Activation of noradrenergic transmission by alpha2-adrenoceptor antagonists counteracts deafferentation-induced neuronal death and cell proliferation in the adult mouse olfactory bulb.
The olfactory bulb is the target of neural progenitor cells that are generated in the subventricular zone of the lateral ventricle in the adult brain. This permanent neurogenesis is likely influenced by olfactory input to the bulb since previous studies have shown that cell proliferation and/or apoptotic death are stimulated by naris closure or surgical transection of the olfactory nerve. Since the olfactory bulb is densely innervated by noradrenergic afferents originating in the locus coeruleus, we have studied the impact of pharmacologically activating this noradrenergic system on cell death and proliferation following unilateral olfactory axotomy in the adult mouse olfactory bulb. We found that noradrenaline release in the olfactory bulb was significantly increased by intraperitoneal injections of the selective alpha(2)-adrenoceptor antagonists, dexefaroxan (0.63 mg/kg) and 5-fluoro-methoxyidazoxan (F 14413; 0.16 mg/kg). A chronic treatment with either compound for 7 days following olfactory axotomy significantly reduced neuronal death, glial activation and cell proliferation in the deafferented olfactory bulb. These data (1) confirm that alpha(2)-adrenoceptor antagonists, presumably by facilitating central noradrenergic transmission, afford neuroprotection in vivo, as previously shown in models of cerebral ischemia, excitotoxicity and devascularization-induced neurodegeneration, and (2) support a role of the locus coeruleus noradrenergic system in promoting survival of neurons in areas of the brain where neurogenesis persists in the adult.
Veyrac
Alexandra
A
Laboratoire Neurosciences et Systèmes Sensoriels, CNRS-UMR 5020, Université Claude Bernard-Lyon 1, 50 Avenue Tony Garnier, F-69366 Lyon, France.
Didier
Anne
A
Colpaert
Francis
F
Jourdan
François
F
Marien
Marc
M
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005911:Gliosis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001578:Benzopyrans; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C451723:dexefaroxan; D009638:Norepinephrine