title: Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson's disease.
abstract: The mitochondria are the most important cytoplasmic organelles in determining cell survival and death. Mitochondrial dysfunction leads to a wide range of disorders, including neurodegenerative diseases. The central events in the mitochondrial‑dependent cell death pathway are the activation of the mitochodrial permeability transition pore (mPTP) and the disruption of mitochondrial membrane potential, which cause the release of apoptogenic molecules and finally lead to cell death. This is thought to be at least partly responsible for the loss of dopaminergic neurons in Parkinson's disease (PD); thus, the attenuation of mitochondrial dysfunction may contribute to alleviating the severity and progression of this disease. Guanosine is a pleiotropic molecule affecting multiple cellular processes, including cellular growth, differentiation and survival. Its protective effects on the central nervous system and and on several cell types by inhibiting apoptosis have been shown in a number of pathological conditions. This study aimed to analyze the ability of guanosine to protect neuronal PC12 cells from the toxicity induced by 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which mediates selective damage to dopaminergic neurons and causes irreversible Parkinson-like symptoms in humans and primates. Our results demonstrated that the apoptosis of PC12 cells induced by MPP+ was significantly prevented by pre-treatment for 3 h with guanosine. In addition, guanosine attenuated the MPP+-induced collapse of mitochondrial transmembrane potential and prevented the sebsequent activation of caspase-3, thereby protecting dopaminergic neurons against mitochondrial stress-induced damage.
authors.affiliation: Department of Neurology, Affiliated Hospital of Beihua University, Jilin City, Jilin, P.R. China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Dong
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Min-Na
authors.initials: MN
authors.lastname: Tang
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Guang-Ren
authors.initials: GR
authors.lastname: Li
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Bi-Quan
authors.initials: BQ
authors.lastname: Sun
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D015655:1-Methyl-4-phenylpyridinium / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006151:Guanosine / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D006151:Guanosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C505410:Casp3 protein, rat; D053148:Caspase 3; D015655:1-Methyl-4-phenylpyridinium