Locus Coeruleus and Noradrenergic Pharmacology in Neurodegenerative Disease.

Autor: Matt RA; CuraSen Therapeutics Inc., San Carlos, CA, USA. matt@curasen.com., Martin RS; CuraSen Therapeutics Inc., San Carlos, CA, USA., Evans AK; Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA., Gever JR; CuraSen Therapeutics Inc., San Carlos, CA, USA., Vargas GA; CuraSen Therapeutics Inc., San Carlos, CA, USA., Shamloo M; Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA., Ford AP; CuraSen Therapeutics Inc., San Carlos, CA, USA.
Jazyk: angličtina
Zdroj: Handbook of experimental pharmacology [Handb Exp Pharmacol] 2024; Vol. 285, pp. 555-616.
DOI: 10.1007/164_2023_677
Abstrakt: Adrenoceptors (ARs) throughout the brain are stimulated by noradrenaline originating mostly from neurons of the locus coeruleus, a brainstem nucleus that is ostensibly the earliest to show detectable pathology in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The α 1 -AR, α 2 -AR, and β-AR subtypes expressed in target brain regions and on a range of cell populations define the physiological responses to noradrenaline, which includes activation of cognitive function in addition to modulation of neurometabolism, cerebral blood flow, and neuroinflammation. As these heterocellular functions are critical for maintaining brain homeostasis and neuronal health, combating the loss of noradrenergic tone from locus coeruleus degeneration may therefore be an effective treatment for both cognitive symptoms and disease modification in neurodegenerative indications. Two pharmacologic approaches are receiving attention in recent clinical studies: preserving noradrenaline levels (e.g., via reuptake inhibition) and direct activation of target adrenoceptors. Here, we review the expression and role of adrenoceptors in the brain, the preclinical studies which demonstrate that adrenergic stimulation can support cognitive function and cerebral health by reversing the effects of noradrenaline depletion, and the human data provided by pharmacoepidemiologic analyses and clinical trials which together identify adrenoceptors as promising targets for the treatment of neurodegenerative disease.
(© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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