Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta.
The endogenous neurotransmitter noradrenaline (NA) can protect neurons from the toxic consequences of various inflammatory stimuli, however the exact mechanisms of neuroprotection are not well known. In the current study, we examined neuroprotective effects of NA in primary cultures of rat cortical neurons. Exposure to oligomeric amyloid beta (Abeta) 1-42 peptide induced neuronal damage revealed by increased staining with fluorojade, and toxicity assessed by LDH release. Abeta-dependent neuronal death did not involve neuronal expression of the inducible nitric oxide synthase 2 (NOS2), since Abeta did not induce nitrite production from neurons, LDH release was not reduced by co-incubation with NOS2 inhibitors, and neurotoxicity was similar in wildtype and NOS2 deficient neurons. Co-incubation with NA partially reduced Abeta-induced neuronal LDH release, and completely abrogated the increase in fluorojade staining. Treatment of neurons with NA increased expression of gamma-glutamylcysteine ligase, reduced levels of GSH peroxidase, and increased neuronal GSH levels. The neuroprotective effects of NA were partially blocked by co-treatment with an antagonist of peroxisome proliferator activated receptors (PPARs), and replicated by incubation with a selective PPARdelta (PPARdelta) agonist. NA also increased expression and activation of PPARdelta. Together these data demonstrate that NA can protect neurons from Abeta-induced damage, and suggest that its actions may involve activation of PPARdelta and increases in GSH production.
Madrigal
Jose L M
JL
Department of Anesthesiology, University of Illinois & Jesse Brown Veteran's Affairs Hospital, Chicago, Illinois, USA.
Kalinin
Sergey
S
Richardson
Jill C
JC
Feinstein
Douglas L
DL
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex; D004622:Embryo, Mammalian; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D009638:Norepinephrine / Q000494:pharmacology*; D009930:Organic Chemicals; D047494:PPAR delta / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D047494:PPAR delta; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C435731:fluoro jade; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione; D009638:Norepinephrine