Abstract
Parkinson disease (PD) is the second-most common age-related neurodegenerative disease and is characterized by the selective destruction of dopaminergic neurons. Increasing evidence indicates that oxidative stress plays a crucial role in the pathogenesis of idiopathic PD. Anti-oxidant agents including catalase, manganese porphyrin and pyruvate confer cytoprotection to different cell cultures when challenged with 6-hydroxydopamine (6-OHDA). Herein we used rat cerebellar granular cell cultures to ascertain the plausible cellular pathways involved in pyruvate-induced cytoprotection against 0.1 mM 6-OHDA. Pyruvate provided cytoprotection in a concentration-dependent manner (2-10 mM). Consistent with its well-established anti-oxidant capacity, pyruvate (10 mM) prevented 6-OHDA-induced lipid peroxidation by blocking the rise in intracellular peroxides and maintaining the intracellular reduced glutathione (GSH) levels. Further experiments revealed that pyruvate increased Akt, but not extracellular signal-regulated kinase phosphorylation. Moreover, phosphatidylinositol 3-kinase (PI3K) inhibitors attenuated pyruvate-induced cytoprotection indicating that PI3K-mediated Akt activation is necessary for pyruvate to induce cytoprotection. On the other hand, pyruvate also up-regulated glutathione peroxidase mRNA levels, but not those of the anti-oxidant enzymes superoxide dismutase-1 and -2, catalase or the anti-apoptotic oncogenes Bcl-2 or Bcl-xL. In summary, our results strongly suggest that pyruvate, besides the anti-oxidant properties related to its structure, exerts cytoprotective actions by activating different anti-apoptotic routes that include gene regulation and Akt pathway activation.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Animals, Newborn
-
Antioxidants / metabolism
-
Antioxidants / pharmacology
-
Apoptosis / drug effects
-
Apoptosis / physiology
-
Cells, Cultured
-
Cerebellar Cortex / drug effects*
-
Cerebellar Cortex / metabolism
-
Cerebellar Cortex / physiopathology
-
Cytoprotection / drug effects
-
Cytoprotection / physiology
-
Dose-Response Relationship, Drug
-
Extracellular Signal-Regulated MAP Kinases / drug effects
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Glutathione Peroxidase / drug effects
-
Glutathione Peroxidase / genetics
-
Glutathione Peroxidase / metabolism
-
Lipid Peroxidation / drug effects
-
Lipid Peroxidation / physiology
-
Nerve Degeneration / drug therapy*
-
Nerve Degeneration / physiopathology
-
Nerve Degeneration / prevention & control
-
Neurons / drug effects*
-
Neurons / metabolism
-
Neurons / pathology
-
Neuroprotective Agents / metabolism
-
Neuroprotective Agents / pharmacology*
-
Neurotoxins / antagonists & inhibitors
-
Neurotoxins / toxicity
-
Oxidative Stress / drug effects
-
Oxidative Stress / physiology
-
Oxidopamine / antagonists & inhibitors
-
Oxidopamine / toxicity
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Proto-Oncogene Proteins c-akt / drug effects*
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pyruvic Acid / metabolism
-
Pyruvic Acid / pharmacology*
-
RNA, Messenger / drug effects
-
RNA, Messenger / metabolism
-
Rats
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Up-Regulation / drug effects
-
Up-Regulation / physiology
Substances
-
Antioxidants
-
Neuroprotective Agents
-
Neurotoxins
-
Phosphoinositide-3 Kinase Inhibitors
-
RNA, Messenger
-
Pyruvic Acid
-
Oxidopamine
-
Glutathione Peroxidase
-
Proto-Oncogene Proteins c-akt
-
Extracellular Signal-Regulated MAP Kinases