Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats

Abstract

The long-acting, highly lipophilic, β2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1β in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250μg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral β2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1β. Moreover, despite increasing central IL-1β expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective β2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety.

Activation of β2-Adrenoceptor Attenuates Sepsis-Induced Hippocampus-Dependent Cognitive Impairments by Reversing Neuroinflammation and Synaptic Abnormalities

“…An in vitro study showed that β2-AR activation dampened the LPS-induced M1 polarization in macrophages (Bacou et al, 2017). Another study confirmed that the peripheral effects of clenbuterol can be dissociated from its central effects and the increased expression of the antiinflammatory molecules IL-1ra and IL-1RII may serve to limit the effects of clenbuterol-induced IL-1β on brain function and behavior (Ryan et al, 2016). In the present study, we extended these prior studies in vivo by demonstrating that activation of the β2-adrenergic receptor not only regulated the production of inflammatory cytokines but also modified the entire microglia phenotype, resulting in an M2 regulatory microglia phenotype.…”

Neuroendocrine Regulation of Brain Cytokines After Psychological Stress

“…It is unclear if the production of IL-1 β via β -AR signaling depends on activation of an inflammasome or if it is mediated by an inflammasome-independent pathway, as is observed with other sterile inflammatory stimuli [77–79]. Clenbuterol, a β 2 -AR agonist, administered to rats selectively induces IL-1 β and not IL-6 or TNF- α in the hypothalamus and hippocampus [80]. Figure 3 demonstrates similar responses in primary microglia incubated with various concentrations of norepinephrine.…”

Sex differences in the regulation of brain IL-1β in response to chronic stress

“…The sex differences may involve the magnitude by which glucocorticoids regulate norepinephrine release between males and females since metyrapone-treatment increased norepinephrine turnover in the hypothalamus and medial prefrontal cortex of male rats while having no effect on norepinephrine turnover in females In both males and females, propranolol blocked the increase in IL-1β mRNA induced by metyrapone-treatment indicating the increase in IL-1β expression was dependent on β-AR activation. Ryan et al (2016) demonstrated that β-ARs regulate IL-1β production in microglia. To examine if microglia were a potential cellular source of IL-1β mRNA in our studies, we used a Percoll gradient to isolate microglia (i.e.…”

“…Catecholamines can stimulate the production of IL-1β in microglia (Ryan et al, 2016), thus we hypothesized that microglia may be a cellular source of the increase in IL-1β following metyrapone. To test this, male Fischer rats (n=4/group) were given an injection of either saline or metyrapone and 2 h later animals were euthanized and microglia were isolated from the hypothalamus and hippocampus for the measurement of IL-1β mRNA.…”