Impairment of the Brain β-Adrenergic System during Experimental Endotoxemia

Kikuchi, Yuji; Saito, Shigeru; Kunimoto, Fumio; Imai, Takasuke; Fujita, Tatsushi

doi:10.1006/jsre.1996.0153

Cited by 56 publications

(33 citation statements)

References 2 publications

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“…21,22 Decreased concentrations of NA and a concomitant loss of ␤ adrenergic sites have been described in the forebrain of rats with experimental septic encephalopathy. 23 Administration of ␤ adrenergic antagonists results in delayed acquisition of motor tasks, 24 and treatment of cirrhotic patients with the ␤ adrenergic antagonist, propranolol, may precipitate encephalopathy, 25,26 a phenomenon that has generally been attributed to a peripheral effect of the drug. However, central ␤ adrenergic mechanisms cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Evidence for altered central noradrenergic function in experimental acute liver failure in the rat

et al. 1998

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The pathophysiological mechanisms responsible for cerebral edema and hepatic encephalopathy (HE), two major central nervous system complications of acute liver failure, have not been fully elucidated. The current consensus of opinion is that neurotransmitter-related mechanisms, 1-3 rather than a primary deficit of cerebral energy metabolism, 4,5 are responsible. Alterations of both glutamatergic 2 and serotoninergic 1 systems have been described in HE resulting from experimental acute liver failure, and there is a growing body of evidence that central noradrenergic systems may also be implicated in the pathogenesis of HE in this setting. Hepatectomy, 3,6,7 liver devascularization, 8 and thioacetamide-induced acute liver failure 1 in the rat consistently result in decreases in brain concentrations of noradrenaline (NA), and hepatectomy results in increased NA release into ventriculocisternal perfusates, 9 suggesting that increased noradrenergic activity could contribute to the pathogenesis of HE in acute liver failure. However, little (if any) information is available on extracellular brain concentrations of monoamines in experimental liver failure, nor of the status of the recently characterized multiple monoamine receptor subtypes in this condition. As part of a series of studies to address these issues, the present study had two objectives, namely to evaluate the effects of acute liver failure resulting from hepatic devascularization on: 1) extracellular brain concentrations of NA in relation to the severity of HE and to the appearance of brain edema; and 2) central NA receptor subtypes, at coma stages of encephalopathy, in these animals. MATERIALS AND METHODS MaterialsRinger' s solution constituents, sodium phosphate (monobasic), ethylenediaminetetraacetic acid, sodium octanesulfonate, Tris-HCl, ascorbic acid, WB4101, phentolamine, serotonin, epinephrine, NA, and isoproterenol were purchased from Sigma Chemical Co. Surgical TechniquesMale Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada) (range, 175-200 g at the time of surgery), were anesthetized with halothane, and an end-to-side portacaval anastomosis was performed as previously described. 2 The inferior vena cava was partially clamped, and an elliptical piece of vein was removed. The portal vein was ligated, cut, and an end-to-side anastomosis (shunt [SH]) was performed under a dissecting microscope, according to the guidelines of Lee and Fisher. 10 Total surgery time was Ϸ15 min. Sham-operated animals (matched for weight) were similarly anesthetized, and, following laparotomy, the inferior vena cava and portal vein were clamped for 15 minutes (sham [SM]). After surgery, the animals had free access to standard laboratory food and water. All rats were housed under constant conditions of temperature, humidity, and light cycles.Twenty-four hours after portacaval shunt or laparotomy, an

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Section: Discussionmentioning

confidence: 99%

Evidence for altered central noradrenergic function in experimental acute liver failure in the rat

et al. 1998

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“…For example, production of the late mediator of sepsis HMGB1 is inhibited by acetylcholine released from the vagus nerve in response to systemic lipopolysaccharide (LPS) (51). Conversely, intraperitoneal lipopolysaccharide induces intracerebral expression of TLR2 (21), interleukin-6 (IL-6) (50), and IL-1␤ (49); activates microglia in the dentate gyrus; decreases hippocampal neurogenesis (29); and causes alteration of neuronal function (18). Greater understanding of how these effects are related to neurological damage is required for the design of therapeutic interventions.…”

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confidence: 99%

Cell Wall-Mediated Neuronal Damage in Early Sepsis

et al. 2006

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Neuronal dysfunction can occur in the course of sepsis without meningitis. Sepsis-associated neuronal damage (SAND) was observed in the hippocampus within hours in experimental pneumococcal bacteremia. Intravascular challenge with purified bacterial cell wall recapitulated SAND. SAND persisted in PAFr ؊/؊ mice but was partially mitigated in mice lacking cell wall recognition proteins TLR2 and Nod2 and in mice overexpressing interleukin-10 (IL-10) in macrophages. Thus, cell wall drives SAND through IL-10-repressible inflammatory events. Treatment with CDP-choline ameliorated SAND, suggesting that it may be an effective adjunctive therapy to increase survival and reduce organ damage in sepsis.During sepsis, organ dysfunction occurs independently of invasion of the organ by circulating bacteria. In the case of early encephalopathy, which occurs in up to 70% of septic patients in intensive care units (42), the pathogenesis is unclear, as it precedes peripheral organ dysfunction and bacterial invasion of the central nervous system (CNS). It is assumed that intravascular inflammation deleteriously affects neuronal function at a distance (i.e., across the blood-brain barrier) since the vascular compartment and the CNS communicate bidirectionally during infection (38). For example, production of the late mediator of sepsis HMGB1 is inhibited by acetylcholine released from the vagus nerve in response to systemic lipopolysaccharide (LPS) (51). Conversely, intraperitoneal lipopolysaccharide induces intracerebral expression of TLR2 (21), interleukin-6 (IL-6) (50), and IL-1␤ (49); activates microglia in the dentate gyrus; decreases hippocampal neurogenesis (29); and causes alteration of neuronal function (18). Greater understanding of how these effects are related to neurological damage is required for the design of therapeutic interventions.Streptococcus pneumoniae is a gram-positive bacterium reported to have the highest case fatality rate (14.5%) of all organisms causing pediatric sepsis (52). Patients are noted for devastating neurological sequelae even in the absence of meningitis (39). However, the mechanism of neuronal injury has been studied only in the context of meningitis, where the presence of a threshold of Ͼ10 5 pneumococci/ml in the subarachnoid space induces strong inflammation, a response that is recapitulated by purified pneumococcal cell wall (47, 48). Neuronal damage during meningitis arises from a combination of direct cytotoxicity of bacterial components and activation of the host response (3,19,20,25,35). Apoptosis of neurons in the dentate gyrus of the hippocampus is particularly prominent both in animal models (3-5, 43) and at human autopsy (31), and detailed analysis has indicated that it arises by both caspase-dependent and -independent pathways. However, the effect of pneumococcal bacteremia on neurons remains unknown. While studying the development of meningitis during sepsis in mice, we observed that neuronal damage was evident prior to entry of bacteria into the subarachnoid space. Although the...

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“…3) suggest the possibility of SIRS occurring without cerebral deregulations. Further, there is evidence from several studies that there are differences between acute and chronic inflammatory disease; acute endotoxin effects indicate transient damages while chronic disease results in nerve-damaged mechanisms of cerebral function [14,22]. Models of inflammatory disease (see [23]) indicate decreasing cerebral blood flow during increasing severity of illness.…”

Section: Discussionmentioning

confidence: 99%