<i>NOS2</i>Gene Deficiency Protects from Sepsis-Induced Long-Term Cognitive Deficits

Weberpals, Marc; Hermes, Michael; Hermann, Sven; Kummer, Markus P.; Terwel, Dick; Semmler, Alexander; Berger, Meike; Schäfers, Michael; Heneka, Michael T.

doi:10.1523/jneurosci.3238-09.2009

Cited by 131 publications

(116 citation statements)

References 53 publications

(60 reference statements)

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“…Data from animal studies also indicate that hippocampus-dependent learning and memory is permanently attenuated after a septic episode (Barichello et al, 2005(Barichello et al, , 2007Semmler et al, 2007;Weberpals et al, 2009). This is likely to involve apoptosis of neuronal progenitor cells within the dentate gyrus.…”

Section: Cognitive Declinementioning

confidence: 96%

Neuro-oxidative-nitrosative stress in sepsis

Berg

Møller

Bailey

2011

J Cereb Blood Flow Metab

136

109

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Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO À ). This activates the inducible NO synthase, which further compounds ONOO À formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain 'at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.

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Section: Cognitive Declinementioning

confidence: 96%

Neuro-oxidative-nitrosative stress in sepsis

Berg

Møller

Bailey

2011

J Cereb Blood Flow Metab

136

109

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“…25 There is no clear evidence to explain in detail how inflammation reaches the brain during sepsis, but both in animals and in humans, inflammation occurs in the CNS early and late after sepsis. [26][27][28][29] The immune system is a complex, highly adaptive system, 29 and it is integrated with the CNS at several levels to maintain homeostasis. [30][31][32] However, it is possible that activation of the immune system may induce brain dysfunction, and, in fact, sepsis is a major risk factor for occurrence of delirium.…”

Section: Introductionmentioning

confidence: 99%

Septic encephalopathy: does inflammation drive the brain crazy?

Dal‐Pizzol

Tomasi

Ritter

2014

Rev. Bras. Psiquiatr.

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Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

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“…Other studies are being conducted to clarify the impact of the synthesis of nitric oxide by iNOS in infectious diseases and in the development of cognitive decline. Weberpals et al also observed that iNOS gene deficiency prevents cognitive decline in addition to promoting a reduction in gliosis (astrocytes and microglia), proinflammatory cytokines TNF-α and IL-1β release, and reduction of synaptic dysfunction in sepsis model [58].…”

Section: As Shown Inmentioning

confidence: 94%

“…In this way, the induction of iNOS may result in the development of cognitive impairment [71]. Experimental models of sepsis [58] and malaria (unpublished data) have shown that the inhibition of iNOS has a beneficial effect on the central nervous system, particularly by abolishing cognitive decline.…”

Section: Nmda-nnos Pathway and Excitotoxicity Developmentmentioning

confidence: 99%

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

Reis¹,

Gonçalves-de-Albuquerque²,

Maron‐Gutierrez³

et al. 2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide (NO) was discovered as an endothelium-derived relaxing factor more than two decades ago. Since then, it has been shown to participate in many pathways. NO has been described as a key mediator of different pathways in the central nervous system (CNS) in both healthy and diseased processes. The three isoforms of nitric oxide synthase differ in their activity patterns and expression in different cells. Neuronal nitric oxide synthase (nNOS) is localized in synaptic spines, astrocytes, and the loose connective tissue surrounding blood vessels in the brain; eNOS is present in both cerebral vascular endothelial cells and motor neurons; and iNOS is induced in astrocytes and microglia under pathological conditions. During physiological processes, NO produced by eNOS/nNOS, respectively, controls blood flow activation, and act as a messenger during long-term potentiation (LTP). However, under pathological conditions, eNOS appears to be impaired, leading to a reduction in blood flow and, consequently, low oxygen/metabolites delivery, efflux of toxicological agents from the brain tissue and disturbance in the blood-brain barrier. The NO produced by iNOS in glial cells and nNOS, which triggers the NMDA-excitotoxic pathway, combines with superoxide anion and results in peroxynitrite synthesis, a potent free radical that contributes to tissue damage in the brain. Here, we intend to show the controversial role of the nitric oxide delivered by the three isoforms of the nitric oxide synthase in the CNS, assess its impact under healthy/pathological conditions and speculate on its possible sequela, particularly in long-term cognitive decline.

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NOS2Gene Deficiency Protects from Sepsis-Induced Long-Term Cognitive Deficits

Cited by 131 publications

References 53 publications

Neuro-oxidative-nitrosative stress in sepsis

Neuro-oxidative-nitrosative stress in sepsis

Septic encephalopathy: does inflammation drive the brain crazy?

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

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