GDNF administration induces recovery of the nigrostriatal dopaminergic system both in young and aged parkinsonian mice

Date, Isao; Aoi, Mizuho; Tomita, Susumu; Collins, Frank M.; Ohmoto, Takashi

doi:10.1097/00001756-199807130-00039

Cited by 49 publications

(25 citation statements)

References 10 publications

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“…GDNF has pronounced neurorestorative effects on dopaminergic markers in mice (Tomac et al, 1995a;Date et al, 1998) or monkeys (Gash et al, 1996;Zhang et al, 1997) when administered after MPTP and shows neuroprotective effects on the concentrations of dopamine and its metabolites when administered before or during MPTP administration (Kojima et al, 1997;Cheng et al, 1998). There is one report of protective effects against MPTPinduced death of dopaminergic SNpc neurons (Tomac et al, 1995a), showing enhanced survival of ipsilateral and contralateral dopaminergic neurons when GDNF was stereotaxically injected above the substantia nigra of one side.…”

Section: Discussionmentioning

confidence: 99%

Protection by Synergistic Effects of Adenovirus-Mediated X-Chromosome-Linked Inhibitor of Apoptosis and Glial Cell Line-Derived Neurotrophic Factor Gene Transfer in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease

Eberhardt

Coelln

Kügler³

et al. 2000

J. Neurosci.

191

155

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD).Here we show that a peptide caspase inhibitor, N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP-and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Protection by Synergistic Effects of Adenovirus-Mediated X-Chromosome-Linked Inhibitor of Apoptosis and Glial Cell Line-Derived Neurotrophic Factor Gene Transfer in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease

Eberhardt

Coelln

Kügler³

et al. 2000

J. Neurosci.

191

155

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“…Exogenous glial cell line-derived neurotrophic factor (GDNF) treatment has been reported to reverse some of the age-related, DA-mediated motor and phenotypic declines in rodents (Bowencamp et al, 1996;Emerich et al, 1996;Hebert and Gerhardt, 1997;Lapchak et al, 1997;Date et al, 1998). The ability of GDNF to restore both DA phenotype and motor behavior in aged animals suggests that sufficient nigral DA neurons remain to respond to the trophic factor, which would be extremely unlikely if these cells were lost during aging.…”

Section: Discussionmentioning

confidence: 99%

Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra

et al. 2000

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Guanosine triphosphate cyclohydrolase I (GTPCHI) is a critical enzyme in catecholamine function and is rate limiting for the synthesis of the catecholamine co-factor tetrahydrobiopterin. The present study assessed the distribution of GTPCHI immunoreactivity (-ir) within the monkey and human ventral midbrain and determined whether its expression is altered as a function of age. Light and confocal microscopic analyses revealed that young monkeys and humans displayed GTPCHI-ir within melanin-containing and tyrosine-hydroxylase-ir neurons in primate substantia nigra. Stereological counts revealed that there was a 67.4% reduction in GTPCHI-ir neuronal number, a 63.5% reduction in GTPCHI-ir neuronal density, and a 37.6% reduction in neuronal volume in aged monkeys relative to young cohorts. Similar age-related changes were seen in humans, in whom there were significant reductions in the number of GTPCHI-ir nigral neurons in middle age (58.4%) and aged (81.5%) cases relative to young cohorts. The density of GTPCHI-ir neurons within the nigra was similarly reduced in middle-aged (63.0%) and aged (81.8%) cases. In contrast to monkeys, aged humans did not display shrinkage in the volume of GTPCHI-ir nigral neurons. The presence of numerous melanin-positive, but GTPCHI-ir immunonegative, neurons in the aged monkey and human nigra indicates that these decreases represent an age-related phenotypic downregulation of this enzyme and not a loss of neurons per se. These data indicate that there is a dramatic decrease in GTPCHI-ir in nonhuman primates and humans as a function of age and that loss of this enzyme may be partly responsible for the age-related decrease in dopaminergic tone within nigrostriatal systems.

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“…Therefore, delineating molecular mechanisms that regulate survival of the SNC dopaminergic neurons may provide an avenue for better treatment or prevention of PD. To this end, numerous studies in vitro, in animal models that recapitulate PD, and in human PD patients, have shown that glial cell-line derived neurotrophic factor (GDNF) family ligands (GFLs) promote increased survival of SNC dopaminergic neurons, reduce functional deficits caused by dopaminergic toxins, and improve parkinsonian symptoms (Gash et al, 1996;Cheng et al, 1998;Date et al, 1998;Horger et al, 1998;Kordower et al, 2000;Tomac et al, 2000;Sun et al, 2004;Jakobsen et al, 2005). GFL ligands (GDNF and Neurturin) have been, or are in clinical trials in the treatment of PD (Gill et al, 2003;Slevin et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice

Jain¹,

Golden²,

Wozniak³

et al. 2006

J. Neurosci.

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Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction. However, it has been difficult to study these processes and the physiological importance of this pathway in adult mice because of the neonatal lethality of Gdnf and Ret null mice. We report successful creation of RET conditional reporter mice to investigate postnatal physiologic roles of RET and monitor the fate of RET-expressing cell types. To delete RET specifically in dopaminergic neurons and determine the physiologic requirement of RET in the maintenance of substantia nigra compacta (SNC) and ventral tegmental area (VTA), we bred the RET conditional mice with mice that specifically express Cre from the dopamine transporter (Dat) locus. A detailed morphometric and biochemical analysis including dopaminergic neuron number and size in SNC and VTA, and fiber density in the striatum and nucleus accumbens, and dopamine levels indicate that RET is not required for providing global trophic support to midbrain dopaminergic neurons in adult mice. Furthermore, RET deficiency in these neurons does not cause major sensorimotor abnormalities. Hence our results support the idea that RET signaling is not critical for the normal physiology of the SNC and VTA in adult mice.

show abstract

GDNF administration induces recovery of the nigrostriatal dopaminergic system both in young and aged parkinsonian mice

Cited by 49 publications

References 10 publications

Protection by Synergistic Effects of Adenovirus-Mediated X-Chromosome-Linked Inhibitor of Apoptosis and Glial Cell Line-Derived Neurotrophic Factor Gene Transfer in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease

Protection by Synergistic Effects of Adenovirus-Mediated X-Chromosome-Linked Inhibitor of Apoptosis and Glial Cell Line-Derived Neurotrophic Factor Gene Transfer in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease

Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra

RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice

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