Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta

• Published in: Journal of neurochemistry Vol. 103; no. 5; pp. 2092 - 2101
• Main Authors: Madrigal, Jose L.M, Kalinin, Sergey, Richardson, Jill C, Feinstein, Douglas L
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.12.2007; Blackwell Publishing Ltd; Blackwell
• Subjects: Adult and adolescent clinical studies; Alzheimer disease; Alzheimer’s disease; Amyloid beta-Peptides - toxicity; Animals; Beta-Amyloid; Biological and medical sciences; Brain; Cell Survival - drug effects; Cerebral Cortex; Chemistry; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Embryo, Mammalian; Fluoresceins; Gene Expression Regulation - drug effects; Glutamic Acid - metabolism; Glutathione - metabolism; L-Lactate Dehydrogenase - metabolism; Medical sciences; Mice; Mice, Knockout; Neurology; neuron; Neurons; Neurons - drug effects; Neuroprotective Agents; Neurosciences; Neurotransmitters; Nitric Oxide Synthase Type II - deficiency; Norepinephrine - pharmacology; Organic Chemicals; Organic mental disorders. Neuropsychology; Peptide Fragments - toxicity; PPAR delta - metabolism; PPARdelta; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rodents; Transfection - methods; Peptides; Rat; Alzheimer disease; Toxicity; Activation; Endogenous; Primary culture; Degenerative disease; Alzheimer's disease; Release; Peroxisome proliferator activated receptor; Glutathione; Nervous system diseases; Enzyme; Rodentia; Beta-Amyloid; Nitric-oxide synthase; Cerebral disorder; Vertebrata; Mammalia; Neuron; PPARdelta; Cell death; Central nervous system disease; Neurotransmitter; Oxidoreductases
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04888.x

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 (Aβ) 1-42 peptide induced neuronal damage revealed by increased staining with fluorojade, and toxicity assessed by LDH release. Aβ-dependent neuronal death did not involve neuronal expression of the inducible nitric oxide synthase 2 (NOS2), since Aβ 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 Aβ-induced neuronal LDH release, and completely abrogated the increase in fluorojade staining. Treatment of neurons with NA increased expression of γ-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 (PPARδ) agonist. NA also increased expression and activation of PPARδ. Together these data demonstrate that NA can protect neurons from Aβ-induced damage, and suggest that its actions may involve activation of PPARδ and increases in GSH production.