Erich Buerger

Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model.

Cell proliferation of neural progenitors in the subventricular zone (SVZ) of Parkinson disease (PD) patients and animal models is decreased. It was previously demonstrated that the neurotransmitter dopamine modulates cell proliferation in the embryonic brain. The aim of the present study was to analyze whether oral treatment with the dopamine receptor agonist pramipexole (PPX) modulates adult neurogenesis in the SVZ/olfactory bulb system in a dopaminergic lesion model. 6-Hydroxydopamine (6-OHDA) lesioned adult rats received either PPX (1.0 mg/kg) or PBS orally twice daily and bromodeoxyuridine (BrdU, a cell proliferation marker) for 10 days and were perfused immediately after treatment or 4 weeks after PPX withdrawal. Stereological analysis revealed a significant augmentation in SVZ proliferation by PPX. Consecutively, enhanced neuronal differentiation and more new neurons were present in the olfactory bulb 4 weeks after PPX withdrawal. In addition, dopaminergic neurogenesis was increased in the olfactory bulb after PPX treatment. Motor activity as assessed by using an open field paradigm was permanently increased even after long term PPX withdrawal. In addition, we demonstrate that D2 and D3 receptors are present on adult rat SVZ-derived neural progenitors in vitro, and PPX specifically increased mRNA levels of epidermal growth factor receptor (EGF-R) and paired box gene 6 (Pax6). Oral PPX treatment selectively increases adult neurogenesis in the SVZ-olfactory bulb system by increasing proliferation and cell survival of newly generated neurons. Analyzing the neurogenic fate decisions mediated by D2/D3 signaling pathways may lead to new avenues to induce neural repair in the adult brain.

Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats.

Treatment with pramipexole, a dopamine D(3)/D(2) receptor agonist, reduces depressive symptoms in patients suffering from Parkinsons disease. To test the putative antidepressant quality of pramipexole, its effects were assessed in one of the most attractive animal models of depression, the olfactory bulbectomized (OBX) rat. Two experiments studied the effects of pramipexole on bulbectomy-induced hyperactivity. In experiment I, pramipexole was tested at 0.3 and 1.0 mg/kg together with the reference dopamine D(3) receptor agonist 7-OH-DPAT (0.1 mg/kg) and the tri-cyclic antidepressant imipramine (10 mg/kg). In experiment II, pramipexole was tested at lower doses: 0.03 and 0.1 mg/kg, with the same reference compounds. All animals were tested in the open field on days one (acute), seven (sub-chronic) and fourteen (chronic) of administration, as well as one week after cessation of treatment. Pramipexole, in a U-shaped dose response, reduced bulbectomy-induced hyperactivity after (sub) chronic but not acute administration (like imipramine and 7-OH-DPAT). The highest dose of pramipexole (1.0 mg/kg) did not reduce OBX hyperactivity during treatment. However, one week after cessation of treatment, all pramipexole (including the 1.0 mg/kg dose), 7-OH-DPAT and imipramine groups showed a reduction in OBX-induced hyperactivity. Pramipexole and 7-OH-DPAT exert an antidepressant profile in the OBX-rat model in normalizing bulbectomy-induced hyperactivity during (sub) chronic treatment. Moreover, treatment with both these compounds induced long-lasting changes in the bulbectomized brain similar to established antidepressants, strongly predicting antidepressant activity in major depression.

Mitochondria-targeted antioxidant effects of S(-) and R(+) pramipexole

BackgroundPramipexole exists as two isomers. The S(-) enantiomer is a potent D3/D2 receptor agonist and is extensively used in the management of PD. In contrast, the R(+) enantiomer is virtually devoid of any of the DA agonist effects. Very limited studies are available to characterize the pharmacological spectrum of the R(+) enantiomer of pramipexole.ResultsUsing differentiated SH-SY5Y neuroblastoma cells as an experimental model, here we show that S(-) and R(+) pramipexole are endowed with equipotent efficacy in preventing cell death induced by H2O2 and inhibiting mitochondrial reactive oxygen species generation. Both pramipexole enantiomers prevented mitochondrial ROS generation with a potency about ten times higher then that elicited for neuroprotection.ConclusionsThese results support the concept of both S(-) and R(+) pramipexole enantiomers as mitochondria-targeted antioxidants and suggest that the antioxidant, neuroprotective activity of these drugs is independent of both the chiral 6-propylamino group in the pramipexole molecule and the DA receptor stimulation.

Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole

Abstract Background: The death of dopaminergic neurons in Parkinsons disease (PD) appears to have various causes, including oxidative stress, excitotoxicity, mitochondrial dysfunction (and associated apoptosis), ubiquitin/proteasomal dysfunction, and inflammation, any of which could in principle be the therapeutic target of a neuroprotective drug. The biology of dopaminergic neurons offers further potential targets, involving neurotrophic factors, dopamine-neuron genes, and even neurogenesis. Objective: To outline each hypothetical neuroprotective mechanism, the evidence suggesting its relevance to PD, and the research on pharmacologic intervention. Methods: A PubMed search was conducted to identify relevant preclinical and clinical literature published between 1989 and 2009. Additional articles were identified by reviewing the reference lists of papers selected in the original search. To circumscribe the survey and facilitate consideration of the conditions required for a neuroprotective effect, emphasis was placed on a single drug class, dopamine agonists, and in particular pramipexole. Review of the field: In a variety of in vitro and in vivo PD models, pramipexole exhibited preclinical evidence of neuroprotective actions of all hypothesized types, and in human neuroimaging studies it slowed the rate of loss of markers of dopaminergic function, consistent with drug-conferred neuroprotection in PD itself. Interpretation of the preclinical data was hampered by differences among models and by uncertainties concerning each models mimicry of PD. Overall, the identified neuroprotection almost always required pretreatment (i.e., before insult) and high drug concentration. Interpretation of the clinical data was hampered by absence of placebo control and of a direct measure of neuroprotection. Conclusions: Although the evidence is promising, neuroprotection in PD remains an elusive goal. In whatever form it emerges, neuroprotective therapy would be a strong argument against deferring PD treatment until symptoms are a significant life impediment, and thus would add urgency to early PD identification.

Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson's disease: A pharmacokinetic‐pharmacodynamic study using in vivo microdialysis in rats

Short‐acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providing continuous dopaminergic stimulation may achieve higher therapeutic benefit for example by alleviating nocturnal disturbances as well as early morning akinesia. In the present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet® minipumps, whereas subcutaneous PPX injections were used to mimic PPX immediate release (IR) in male Wistar rats. In the catalepsy bar test, PPX‐CR (1 mg/kg/day) reversed the haloperidol‐induced motor impairment in the morning and over the whole observation period of 12h. In contrast, PPX‐IR (tid 1 mg/kg, pre‐treatment the day before) was not effective in the morning but catalepsy was reduced for 6 h after PPX‐IR (1 mg/kg) injection. In the reserpine model, early morning akinesia indicated by the first motor activity measurement in the morning was significantly reversed by PPX‐CR (2 mg/kg/day). Again, PPX‐IR (tid 0.3 mg/kg, pre‐treatment the day before) was not able to antagonise early morning akinesia. These results are in agreement with in vivo microdialysis measurements showing a continuous decrease of extracellular DA levels and a continuous PPX exposure in the PPX‐CR (1 mg/kg/day) group. In contrast, PPX‐IR (0.3 mg/kg) produced a transient decrease of extracellular DA levels over 6 h and showed maximum PPX levels 2 h after dosing which decreased over the following 6–8 h. The present study demonstrates that PPX‐CR may offer a higher therapeutic benefit than PPX‐IR on early morning akinesia and confirms earlier reports that PPX‐IR reverses motor impairment for several hours. Synapse 64:533–541, 2010.