Inflammation in the brain during heart failure
Creators: name: Dworak, Melissa
Publisher: name: RMIT University
Year: 2024

description: Heart failure is a major cardiovascular disease state and an increasing burdon on our society and health care budget. Following a myocardial infarction there is an increase in inflammatory cytokine levels in the brain. This occurs within 30 minutes of a myocardial infarction. The increase in cytokines may result from (i) peripherally produces cytokinds being transported across the blood brain barrier, and (ii) local production, as mRNA levels of pro-inflammatory cytokines are elevated. This local production could involve the immune cells of the brain. Microglia are the primary immune cells in the brain and when activated they secrete cytokines thereby potentially contributing to the local elevation in pro-inflamatory cytokines. A recent study showed that 2-5 weeks following a myocardial infarction, microglia become activated within the hypothalamic paraventricular nucleus (PVN). It is not known whether microalgia are activated earlier. Furthermore, it is not known whether activation of microglia is limited to the PVN, or if inhibiting the microglial activation influences local neuronal function and cardiac function. The first study in the work aimed to investigate the time course of activated microglia following and myocardial infarction. To investigate the time course of activated microglia, Sprague-Dawley rats were sacrificed at 25 hours, 1, 4, 8, 12 or 16 weeks following a myocardial infarction. The hypothalamus was cut and processed immunohistochemically to detect the microglial marker CD11b (clone OX-42_. The presence of this marker together with morphological changes of the microglia was used to identify activated microglia. Compared to control rates, there was a significant increase in microglia in the PVN at 4, 8, 12 and 16 weeks after the MI. No significant difference from control rats was observed at 25 hours or 1 weeks post MI. There was no correlation found between the echocardiography measures of heart function and the proportion of activated micoglia. The second study used rats 12 weeks post myocardial infarction. In order to determine what effect miroglia were having following myocardial infarction, rats were infused with either minocycline or saline into the lateral ventricle. The brains were collected and processed immunohistochemically to detect the microglial marker CD11b (clone OX-42) as well as a marker of neuronal activaltioin, Fos related antigen (FRA). At 12 weeks following a myocardial infarction there was a significant increase in microglial activation within the paraventricular neucleus (PVN), periaquaducal grey (PAG), rostro ventral lateral medulla (RVLM), nucleus tract solitarus (NTS) and area postrema (AP). Minocycline treatment was able to reduce the microglial activation in these areas by 10-50%. At 12 weeks following myocardial infarction there was a significant increase in neuronal activation within the PVN, PAG, RVLM and NTS, which minocycline treatment was able to drastically reduce. However no improvement in cardical function was observed. In conclusion following MI, microglia are activated within the PVN, RVLM and NTS. This may contribute to the increase in neuronal activation as decreasing microglial activation reduced neuronal activation. However a reduction in microglial activation did not improve cardiac function, suggesting inflammation in those cardiocascular areas of the brain are not playing a key role in cardiac function. This does not preclude these areas from influencing other cardiovascular functions which needs to be further investigated.