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)

At this large and varied meeting on neuropharmacotherapy, progress was reported on the newer more selective antipsychotics. The selective D(2) dopamine receptor partial agonist, aripiprazole (Otsuka Pharmaceutical Co Ltd) was recently proved effective over the medium term. The atypical antipsychotics generally, such as clozapine, have a good side effect profile and better patient compliance, even in Parkinson's disease (PD). Reboxetine (Pharmacia & Upjohn AB), having a far greater selectivity for norepinephrine reuptake inhibition than for serotonin or dopamine reuptake, is of particular value in treating depression. Paroxetine (Novo Nordisk A/S), a selective serotonin reuptake inhibitor (SSRI), has just completed a multicenter clinical trial, being effective in about 50% of cases of post-traumatic stress disorder. A meta-analysis of trials of other uptake inhibitors showed that ability to block serotonin (rather than norepinephrine) uptake correlated well with efficacy. Bipolar and other disorders were hoped to benefit from more selective agents in the future, the potential for which has been revealed through basic neurobiology, with, for example, only non-alpha7 nicotinic receptor subunits being expressed by those interneurons mediating nicotinic responses. An open label, 30-day study of a pyrrolopyrimidine, the corticotrophin releasing factor (CRF) type 1 receptor inhibitor, NBI-30775 (Neurocrine Biosciences Inc/Janssen Pharmaceutica NV) produced good antidepressant effects, but has had to be abandoned as a product due to indications of potential liver damage. Similarly, although glial-derived neurotrophic factor (GDNF) had proved ineffective in a 1999 trial for PD, due to failure to access the striatum, there was however much evidence to suggest that small molecule agonists of the TRK-B receptor should be effective. Of these, quinones such as L-783281 (Merck Research Laboratories) appear to activate all TRK subtypes by a common intracellular, rather than receptormediated action, which may limit their usefulness. Although such agents would have many potential applications, it is likely that highly selective receptor activation will be needed.
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PMID:CINP 2000 - Collegium Internationale Neuro-Psychopharmacologicum 22nd Congress. 1604 59

Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.
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PMID:A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions. 2522 86