title: Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo.
abstract: Synthesis of poly(ADP-ribose) (PAR) is catalyzed by PAR polymerase-1 (PARP-1) in neurons. PARP1 plays a role in various types of brain damage in neurodegenerative disorders. In neurons, overactivation of PARP-1 during oxidative stress induces robust PAR formation, which depletes nicotinamide adenine dinucleotide levels and leads to cell death. However, the role of the newly-formed PAR in neurodegenerative disorders remains elusive. We hypothesized that the effects of PAR could occur in the extracellular space after it is leaked from damaged neurons. Here we report that extracellular PAR (EC-PAR) functions as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor (GDNF) in astrocytes during neuronal cell death, both in vitro and in vivo. In primary rat astrocytes, exogenous treatment with EC-PAR produced GDNF but not other neurotrophic factors. The effect was concentration-dependent and did not affect cell viability in rat C6 astrocytoma cells. Topical injection of EC-PAR into rat striatum upregulated GDNF levels in activated astrocytes and improved pathogenic rotation behavior in a unilateral 6-hydroxydopamine model of Parkinson disease in rats. These findings indicate that EC-PAR acts as a neurotrophic enhancer by upregulating GDNF levels. This effect protects the remaining neurons following oxidative stress-induced brain damage, such as that seen with Parkinson disease.
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan. Electronic address: hnakajima@vet.osakafu-u.ac.jp.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Itakura
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan.
authors.forename: Sunao
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan.
authors.forename: Yasu-Taka
authors.initials: YT
authors.lastname: Azuma
authors.affiliation: Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinkuourai-kita, Izumisano, Osaka, 5988531, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D066298:In Vitro Techniques; D009414:Nerve Growth Factors / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011064:Poly Adenosine Diphosphate Ribose
keywords: Cell death; GDNF; PAR; PARP-1; Parkinson disease