptors and an antagonist at 5HT2a receptors. It also has a high 5HT2/D2 ratio and may therefore carry a low risk of extrapyramidal side effects and alleviate psychosis in Parkinson-vulnerable populations. We report our preliminary experience in 8 patients with probable Parkinson disease (PD) treated with aripiprazole for drug-induced psychosis. Two patients were neuroleptic-naive, 5 patients were "quetiapine failures", and 1 patient was switched from olanzapine to aripiprazole. Aripiprazole was started at 5 mg to 10 mg a day and slowly increased over 3 to 7 days until side effects or improvement of psychosis occurred. Only 2 out of 8 patients experienced near complete resolution of their psychosis using aripiprazole. The other six patients discontinued aripiprazole within 40 days, 2 of whom discontinued due to motor worsening. Our preliminary experience with aripiprazole is mixed but not very encouraging. Controlled studies are needed to evaluate aripiprazole in parkinsonian patients.
 ...
PMID:Aripiprazole for drug-induced psychosis in Parkinson disease: preliminary experience. 1509 Sep 28

In Parkinson's disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brain's capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.
 ...
PMID:MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice. 2252 Apr 37

Parkinson's disease has been traditionally thought of as a dopaminergic disease in which cells of the substantia nigra pars compacta (SNc) die. However, accumulating evidence implies an important role for the serotonergic system in Parkinson's disease in general and in physiological responses to levodopa therapy, the first line of treatment. We use a mathematical model to investigate the consequences of levodopa therapy on the serotonergic system and on the pulsatile release of dopamine (DA) from dopaminergic and serotonergic terminals in the striatum. Levodopa competes with tyrosine and tryptophan at the blood-brain barrier and is taken up by serotonin neurons in which it competes for aromatic amino acid decarboxylase. The DA produced competes with serotonin (5HT) for packaging into vesicles. We predict the time courses of LD, cytosolic DA, and vesicular DA in 5HT neurons during an LD dose. We predict the time courses of DA and 5HT release from 5HT cell bodies and 5HT terminals as well as the changes in 5HT firing rate due to lower 5HT release. We compute the time course of DA release in the striatum from both 5HT and DA neurons and show how the time course changes as more and more SNc cells die. This enables us to explain the shortening of the therapeutic time window for the efficacy of levodopa as Parkinson's disease progresses. Finally, we study the effects 5HT1a and 5HT1b autoreceptor agonists and explain why they have a synergistic effect and why they lengthen the therapeutic time window for LD therapy. Our results are consistent with and help explain results in the experimental literature and provide new predictions that can be tested experimentally.
 ...
PMID:Mathematical insights into the effects of levodopa. 2278 73