Abstract
Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3β) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3β activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3β inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3β with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3β signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM.
Highlights
Cerebral malaria (CM) resulting from infection with Plasmodium falciparum remains one of the deadliest diseases in the developing world, resulting in nearly 1 million annual deaths worldwide
Alterations in Akt/GSK3b signaling with acute experimental cerebral malaria model (ECM) Glycogen synthase kinase 3 (GSK3b) is a ubiquitously active enzyme which is inhibited upon phosphorylation at Ser9 by activated protein kinase B (PKB or Akt)
In order to determine the effect of malarial infection on cell survival regulatory proteins, we examined the kinases involved in the Akt pathway in the brains of mice at day eight post-infection with Plasmodium berghei ANKA (PbA) in comparison to that of mice infected with the non-neurotrophic P. berghei NK65 (PbN) and in uninfected control mice
Summary
Cerebral malaria (CM) resulting from infection with Plasmodium falciparum remains one of the deadliest diseases in the developing world, resulting in nearly 1 million annual deaths worldwide. Recent microarray analysis suggests that neuronal and glial disturbances may be etiologic in the development of ECM [15]. A little-recognized effect of CM is the metabolic dysfunction that occurs as a result of this vasculopathy and the neuronal damage which ensues. Primate studies of CM have demonstrated metabolic abnormalities in brains of infected animals with impairment in glucose uptake preceding parenchymal damage or manifestations of ECM [16]. Our previous studies in a murine model of CM demonstrating that n-acetyl aspartate (NAA), an inverse indicator of both of neuronal loss and recent or ongoing neuronal injury/dysfunction [17,18,19], is decreased in the brains of mice with CM reflects this impairment of metabolic function in affected neurons [20]
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