Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium

Noradrenaline acting at β-adrenoceptors induces expression of IL-1β and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex

Evidence indicates that noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and plays a neuroprotective role where inflammatory events contribute to pathology. Here we examined the ability of pharmacological enhancement of central noradrenergic tone to impact upon activation of the IL-1 system in rat brain. Treatment with the noradrenaline reuptake inhibitor reboxetine combined with the α2-adrenoceptor antagonist idazoxan induced expression of IL-1β as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1 type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by β-adrenoceptors, as the aforementioned effects were blocked by the β-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant β2-adrenoceptor agonist clenbuterol induced expression of IL-1β, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-α, IL-6 or IFN-γ were not induced by clenbuterol. Induction of IL-1β was accompanied by activation of NFκB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1β-inducible gene CINC-1. The ability of clenbuterol to activate the IL-1 system was blocked by propranolol, and was mimicked by the highly selective β2-adrenoceptor agonist formoterol. Despite the ability of clenbuterol to activate the central IL-1 system, it largely combated the neuroinflammatory response induced by systemic inflammatory stimulus (bacterial lipopolysaccharide; LPS). Specifically, whilst the ability of clenbuterol to induce expression of IL-1RII and IL-1Ra was maintained following the inflammatory challenge, its ability to induce IL-1β was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-α and IL-6, the inflammatory chemokines RANTES and IP-10, the co-stimulatory molecules CD40 and ICAM-1. Thus overall, clenbuterol suppresses the innate inflammatory response in rat brain

La noradrenalina que actúa en los ?-adrenoceptores centrales induce la interleucina-10 y el supresor de la expresión de la citocina señalización-3 en el cerebro de rata: implicaciones para la neurodegeneración

Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15 mg/kg; ip) combined with the ?2-adrenoceptor antagonist idazoxan (1 mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling-3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti-inflammatory cytokines IL-4 and TGF-? were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by ?-adrenoceptor activation, as their induction was blocked by pre-treatment with the ?-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant ?2-adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting ?-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective ?2-adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration

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

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, 250 μg/kg), clenbuterol (0.5 mg/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 (0.03 mg/kg; twice daily for 21 days) 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