Noradrenergic mechanisms in neurodegenerative diseases: a theory.
A deficiency in the noradrenergic system of the brain, originating largely from cells in the locus coeruleus (LC), is theorized to play a critical role in the progression of a family of neurodegenerative disorders that includes Parkinson's disease (PD) and Alzheimer's disease (AD). Consideration is given here to evidence that several neurodegenerative diseases and syndromes share common elements, including profound LC cell loss, and may in fact be different manifestations of a common pathophysiological process. Findings in animal models of PD indicate that the modification of LC-noradrenergic activity alters electrophysiological, neurochemical and behavioral indices of neurotransmission in the nigrostriatal dopaminergic system, and influences the response of this system to experimental lesions. In models related to AD, noradrenergic mechanisms appear to play important roles in modulating the activity of the basalocortical cholinergic system and its response to injury, and to modify cognitive functions including memory and attention. Mechanisms by which noradrenaline may protect or promote recovery from neural damage are reviewed, including effects on neuroplasticity, neurotrophic factors, neurogenesis, inflammation, cellular energy metabolism and excitotoxicity, and oxidative stress. Based on evidence for facilitatory effects on transmitter release, motor function, memory, neuroprotection and recovery of function after brain injury, a rationale for the potential of noradrenergic-based approaches, specifically alpha2-adrenoceptor antagonists, in the treatment of central neurodegenerative diseases is presented.
Marien
Marc R
MR
Centre de Recherche Pierre Fabre, Neurobiology I, 17 Avenue Jean Moulin, 81106 Castres Cedex, France. marc.marien@pierre-fabre.com
Colpaert
Francis C
FC
Rosenquist
Alan C
AC
D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D001930:Brain Injuries / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008125:Locus Coeruleus / Q000033:anatomy & histology / Q000502:physiology; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000145:classification / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009638:Norepinephrine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000975:Antioxidants; D009414:Nerve Growth Factors; D004298:Dopamine; D009638:Norepinephrine