Possible central role of nitric oxide in conditions clinically similar to cerebral malaria

doi:10.1016/0140-6736(92)93295-X

The Lancet

Volume 340, Issue 8824, 10 October 1992, Pages 894-896

https://doi.org/10.1016/0140-6736(92)93295-X Get rights and content

Abstract

The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the bloodbrain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.

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In this study, the difference in mice strain susceptibility to infection is related to the difference in response of mice glutathione, catalase, malondialdehyde and nitric oxide. Clark et al. (1992) postulated that, pathogenesis of cerebral malaria is due to the increase in nitric oxide, which in turn leads to cerebral coma due to a difference in the neurotransmitters (Taylor-Robinson, 2010). In the current study, we observed an increase in the measured, dopamine, epinephrine, norepinephrine and serotonin.
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Cytokines may act through induction of the production of nitric oxide. It has been hypothesized that heightened local production of nitric oxide, increased due to upregulation of inducible nitric oxide synthase (iNOS) in brain endothelium, may diffuse into the neuropil and disrupt normal neurotransmission (Clark et al., 1992; Rockett et al., 1992). This hypothesis is attractive in that nitric oxide readily diffuses across the blood−brain barrier, rapidly and reversibly interrupts consciousness, and has short-lived effects.
Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood−brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed.
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Malaria is still the world's major important parasitic disease and is responsible for the death of more people than any other communicable disease except tuberculosis. A major change in recent years has been the recognition that severe malaria, predominantly caused by Plasmodium falciparum, is a complex multi-system disorder presenting with a range of clinical features. Some surviving patients have an increased risk of neurological and cognitive deficits, behavioural difficulties and epilepsy, making cerebral malaria a leading cause of childhood neurodisability in the malaria transmission area. It is unclear how an intravascular parasite causes such brain injury. Understanding of these mechanisms is important to develop appropriate neuroprotective interventions. However, due to the high specificity of P. falciparum to the human host and to the fact that clinical studies in human are not always feasible, our knowledge about this syndrome mainly comes from autopsy studies which can only give us a limited view of this deadly syndrome. Efforts developed by the scientific community have shown that development of severe malaria probably results from a combination of parasite-specific factors such as adhesion and sequestration to the vascular endothelium, the release of bioactive molecules, together with host inflammatory responses and metabolic acidosis. Recent studies have shown that endothelial cells could play a central role in the onset of the severe malaria. Indeed, adhesion of parasitized erythrocytes to these cells could drive their activation, which could participate in the trigger of an immune response and haemostatic derangements. Moreover, death of endothelial cells could be at the origin of the blood-lung/brain barrier breakdown. Despite the efforts to find new mechanisms, which explain the physiopathology of severe malaria, research progress is slowed down by the lack of experimental models, which reproduce this complex multi-system disorder. In absence of a vaccine so far, the rapid diagnosis of the disease, an efficient treatment, a correct management and nursing care are the only weapons to control mortality due to P. falciparum. It is important to note that in the future, the treatment of severe malaria may involve adjuvant treatments in addition to a potent antimalarial drug. In the present review, we summarize both what is known and practically useful for a physician, and the most promising and current topics of research.
Le paradoxe du paludisme est qu’il reste un fléau sanitaire planétaire (50 % de la population mondiale exposée ; 225 millions de cas annuels) alors qu’il est l’une des pathologies infectieuses (pour laquelle il n’existe pas encore de vaccin) les plus simples à la fois à prévenir, à diagnostiquer et à traiter en phase non compliquée. Le recul malgré tout important obtenu ces dernières décennies est le résultat de stratégies de lutte antipaludique, mais aussi la conséquence du développement. Pour autant, le paludisme (essentiellement dû à l’espèce Plasmodium falciparum) se classe au deuxième rang des causes de mortalité (près de 800 000 décès annuels) derrière la tuberculose. Malgré un arsenal thérapeutique efficace, bien toléré et de plus en plus accessible avec l’appui d’une solidarité internationale, il est difficile de réduire la létalité moyenne des accès graves en dessous de 15 à 20 %. Seule une meilleure compréhension de la physiopathologie des accès graves, dont le neuropaludisme, permettra d’identifier des cibles thérapeutiques adaptées. Divers modèles expérimentaux (in vitro et in vivo) peuvent y contribuer. L’une des voies explorées est celle de l’usage d’adjuvants thérapeutiques intervenant aux côtés des antipaludiques afin de prévenir ou d’entraver des processus moléculaires, cellulaires et tissulaires à l’origine des complications observées.
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Expression of these same genes is inhibited by TNF in experimental sepsis [48], rationalizing seizures whenever brain TNF is increased. Recent data on TNF in brain function recalls that nitric oxide (NO), generated through the ability of TNF to induce iNOS, has the potential to mediate many of its brain effects, one of which is to inhibit N-methyl D-aspartate receptors and, thus, synaptic NO generation from nNOS (as reviewed in Ref. [49]). Recent literature reports that synaptic NO integrates synaptic firing in a globally important fashion [50].
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HYPOTHESESPossible central role of nitric oxide in conditions clinically similar to cerebral malaria

Abstract

Parasitol Today

Lancet

Neuron

Trends Neurosci

Eur J Pharmacol

Neurosci Lett

Prog Neurobiol

In vivo induction of nitrite/nitrate by TNF, LTand II-1: roles in malaria

Infect Immun

Endotoxemia and release of tumor necrosis factor and interleukin 1α in acute heatstroke

J Appl Physiol