Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo

Hoffer, Barry J.; Hoffman, Alexander F.; Bowenkamp, Kate; Huettl, Peter; Hudson, John L.; Martin, David; Lin, Leu‐Fen H.; Gerhardt, Greg A.

doi:10.1016/0304-3940(94)90218-6

Cited by 420 publications

(246 citation statements)

References 17 publications

Supporting

Mentioning

232

Contrasting

Unclassified

Order By: Relevance

“…Astrocytes produce several neurotrophic and neurite-promoting agents (Engele et al, 1991;Nagata et al, 1993;Hoffen et al, 1994;Takeshima et al, 1994;Muller et al, 1995) that influence development, survival, neunte extension, and neurotoxin resistance (Engele et al, 1991;Nagata et al, 1993;Takeshima et al, 1994). Among the systems identified are a glutamate uptake activity that protects against excitotoxicity (Rosenberg et al, 1991) and stimulation of GSH synthesis and enzymes involved in GSH metabolism (Nisticè et al, 1992).…”

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 99%

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

View full text Add to dashboard Cite

L-DOPA IS toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of L-DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum-free, glia-conditioned medium. L-DOPA (50 tiM) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia-free cultures, where L-DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 1iM L-DOPA. The stereoisomer D-DOPA (50-400 btM) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25~zM) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of L-DOPA is stereospecific but independent of the production of dopamine. However, L-DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by Lbuthionine sulfoximine (3 1iM for 24 h) blocked the neurotrophic action of L-DOPA. N-Acetyl-L-cysteine (250 1iM for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of L-DOPA. These data suggest that the neurotrophic effect of L-DOPA may be mediated, at least in part, by elevation of glutathione content. Key Words: L-DOPA-Glia-Glutathione-Parkinson's disease-Dopamine neurons.

show abstract

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 99%

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

View full text Add to dashboard Cite

show abstract

“…Unlike other neurodegenerative disorders, identification of the genetic marker provides the unique opportunity to intercede therapeutically before the onset of symptoms that result from neuronal degeneration. Toward this end, trophic factors in general, and glial cell line-derived neurotrophic factor (GDNF) in particular, have shown promise in animal models of several different neurodegenerative disorders, including HD (19)(20)(21)(22). In addition to its potent trophic effects on dopaminergic midbrain neurons (23, 24), GDNF has also been shown to protect striatal, medium-sized spiny GABA projection neurons, the neuronal population most vulnerable in HD (22).…”

mentioning

confidence: 99%

Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease

McBride

Ramaswamy

Gasmi³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.gene therapy ͉ neurodegeneration ͉ neuroprotection ͉ polyglutamine ͉ adenoassociated virus H untington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an expanded trinucleotide (CAG: cytosine, adenine, and guanine) repeat at the IT15 locus on chromosome 4 (1) within the huntingtin gene. The abnormal DNA is translated into mutant huntingtin with an expanded glutamine stretch at the N terminus of the protein. The excessive number of glutamine repeats is responsible for the misfolding of huntingtin and the subsequent formation of neuronal inclusions, degeneration of striatal and cortical neurons, and a triad of symptoms including severe motor, cognitive, and psychological disturbances that are ultimately fatal.To date, HD remains incurable. Several therapies have yielded positive results in animal models, including those that alleviate potential glutamate-induced excitotoxicity such as riluzole and remacemide (2-4); those that increase the production of energy in the form of ATP in the cell, including creatine and coenzyme Q 10 (5-9); those that inhibit caspase activation and apoptosis, such as minocycline (10, 11); and those that aim at replacing degenerating cells by means of fetal tissue transplantation (12-18). However, when tested clinically, none has made a major impact in the symptomatic treatment of HD, nor have any demonstrated the ability to alter the natural history of the disease by preventing cell death.Genetic testing can identify mutated gene carriers destined to suffer from HD. Unlike other neurodegenerative disorders, identification of the genetic marker provides the unique opportunity to intercede therapeutically before the onset of symptoms that result from n...

show abstract

“…Presumably they also induced dopaminergic neurite growth and axonal sprouting. GDNF induces sprouting of striatal dopaminergic fibers and upregulation of TH expression (Hoffer et al, 1994;Hudson et al, 1995). Further studies are needed to reveal the effects of CDNF and MANF on dopaminergic neurites and TH levels in vivo.…”

Section: Cdnf and Manf Activities In Vivomentioning

confidence: 99%

Novel CDNF/MANF family of neurotrophic factors

Lindholm

Saarma

2010

Developmental Neurobiology

174

136

View full text Add to dashboard Cite

Current therapeutic interventions for neurodegenerative diseases alleviate only disease symptoms, while treatments that could stop or reverse actual degenerative processes are not available. Parkinson's disease (PD) is a movement disorder with characteristic degeneration of dopaminergic neurons in the midbrain. Few neurotrophic factors (NTFs) that promote survival, maintenance, and differentiation of affected brain neurons are considered as potential therapeutic agents for the treatment of neurodegenerative diseases. Thus, it is important to search and study new NTFs that could also be used in therapy. In this review, we discuss novel evolutionary conserved family of NTFs consisting of two members in the vertebrates, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Invertebrates, including Drosophila and Caenorhabditis have a single protein homologous to vertebrate CDNF/ MANF. Characteristic feature of these proteins is eight structurally conserved cysteine residues, which determine the protein fold. The crystal structure analysis revealed that CDNF and MANF consist of two domains; an amino-terminal saposin-like domain that may interact with lipids or membranes, and a presumably unfolded carboxy-terminal domain that may protect cells against endoplasmic reticulum stress. CDNF and MANF protect midbrain dopaminergic neurons and restore motor function in 6-hydroxydopamine rat model of PD in vivo. In line, Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly, suggesting that the function of CDNF/MANF proteins is evolutionary conserved. Future studies will reveal the receptors and mode of action of these novel factors, which are potential therapeutic proteins for the treatment of PD. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 360-371, 2010

show abstract

Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo

Cited by 420 publications

References 17 publications

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease

Novel CDNF/MANF family of neurotrophic factors

Contact Info

Product

Resources

About