Beta₂-adrenoceptor modulation of the inflammatory response induced by thrombin and amyloid-beta in glial cells

Abstract

Thrombin is a blood protein that leaks into the brain parenchyma when the blood- brain barrier is damaged, and has been implicated in the neuropathology associated with stroke, traumatic brain injury and Parkinson’s disease (PD). Amyloid-β (Aβ) is a protein which aggregates to form senile plaques during Alzheimer’s disease (AD) and is thought to mediate the neuronal loss observed in this disorder. Both molecules can elicit neuroinflammation which contributes to the neurodegenerative process. Evidence suggests that the monoamine neurotransmitter noradrenaline (NA) elicits anti-inflammatory actions in the brain, and consequently may play an endogenous neuroprotective role. Studies indicate that the anti-inflammatory actions of NA occur via activation of β2-adrenoceptors (ARs) on microglia and astrocytes, which increases intracellular cAMP concentrations and subsequent downstream activation of PKA. Experiments in this thesis were conducted on rat primary cortical glial or neuronal cultures. Cell viability was assessed using an alamar blue assay or LDH assay, mRNA expression of inflammatory and neurotrophic molecules was measured using RT-PCR, and protein concentration of inflammatory molecules was determined using ELISA.