β-Adrenergic receptor modulation of the LPS-mediated depression in CYP1A activity in astrocytes

CYP1A1 and 1A2, two important P450 isoforms in the brain that metabolize many endogenous and exogenous substrates, are downregulated during central nervous system (CNS) inflammation. The stimulation of β-adrenergic receptors has been demonstrated to be anti-inflammatory in many cell types, leading us to hypothesize that stimulation of β-adrenergic receptors could prevent the downregulation in CYP1A1 and 1A2 activity in an in vitro model of CNS inflammation. Isoproterenol, a general β₁/β₂ receptor agonist, and clenbuterol, a specific β₂ receptor agonist, were both able to prevent the LPS-induced downregulation in CYP1A1/2 activity in astrocytes. The involvement of β-adrenergic receptors was confirmed using the general β₁/β₂ receptor antagonist propranolol, which was able to abrogate the protection conferred by isoproterenol and clenbuterol in astrocytes treated with LPS. The isoproterenol and clenbuterol mediated protective effect on the LPS-induced downregulation in CYP1A activity was a cyclic AMP (cAMP) dependent process, since forskolin was able to mimic the protective effect. Isoproterenol and clenbuterol may also prevent the LPS-induced downregulation in CYP1A activity through changes in TNFα expression. Despite a slight reduction in the LPS-induced nuclear translocation of the p65 subunit of NF-κB, isoproterenol and clenbuterol had no effect on the DNA binding ability of this transcription factor, indicating that the β-adrenergic protective effects on CYP1A activity occurred independent of changes in NF-κB activity. The results presented in this paper reveal that β-adrenergic receptor stimulation can modulate cytochrome P450 activity in an in vitro model of CNS inflammation by a cAMP mediated pathway.