Review
Noradrenergic mechanisms in neurodegenerative diseases: a theory

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Abstract

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.

Section snippets

Presentation of a theory

This review evaluates the evidence for a theory that a deficiency in the noradrenergic system of the brain, originating largely from cells in the locus coeruleus (LC), plays a decisive role in the progression of a family of neurodegenerative diseases that includes Parkinson's disease (PD) and Alzheimer's disease (AD). The theory as it was first proposed by Colpaert [107] focused primarily upon the role of noradrenergic deficits in the etiology of idiopathic PD (see also [106], [213], [367],

Anatomical locus

Important commonalities between AD and PD have been described [150], [156], [285], [424], [520]. Among the shared features are clinical signs, neuropathological findings, onset in the fifth or sixth decades of life, and loss of cells in the LC with consequent reduction in brain noradrenergic markers. These and other common elements have led some authors to conclude that a number of neurodegenerative diseases and syndromes are, in fact, different manifestations of a single disease process [24],

Clinico-pathological description

Idiopathic Parkinson's disease is a non-hereditary, chronic, and progressive neurodegenerative disorder of unknown cause that usually appears after the age of 50 and affects both sexes equally [298]. It is characterized by major reductions of dopaminergic cell numbers in the substantia nigra pars compacta, dopamine content in the striatum and noradrenergic cells in the LC [4], [248], [424]. Significant depletions (>80%) of noradrenaline in the substantia nigra pars compacta and reticulata and

Clinico-pathological description

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of unknown etiology that most commonly affects persons over the age of 60. AD is characterized by the gradual onset and a steady decline in cognitive functions including memory for recent and remote events, language, judgment, attention, and executive functions such as planning and organizing. There is no cure for this disease and pharmacological treatments to date have met with only modest symptomatic improvement [36], [39],

The LC-noradrenergic system in other neurodegenerative diseases and conditions

The LC-noradrenergic system shows pathological changes in a number of other neurodegenerative diseases and conditions less common than PD and AD. Compared to age-matched controls, significant reductions in LC cell numbers have been reported in Huntington's disease [574] (but see Ref. [358]), progressive supranuclear palsy [299], [362], [518], corticobasal degeneration [218], dementia pugilistica [362], multiple system atrophy [386], [530], [553], Lewy body disease [508], Down's syndrome [212],

The LC-noradrenergic system in functional recovery after brain injury

Recovery of function after cortical injury, and the maintenance of that recovery in both animals and humans, appears to depend importantly upon the integrity of the LC-noradrenergic system. Rats sustaining a unilateral injury to the sensorimotor cortex (e.g., by ablation, undercutting or contusion) display a transient contralateral paresis (hemiplegia) such that their ability to traverse a narrow elevated beam is impaired. The training, adaptation and testing of animals in the beam-walking

Role of the LC-noradrenergic system in mechanisms putatively involved in neurodegenerative diseases

The postsynaptic net effect of noradrenaline is to enhance the responsivity of neurons to other powerful excitatory and inhibitory inputs while reducing spontaneous activity, thereby increasing the signal-to-noise ratio for trans-synaptic information transfer [480], [549], [550], [569]. The tonic firing rate of LC neurons, and therefore the release and availability of noradrenaline, is related to the presence of salient events, as well as arousal, vigilance, and attention [32], [33], [34], [35]

A rationale for the treatment of neurodegenerative disorders with alpha2-adrenoceptor antagonists

The activity of the LC-noradrenergic system is regulated by presynaptic inhibitory alpha2-adrenergic autoreceptors (for review, see Ref. [504]). By blocking these receptors, alpha2-adrenoceptor antagonists disinhibit the LC system, leading to an increase in LC neuronal activity and a consequent increase in noradrenaline synthesis and release [134]. Concomitantly, alpha2-adrenoceptor antagonists facilitate, by disinhibition, the activity of neuronal and glial targets downstream from the

Conclusions and perspectives

Noradrenaline assumes critical physiological roles in regulating cellular signaling and in governing compensatory and protective mechanisms that determine neuronal function and survival in the brain. Based on the evidence reviewed, a deficiency in the major noradrenergic nucleus of the brain, the locus coeruleus, is hypothesized to be a critical factor in determining the evolution of progressive degenerative disorders such as PD and AD. A treatment strategy using an alpha2-adrenoceptor

Further issues: caveats for experimental studies

In the interest of testing further the concepts exposed in this review, consideration is given here to some caveats regarding the pharmacological tools and lesioning procedures that are commonly used in studying noradrenergic influences on brain function in animal models. Certain of these caveats may apply also to clinical studies.

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