Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor j33 Parkinson disease is one of the most common neurological disorders of the elderly. It is characterized by a progressive degeneration of the dopaminergic neurons in the substantia nigra of the midbrain, leading to a loss of dopamine in the striatum, which constitutes the main projection field of these cells. Although therapeutically relevant augmentation of striatal dopamine can be achieved by drug therapy or intrastriatal transplantation of fetal dopaminergic neurons (1), there is at present no means by which the primary nigral degeneration can be halted. Neurotrophic factors capable of sustaining the survival of otherwise degenerating dopamine neurons are thus of considerable interest (2). GDNF was initially purified and cloned as a potent neurotrophic factor for cultured dopaminergic neurons of the developing substantia nigra (3), and it has been shown that the related transforming growth factors 32 and ,B3 (TGF-f32 and TGF-f33) exert a similar survival-promoting activity on this cell population in vitro (4-6). The expression patterns of GDNF, TGF-j32, and TGF-,B3 mRNAs in the developing rat striatum and substantia nigra further support the notion that one or several of these factors play important physiological roles for immature nigral dopamine neurons (4, 7-9). More recently, administration of GDNF to the basal ganglia has been shown to partially attenuate the disappearance of tyrosine hydroxylase (TH)-immunoreactive nigral neurons following surgical axotomy (10) and the acute toxic effects of systemic doses of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult mice (11) or of intracerebral 6-hydroxydopamine (6-OHDA) in rats (12).The aim of the present study was (i) to investigate whether GDNF would exert a protective effect in a model of delayed and progressive nigral cell death more closely related to the cell death seen in human Parkinson disease and (ii) to compare GDNF and the related TGF-f33 with respect to their capacity to counteract nigral dopamine cell degeneration in the adult rat brain.To do so, we used a recent modification of the standard 6-OHDA lesion of the rat nigrostriatal projection (13-15). Unilateral 6-OHDA-lesioning of the dopaminergic terminals in the striatum rather than the medial forebrain bundle or the substantia nigra itself produces a delayed and progressive degeneration of ipsilateral nigral dopamine neurons with an onset 1 week after 6-OHDA injection (15). One week prior to striatal 6-OHDA lesion, nigral cells were retrogradely labeled at the site of subsequent striatal toxin injection with the fluorescent retrograde tracer fluorogold. This allows a specific examination of those nigrostriatal neurons projecting to, or through, the focus of the 6-OHDA lesion. For within-animal controls, fluorogold injections were performed bilaterally, and only one of the labeled striata was subsequently lesioned with 6-OHDA. into both striata at sites 1 mm anterior to bregma and 3 mm later...

Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

“…A similar result has been reported in rat models of PD in which GDNF was administered into the SN before or after striatal lesions. 33,34 The GDNF treatment in these studies did not restore DA innervation in the lesioned striatum although DA cells were protected.…”

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

“…It has been shown in numerous experiments to both protect and restore DA neurons of the substantia nigra (SN) in many different lesion models (Bowenkamp et al, 1995;Sauer et al, 1995;Tomac et al, 1995a;Gash et al, 1996;Choi-Lundberg et al, 1997;Kordower et al, 2000). Although initial attempts to use it therapeutically for Parkinson's disease by intraventricular injection were unsuccessful (Nutt et al, 2003), more recent efforts using direct intraputaminal infusion have been more promising (Gill et al, 2003).…”

Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat

“…16,17 Systemic administration is an inefficient way of delivering neurotrophic factors into the CNS. Although single or repeated injections of GDNF protein directly into the CNS have been reported to be effective in animal studies, 9,13,18 continuous targeted delivery of neurotrophic factors to specific neurons in humans remains a challenge. This challenge might be met by gene therapy where increased levels of neurotrophic factor biosynthesis might prevent neuronal cell death and enhance neuronal function in neurodegenerative disorders such as Parkinson's disease.…”

“…8 GDNF protects and restores DA neurons in several rodent and primate models of Parkinson's disease when administered to the adult nigrostriatal system. [9][10][11][12][13][14][15] In addition, GDNF stimulates regenerative growth or axonal sprouting after partial lesions of the DA system and induces stimulatory effects on metabolism and function of DA neurons. 16,17 Systemic administration is an inefficient way of delivering neurotrophic factors into the CNS.…”