Effect of the beta₂-adrenoceptor agonist clenbuterol on inflammatory signalling in the CNS and behaviour

Abstract

This thesis explored the anti-inflammatory and neuroprotective properties elicited by stimulation of the noradrenergic receptor, the P2-adrenoceptor, in the rat brain. Neuroinflammation is a feature of many chronic neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and is driven mainly by activated microglia. The release of inflammatory mediators such as cytokines, chemokines, cell adhesion molecules and free radicals by microglia leads to slow and progressive destruction of neurons and axons in the CNS. Impairment of noradrenergic function is also suspected to contribute to the pathogenesis of neurodegenerative diseases. For example, in Alzheimer’s disease and Parkinson’s disease a profound loss of noradrenergic neurons occurs in the locus coeruleus. In addition, the noradrenergic system is reported to play an important role in the recovery from brain injury. There is growing interest in the central P2-adrenoceptors as a neuroprotective target due to the fact that stimulation of Pi-adrenoceptors on glial cells induces expression of neurotrophic factors and promotes an anti-inflammatory phenotype. Thus, mechanisms that increase central noradrenergic tone may be beneficial in treating inflammation-related neurodegeneration.