Effect of long-term treatment with pramipexole or levodopa on presynaptic markers assessed by longitudinal [123I]FP-CIT SPECT and histochemistry.

A previous clinical trial studied the effect of long-term treatment with levodopa (LD) or the dopamine agonist pramipexole (PPX) on disease progression in Parkinson disease using SPECT with the dopamine transporter (DAT)-radioligand [(123)I]ß-CIT as surrogate marker. [(123)I]ß-CIT binding declined to significantly lower levels in patients receiving LD compared to PPX. However, the interpretation of this difference as LD-induced neurotoxicity, PPX-induced neuroprotection/-regeneration, or only drug-induced regulatory changes of DAT-availability remained controversial. To address this question experimentally, we induced a subtotal lesion of the substantia nigra in mice by bilateral injection of the neurotoxin 6-hydroxydopamine. After 4 weeks, mice were treated for 20 weeks orally with LD (100mg/kg/day) or PPX (3mg/kg/day), or water (vehicle) only. The integrity of nigrostriatal projections was assessed by repeated [(123)I]FP-CIT SPECT in vivo and by immunostaining for DAT and the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) after sacrifice. In sham-lesioned mice, we found that both LD and PPX treatment significantly decreased the striatal FP-CIT binding (LD: -21%; PPX: -14%) and TH-immunoreactivity (LD: -42%; PPX: -45%), but increased DAT-immunoreactivity (LD: +42%; PPX: +33%) compared to controls without dopaminergic treatment. In 6-hydroxydopamine-lesioned mice, however, neither LD nor PPX significantly influenced the stably reduced FP-CIT SPECT signal (LD: -66%; PPX: -66%; controls -66%), TH-immunoreactivity (LD: -70%; PPX: -72%; controls: -77%) and DAT-immunoreactivity (LD: -70%; PPX: -75%; controls: -75%) in the striatum or the number of TH-positive cells in the substantia nigra (LD: -88%; PPX: -88%; controls: -86%), compared to lesioned mice without dopaminergic treatment. In conclusion, chronic dopaminergic stimulation with LD or PPX induced similar adaptive presynaptic changes in healthy mice, but no discernible changes in severely lesioned mice. These findings allow to more reliably interpret the results from clinical trials using neuroimaging of DAT as surrogate parameter.

Neurogenesis in substantia nigra of parkinsonian brains?

The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.