Basic fibroblast growth factor stimulation of glial cells protects dopamine neurons from 6-hydroxydopamine toxicity: involvement of the glutathione system.
Neurotrophic factors have been shown to support the survival and promote the recovery of injured neurons both in vivo and in vitro. Here, we investigated whether glial cell line-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) could modify the damage to dopamine (DA) neurons in mesencephalic cultures caused by the neurotoxin 6-hydroxydopamine (6-OHDA). The data show that bFGF, but not GDNF, effectively protected DA neurons from 6-OHDA toxicity. Because bFGF is a glial mitogen, whereas GDNF is not, we tested whether glial cells participated in bFGF neuroprotection. Inhibition of glial cell proliferation completely prevented the protective effect of bFGF. Because oxidative events have been associated with 6-OHDA-induced damage, we examined the levels of glutathione (GSH) in control and bFGF-treated cultures. Cultures treated with bFGF had higher levels of GSH, which increased even further in response to 6-OHDA exposure. Control cultures failed to up-regulate GSH levels after 6-OHDA, suggesting a relationship between increased GSH levels and protection from 6-OHDA. Inhibition of glial cell proliferation prevented the rise in GSH in bFGF-treated cultures and abolished the increase after 6-OHDA treatment. Protection from 6-OHDA by bFGF was also diminished when GSH levels were decreased by the GSH synthesis inhibitor L-buthionine sulfoximine. Our study shows that stimulation of glial cells by bFGF allows the up-regulation of antioxidant defenses and supports cell survival during oxidative stress.
Hou
J G
JG
Department of Neurology and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, U.S.A.
Cohen
G
G
Mytilineou
C
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005467:Floxuridine / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005721:Glutamate-Cysteine Ligase / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000633:toxicity
D000964:Antimetabolites, Antineoplastic; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D013565:Sympatholytics; D005467:Floxuridine; D016222:Fibroblast Growth Factor 2; D016627:Oxidopamine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione