TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

Abstract

Proinflammatory cytokines, including tumor necrosis factor (TNF)-α , augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.

Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents

“…Although etanercept is too large a molecule for all but a small amount of a subcutaneous (s.c.) dose to enter the cerebrospinal fluid (CSF), intentionally compensating for this by giving a 20-fold larger dose reduces brain glutamate in a rat model of traumatic brain injury [117]. Etanercept has also been reported, in a heart failure model in which TNF is increased [118, 119], to lower rat brain glutamate dramatically when given intracerebroventricularly (i.c.v), although, again because of its high molecular weight, not when administered intraperitoneally (i.p. ).…”

“…This is evolutionarily essential because of the key role of this amino acid in the synaptic cleft, where it is responsible for the fast excitatory neurotransmission necessary for the rapid brain responses demanded for survival in the real world. Thus, given the role of TNF to influence both glutaminase and re-uptake proteins described earlier, the capacity of intracerebral etanercept to lower brain glutamate, as summarized above [117–119], can be expected to act with somewhat the same degree of rapidity. It seems likely, therefore, that these data rationalize the unexpected but clearly rapid response in case reports and open trials to perispinal etanercept, initially reported in 2003 [121] and 2008 [122], and regularly confirmed since [123–127].…”

Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCγ/Rac1 pathway in salt-induced hypertension

“…The method for PVN minipump has been previously described82627. Each rat head was placed into a stereotaxic apparatus after anesthetized with ketamine (90 mg/kg) and xylazine (10 mg/kg) intraperitoneally (i.p).…”

“…Maximum renal sympathetic nerve activity (RSNA) was detected using an intravenous bolus administration of sodium nitroprusside (SNP, 10 mg). The recordings of rectified and integrated RSNA were analyzed using methods described as previously826.…”

Hypothalamic inflammation and food intake regulation during chronic illness

“…The hypothesis that the hypothalamus plays a crucial role in both reduced food intake and cachectic body wasting is supported by a combination of findings. Firstly, neuroinflammation and disturbed hypothalamic signalling is present in cachectic chronic diseases such as cancer [5], HIV [26,27], COPD [28] and heart failure [29,30]. Secondly, the hypothalamus has the highest density of receptors for these pro-inflammatory cytokines in the brain [31].…”