Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist.
The neurotransmitter noradrenaline (NA) exerts important antiinflammatory effects on glial cells including suppression of the inducible form of nitric oxide synthase (NOS2). The authors examined the consequences of manipulating NA in vivo by treating adult rats with the neurotoxin DSP4, which selectively lesions noradrenergic neurons of the locus ceruleus (LC), and reduces cortical NA levels. Following LC lesion, intracortical injection of aggregated amyloid beta 1-42 (Abeta1-42) caused appearance of NOS2 within neurons, and increased neuronal damage assessed by staining for nonphosphorylated neurofilament proteins with antibody SMI-32. Co-treatment with a selective alpha2-adrenergic antagonist reduced neuronal NOS2 staining as well as SMI-32 staining. Neuronal damage was dependent on NOS2 expression since injection of Abeta1-42 into DSP4-treated NOS2-deficient mice did not result in neuronal damage. These results demonstrate that decrease of NA levels in vivo can exacerbate inflammatory responses and neuronal damage due to inflammatory stimuli such as Abeta. These findings suggest that alpha2-adrenergic antagonists could provide therapeutic benefit in neurological diseases such as AD or PD where LC loss is known to occur.
Kalinin
Sergey
S
Department of Anesthesiology, University of Illinois, Chicago, 60612, USA.
Polak
Paul E
PE
Madrigal
Jose L M
JL
Gavrilyuk
Vitaliy
V
Sharp
Anthony
A
Chauhan
Neelima
N
Marien
Marc
M
Colpaert
Francis
F
Feinstein
Douglas L
DL
D018663:Adrenergic Agents / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D008125:Locus Coeruleus; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D016229:Amyloid beta-Peptides; D001596:Benzylamines; D010446:Peptide Fragments; D018341:Receptors, Adrenergic, alpha-2; C075222:amyloid beta-protein (1-42); D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C012102:DSP 4; D009638:Norepinephrine