Abstract
In the developing and adult brain, neurotrophic growth factors support the growth and protec tion of dopaminergic neuronal systems. Recently, links between impaired neurotrophin support of dopamine (DA) neurons has been described in Parkinson’s Disease (PD). Fibro- blast growth factor (FGF) has a unique association with DA neurons in that FGF signaling is vitally important for the development and protection of adult DA neurons. We assessed the role of substantia nigra (SN)-expressed FGFs in the nigrostriatal dopaminergic system using a transgenic mouse, th-fgfr1(tk-). In these mice, generated by expression of dominant negative FGFR1(TK-) from the tyrosine hydroxylase (TH) gene promoter, reduced FGF signaling results in smaller and less dense adult nigrostriatal DA neurons, similar to what is observed in PD. With unilateral 6-hydroxydopamine (6-OHDA) lesions, th-fgfr1(tk-) mice exhibited extensive unilateral nigrostriatal damage with robust spontaneous (non-drug induced) asymmetrical turning and a decreased latency to remain on the accelerating rotarod. L-DOPA remains the gold standard for PD therapy despite debilitating hyperkinetic and dyskinetic side effects. The nicotinic acetylcholine system has recently been targeted as an alternative system to combat PD motor symptoms. Nicotine effectively stimulates dopaminergic transmission in the nigrostriatal pathway and mediates movement. Using unilaterally lesioned th-fgfr1(tk-) mice, long term (11 day) oral administration of nicotine increased spontaneous bidirectional turning and increased the latency before falling from the accelerating rotarod. In a separate analysis, L-DOPA treatment reversed directionality of rotation and further deepened motor discoordination, suggesting activation of hypersensitive postsynaptic DA receptors in the denervated striata. These results in a transgenic model of PD provide insights into the cellular mechanisms underlying L-DOPA and nicotinic therapies and offer further evidence of nicotine’s capacity to facilitate movement and enhance motor coordination in PD.
Highlights
The central pathological feature of Parkinson’s Disease (PD) is a degeneration of nigrostriatal dopamine (DA) neurons that project from the substantia nigra pars compacta (SNc) to the dorsolateral striatum
In a group of 8 [4 th-fgfr1(tk) and 4 nontransgenic] mice with unilateral 6-OHDA lesions, transgenic mice made a significantly higher percentage of full and partial counterclockwise turns than control mice (Figure 2)
We show that mice with a deficiency of Fibroblast growth factor (FGF) signaling in nigrostriatal DA neurons [37] are highly susceptible to damage from oxidative stress incurred by administration of neurotoxin 6-OHDA
Summary
The central pathological feature of Parkinson’s Disease (PD) is a degeneration of nigrostriatal dopamine (DA) neurons that project from the substantia nigra pars compacta (SNc) to the dorsolateral striatum. Over the past several years it has become increasingly evident that the loss of DA neurons in PD may be due to a combination of environmental insults, such as excessive levels of reactive oxygen species (ROS), combined with varying degrees of genetic/metabolic susceptibility. A. Kucinski et al / Health 4 (2012) 1178-1190 jected to high levels of oxidative stress from oxygen and glucose consumption and breakdown, which contributes to their selective degeneration in PD and related neurodegenerative disorders [2,3]. Healthy neurons have various protective mechanisms against ROS-induced cell death, and the decline or absence of these systems may leave neurons more vulnerable to deterioration [4]
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