Inhibition of inflammation by minocycline improves heart failure and depression-like behaviour in rats after myocardial infarction

Abstract

Rationale Patients with heart failure have an increased incidence of depression. Central and peripheral inflammation play a major role in the pathophysiology of both heart failure and depression. Aim Minocycline is an antibiotic that inhibits microglia activation and release of pro-inflammatory cytokines. We assessed effects of minocycline on extent of heart failure and depression at 2 and 8 weeks post myocardial infarction. Methods/Results Male Wistar rats were randomly divided into 3 groups: (i) sham + vehicle; (ii) MI + vehicle; and (iii) MI + minocycline with n/group of 8, 9 and 9 at 2 weeks, and 10, 16, 8 at weeks, respectively. Oral minocycline (50 mg/kg/day) or vehicle started 2 days before surgery. Depression-like behaviour was assessed with sucrose preference and forced swim tests, and cardiac function with echo and hemodynamics. After myocardial infarction, microglia activation and plasma/brain pro-inflammatory cytokines increased, which were mostly prevented by minocycline. At 8 weeks, cardiac dysfunction was attenuated by minocycline: infarct size (MI + Vehicle 29±1, MI + Min 23±1%), ejection fraction (Sham 80±1, MI + Vehicle 48±2, MI + Min 58±2%) and end diastolic pressure (Sham 3.2±0.3, MI + Vehicle 18.2±1.1, MI + Min 8.5±0.9 mm Hg). Depression-like behaviour was significantly improved by minocycline in sucrose preference test (% Sucrose Intake: Sham 96±1, MI + Vehicle 78±2, MI + Min 87±2) and forced swim test (% Immobile: Sham 40±4, MI + Vehicle 61±3, MI + Min 37±6). Conclusion Rats post myocardial infarction develop systemic inflammation, heart failure and depression-like behaviour that are all attenuated by minocycline. Targeting (neuro) inflammation may represent new therapeutic strategy for patients with heart failure and depression.

A Multi-Gene Synaptic Plasticity Array Identifies Candidate Molecular Underpinnings of Cognitive and Mood Deficits in Rats with Heart Failure

“…The present findings are consistent with previous research showing that HF decreases sucrose preference and increases anxiety in the EPM (Prickaerts et al, 1996;Lu et al, 2017;Najjar et al, 2018b;Liu et al, 2019;Wang et al, 2019). The present results extend those findings by showing that these effects are observed in a rat model of HF characterized by severely reduced ejection fraction.…”

“…Although both clinical and experimental studies in animal models support a link between HF and cognitive/mood impairments, (Rutledge et al, 2006;Angermann et al, 2012;Lossnitzer et al, 2013;Cameron et al, 2014;Cannon et al, 2017;Toledo et al, 2019;Wang et al, 2019), the precise mechanisms and molecular underpinnings remain elusive. Cognitive impairment in neurodegenerative disorders and aging, as well as mood disorders have been linked to altered synapse structure/functional properties as well as to deficits in synaptic plasticity mechanisms including blunted LTP.…”

“…It is now becoming well-accepted that, in addition to neurohumoral activation and the associated systemic cardiac, renal and vascular complications, HF is comorbid with depression, anxiety and memory deficits, both in human patients (Rutledge et al, 2006;Angermann et al, 2012;Lossnitzer et al, 2013;Cameron et al, 2014;Cannon et al, 2017) and experimental animal models (Toledo et al, 2019;Wang et al, 2019). These mood and cognitive disturbances have serious implications for quality of life and self-care in patients who have HF because hospital readmission and mortality rates are significantly higher in HF patients that have depression and/or cognitive impairments compared to HF patients without these comorbidities (Dickson et al, 2007;Pressler et al, 2010a;Lee et al, 2013;Lossnitzer et al, 2013).…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…HF-induced cognitive impairments in both rats and mice has been previously described (82,83) and while it is well established that the PVN is a main neuronal substrate contributing to mood regulation, our studies provide an indirect evidence that neuroin ammation within the amygdala may constitute a neuronal substrate contributing to HF-induced mood de cits. A recent study showed that the microglia inhibitor minocycline improved depression-like behavior in HF rats (84). However, the authors performed oral delivery of minocycline so that the precise site of action within the brain underlying this improvement could not to be determined.…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…HF-induced cognitive impairments in both rats and mice have been extensively studied (82,83) and while it is well established that the PVN is a main neuronal substrate contributing to mood regulation, our studies provide an indirect evidence that NI within the amygdala may constitute a neuronal substrate contributing to HF-induced mood deficits. A recent study showed that the microglia inhibitor minocycline improved depression-like behavior in HF rats (84). However, the authors performed oral delivery of minocycline so that the precise site of action within the brain underlying the improvement of the depression-like behavior could not to be determined.…”