Skip to main content
. Author manuscript; available in PMC: 2010 Jan 1.
Published in final edited form as: Nat Biotechnol. 2009 Jul 5;27(7):659–666. doi: 10.1038/nbt.1549

Figure 5.

Figure 5

Selective synergy between glucocorticoids (GC) and tricyclic anti-depressants (TCA). (a) The synergy against TNFα secretion in PBMCs remains when related drugs are substituted (Suppl. Note 4), so the synergy operates via the primary drug targets. Moreover, 59 of 63 combinations we have tested in this assay on these targets at sufficient concentrations were also synergistic (S > 5 standard errors, data not shown). (b) Mechanistically, GCs activate the glucocorticoid receptor (GCR) which suppresses inflammatory signaling. In response to stress, lymphocytes secrete catecholamine hormones, such as norepinephrine (NE), which suppress inflammatory signaling via beta-adrenergic receptors (ADRB2)39. TCAs block NE transporters (SLC6A2), which increases extracellular NE levels, with a synergistic anti-inflammatory effect when combined with GCs40. Directly adding NE and modulating ADRB2 in combination with GC confirms the role of this pathway in the GC-TCA synergy (Suppl. Note 4). The in vivo therapeutic selectivity arises because while GCR, SLC6A2 and ADRB2 are co-expressed in lymphoid cells, ADRB2 is expressed 3–10 fold lower41 in tissues such as liver and pituitary that mediate major GC-associated adverse effects42, weakening the NE-mediated pathway and attenuating the GC-TCA synergy. In rats, the combination of nortriptyline with another GC that is widely used for asthma treatment, budesonide, was tested in an asthma model via ovalbumin challenge (c). The combination at individually sub-therapeutic doses was able to restore lung infiltration by eosinophils to levels seen with high-dose dexamethasone or unchallenged rats (ANOVA p < 0.05 over single agents). Anti-inflammatory synergy with prednisolone was also confirmed in a rat pain model (Suppl. Note 4). By contrast, rat liver toxicity (d), modeled by a corticosteroid side effect marker tyrosine aminotransferase (TAT), showed elevated expression only for high dose prednisolone (ANOVA p < 0.05), while the effects at doses showing anti-inflammatory synergy were consistent with or lower than negative controls. In vivo data are detailed in Tab. S8.