Neuro-oxidative-nitrosative stress in sepsis

Abstract

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.

Disassociation of static and dynamic cerebral autoregulatory performance in healthy volunteers after lipopolysaccharide infusion and in patients with sepsis

“…Both cerebral hypoxia due to low CaO 2 levels (anemic hypoxia) and changes in Pa CO 2 may be of importance to these changes, and may, indeed, be further augmented by cerebral microvascular dysfunction. A number of complementary mechanisms that were not addressed in the present study, such as the direct cerebrovascular effects of circulating proinflammatory mediators, as well as neuro-oxidative-nitrosative stress with concomitant effects on the vascular nitric oxide bioavailability, may be involved in this vicious cycle (6). Further studies focusing on the relationship between cerebral CO 2 reactivity, cerebral oxygen vasoreactivity, neurovascular coupling, and dynamic autoregulation in patients with sepsis are warranted to elucidate their potential relationship to neuro-oxidative-nitrosative stress and the occurrence of encephalopathy at various stages of disease.…”

“…Notwithstanding that the brief systemic inflammatory response evoked by LPS infusion may not have been sufficient to adversely affect dynamic autoregulation, the enhanced dynamic autoregulation observed after LPS may suggest that dynamic autoregulation is preserved during the very early stages of sepsis, whereas the prolonged response time of the autoregulatory responses in patients may reflect a progressive cerebral microvascular "indolence" during the course of sepsis into more advanced stages. This could potentially expose the brain to intermittent hypoxia and/or bloodbrain barrier breaching upon fluctuations in blood pressure and, thus, contribute to the widespread ischemic zones and hemorrhages that have been observed in neuropathological studies of patients dying from septic shock (6,32,33). Thus, our findings stress that neuroprotective strategies instituted for the prevention of encephalopathy and permanent cognitive deficits in critically ill patients with sepsis should take the potentially deleterious effects of acute surges in blood pressure on CBF into account.…”

“…It is often the first symptom of sepsis and may herald an unfavorable neurocognitive outcome (6). Although the underlying mechanisms remain unresolved, SAE may involve changes in cerebral hemodynamics; accordingly, patients with sepsis appear to be particularly susceptible to cerebral ischemia and breaching of the blood-brain barrier (32,33), both of which may be facilitated by a functional impairment of cerebral autoregulation (6).…”

“…cerebral autoregulation; endotoxin; human; lipopolysaccharide; sepsis-associated encephalopathy SEPSIS, THE SYSTEMIC INFLAMMATORY response to infection, is frequently complicated by acute brain dysfunction, also termed sepsis-associated encephalopathy (SAE), which is characterized by confusion, agitation, and impaired consciousness (13,16). It is often the first symptom of sepsis and may herald an unfavorable neurocognitive outcome (6). Although the underlying mechanisms remain unresolved, SAE may involve changes in cerebral hemodynamics; accordingly, patients with sepsis appear to be particularly susceptible to cerebral ischemia and breaching of the blood-brain barrier (32,33), both of which may be facilitated by a functional impairment of cerebral autoregulation (6).…”

African locust bean (Parkia biglobosa, Jacq Benth) leaf extract affects mitochondrial redox chemistry and inhibits angiotensin-converting enzyme in vitro

“…Sodium nitroprusside (SNP), on the other hand, has been reported to cause cytotoxicity through the release of cyanide and/or nitric oxide [27]. The released NO is capable of causing neuronal damage in cooperation with other reactive oxygen species (ROS) notably superoxide radical to form peroxynitrite radical [28]. The considerable inhibition of SNP-induced lipid peroxidation by PBE could be attributed to the ability of the extract to scavenge NO˙radical produced by the SNP, thus protecting the tissues against oxidative insults [28].…”