Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia

Abstract

Prolonged and continuous exposure of mammals to a low oxygen environment (chronic hypoxia) elicits remarkable morphological and physiological adjustments. These include altered gene expression, increased peripheral chemosensitivity, enhanced respiratory drive and sympathoexcitation. The current study examines the hypothesis that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. Male Wistar rats pretreated with vehicle or minocycline (30 mg kg day for 5 days) were subjected to AH (8% O , balance N ) or normoxia (21% O ) for 3 h. AH increased interleukin (IL)-6, IL-1β and matrix metalloprotease 9 (MMP9) mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) and rostral ventrolateral medulla (RVLM) and tumour necrosis factor α (TNFα) in the RVLM. Treatment with minocycline, an inhibitor of microglial activation, decreased IL-1β, TNFα and MMP9 mRNA expression in the RVLM, and increased IL-6 mRNA expression in the RVLM and PVH of rats exposed to AH. Minocycline treatment also elicited a decrease in the number of activated neurons in the RVLM/C1 neurons (expressed as Fos /tyrosine hydroxylase ), the number of Fos-activated neurons in the PVH and the increase in ventilation elicited by AH. When viewed together, these results suggest that AH modulates the expression of inflammatory mediators in autonomic brain nuclei that may be involved in the responses to chemoreceptor activation.

Neuroimmune modulation of cardiorespiratory responses to acute severe hypoxia

“…The suppression of hypoxic ventilation is consistent with recent observations that microglial inactivation blunts time-dependent ventilatory responses to hypoxia (Lorea-Hernández, Morales, Rivera-Angulo, Alcantara-Gonzalez, & Peña-Ortega, 2016;Stokes, Arbogast, Moya, Fu, & Powell, 2017;Tadmouri, Champagnat, & Morin-Surun, 2014). The observation of Silva et al (2018) suggests a dynamic contributory role for microglia and neuroimmune interactions as an essential component of the integrative ventilatory response to acute severe hypoxia, which clearly warrants further investigation to delineate the underlying mechanism, with prostaglandin E 2 a probable candidate. The finding adds to a growing interest in the interplay between neuroinflammation and respiratory plasticity, which together have implications for ventilatory acclimatization to hypoxia, sleepdisordered breathing and therapeutic intermittent hypoxia strategies for conditions characterized by respiratory insufficiency.…”

“…Arguably the most striking observation of the study by Silva et al. () was a finding of blunted ventilation during hypoxia in minocycline‐treated rats compared with vehicle‐treated control animals, whereas normoxic ventilation was unaffected by minocycline treatment. The suppression of hypoxic ventilation is consistent with recent observations that microglial inactivation blunts time‐dependent ventilatory responses to hypoxia (Lorea‐Hernández, Morales, Rivera‐Angulo, Alcantara‐Gonzalez, & Peña‐Ortega, ; Stokes, Arbogast, Moya, Fu, & Powell, ; Tadmouri, Champagnat, & Morin‐Surun, ).…”

“…The observation of Silva et al. () suggests a dynamic contributory role for microglia and neuroimmune interactions as an essential component of the integrative ventilatory response to acute severe hypoxia, which clearly warrants further investigation to delineate the underlying mechanism, with prostaglandin E 2 a probable candidate. The finding adds to a growing interest in the interplay between neuroinflammation and respiratory plasticity, which together have implications for ventilatory acclimatization to hypoxia, sleep‐disordered breathing and therapeutic intermittent hypoxia strategies for conditions characterized by respiratory insufficiency.…”

Enhancement of excitatory transmission in NTS neurons projecting to ventral medulla of rats exposed to sustained hypoxia is blunted by minocycline

“…The treatment was carried out for 3 days and on the third day the rats were placed into hypoxia (SH) or control chambers. The dose and treatment time chosen are within the range used in previous studies reporting the anti-inflammatory and microglial inhibitor effects of minocycline in rodents (Raghavendra et al 2003;Piao et al 2006;Liu et al 2009;Silva et al 2018).…”

Increased lipopolysaccharide‐induced hypothermia in neurogenic hypertension is caused by reduced hypothalamic PGE2 production and increased heat loss

“…Using a cryostat, slices of 1200 μm thickness were prepared to obtain punches of the NTS and slices of 600 μm thickness were prepared for the RVLM. NTS samples were dissected based on our previous study (Amorim et al 2019) and RVLM samples were obtained at the level of 2.7 mm caudal to lambda, 8.3 mm below the dorsal surface of the medulla and 1.8 mm lateral to the midline (Silva et al 2018).…”