Dopamine D3 receptor‐preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons

Abstract

Anti-parkinsonian agents, pramipexole (PPX) and ropinirole (ROP), have been reported to possess neuroprotective properties, both in vitro and in vivo. The mechanisms underlying neuroprotection afforded by the D3-preferring receptor agonists remain poorly understood. The present study demonstrates that incubation of primary mesencephalic cultures with PPX and ROP or the conditioned medium from PPX- or ROP-treated primary cultures induced a marked increase in the number of dopamine (DA) neurons in the cultures. Similar effects can be observed after incubating with the conditioned medium derived from PPX- and ROP-treated substantia nigra astroglia. Meanwhile, PPX and ROP can protect the primary cells from insult of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Furthermore, the neurotrophic effects of PPX and ROP on mesencephalic dopamine neurons could be significantly blocked by D3 receptor antagonist, but not by D2 receptor antagonist. Moreover, we found that the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX and ROP, exert neurotrophic effects on cultured DA neurons by modulating the production of endogenous GDNF and BDNF, which may participate in their neuroprotection.

Dopamine D3Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

“…Here, we demonstrate both the appearance of PCNA-positive cells within the SN C and their induction after chronic intraventricular administration of 7-OH-DPAT. This increase in PCNA labeling suggests that 7-OH-DPAT-induced increases in BrdU-positive cell counts reflect an effect on cell proliferation rather than an indirect effect on cell survival (Carvey et al, 2001;Du et al, 2005). These findings also suggest that cells are proliferating within the SN C itself.…”

“…Because PCNA is an endogenous marker, antibodies only label cells proliferating at the time of death, in contrast to BrdU, which is taken within the cell and maintained through migration and differentiation. Thus, the increase in PCNA labeling within the SN C suggests that 7-OH-DPATinduced increases in BrdU-positive cell counts are likely to reflect an effect on cell proliferation rather than an indirect effect on cell survival (Carvey et al, 2001;Du et al, 2005). It has been reported that cell cycle markers, including PCNA, may be expressed by injured cells undergoing DNA repair (Maga and Hubscher, 2003).…”

Driving GDNF expression: The green and the red traffic lights

“…While cultured foetal striatal cells respond to apomorphine treatment by increasing BDNF and GDNF, hippocampal cells are unable to respond (Guo et al, 2002). Conditioned medium from substantia nigra astroglial cultures treated with D3 agonists show remarkably increased levels of GDNF and BDNF, while no changes are observed in medium from striatal or cortical astroglia (Du et al, 2005). Moreover, D2RÀ/À mice show a 40-50% reduction of GDNF mRNA in the major target areas of substantia nigra/VTA dopaminergic neurons, whereas GDNF mRNA levels are unaltered in other brain areas receiving dopaminergic innervation (Bozzi and Borrelli, 1999).…”

“…Although other mechanisms have been proposed, such as the induction of antioxidant defences (Iida et al, 1999), the neuroprotection afforded by dopamine or dopamine receptor agonists has been associated with their ability to promote the expression of several neurotrophic factors. In fact, D3 receptor preferring agonists protect mesencephalic neurons against a MPP + lesion by increasing the secretion of both GDNF and BDNF (Du et al, 2005). Serotonin (5-HT) is another monoamine shown to promote GDNF mRNA expression in rat C6 glioma cells.…”

“…Schematic overview of pathways leading to an increase in dopaminergic transmission and their regulation by agents known to increase GDNF expression. (Presgraves et al, 2004;Du et al, 2005) and in vivo (Rascol et al, 2000;Parkinson Study Group, 2002b). Incubation of mesencephalic cultures with pramipexole and ropinirole, or with conditioned medium from pramipexole-and ropinirole-treated mesencephalic cultures or substantia nigra astroglia increases the number of dopaminergic neurons in culture (Du et al, 2005).…”