Failure of Two Distinct Anti-apoptotic Approaches to Reduce Mortality in Experimental Cerebral Malaria

Helmers, Andrew; Lovegrove, Fiona; Harlan, John M.; Kain, Kevin C.; Liles, W. Conrad

doi:10.4269/ajtmh.2008.79.823

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…On the other hand, the number of astrocytes and oligodendrocytes was further increased, which suggests tissue repair [ 30 ]. Glial cells have been described as undergoing apoptosis during ECM [ 31 ]; nevertheless, the outcome of ECM does not depend on the attenuation of glial cell dysfunction [ 32 , 33 ], suggesting that this process is not involved in ECM development. Furthermore, glial cells increase neutrophil survival and phagocytosis, which could provide protection against brain infection [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria

et al. 2015

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IntroductionMalaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year. Since current antimalarial drugs are unable to prevent death in severe cases, new therapeutic strategies have been developed. Mesenchymal stromal cells (MSC) confer host resistance against malaria; however, thus far, no study has evaluated the therapeutic effects of MSC therapy on brain and distal organ damage in experimental cerebral malaria.MethodsForty C57BL/6 mice were injected intraperitoneally with 5 × 106Plasmodium berghei-infected erythrocytes or saline. After 24 h, mice received saline or bone marrow (BM)-derived MSC (1x105) intravenously and were housed individually in metabolic cages. After 4 days, lung and kidney morphofunction; cerebrum, spleen, and liver histology; and markers associated with inflammation, fibrogenesis, and epithelial and endothelial cell damage in lung tissue were analyzed.ResultsIn P. berghei-infected mice, BM-MSCs: 1) reduced parasitemia and mortality; 2) increased phagocytic neutrophil content in brain, even though BM-MSCs did not affect the inflammatory process; 3) decreased malaria pigment detection in spleen, liver, and kidney; 4) reduced hepatocyte derangement, with an increased number of Kupffer cells; 5) decreased kidney damage, without effecting significant changes in serum creatinine levels or urinary flow; and 6) reduced neutrophil infiltration, interstitial edema, number of myofibroblasts within interstitial tissue, and collagen deposition in lungs, resulting in decreased lung static elastance. These morphological and functional changes were not associated with changes in levels of tumor necrosis factor-α, keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8), or interferon-γ, which remained increased and similar to those of P. berghei animals treated with saline. BM-MSCs increased hepatocyte growth factor but decreased VEGF in the P. berghei group.ConclusionsBM-MSC treatment increased survival and reduced parasitemia and malaria pigment accumulation in spleen, liver, kidney, and lung, but not in brain. The two main organs associated with worse prognosis in malaria, lung and kidney, sustained less histological damage after BM-MSC therapy, with a more pronounced improvement in lung function.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria

et al. 2015

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“…Many authors have initiated empiric adjuvant therapy prior to, on, or just after the first day of inoculation [11], [39], [40]. Alternatively, empiric treatments have been provided around the proposed time MCM symptoms have historically been documented to start, on days 3 to 7, post-infection [30], [39], [41], [42]. While the results of these experiments have been promising, they do not fully emulate the human clinical experience—patients are treated at the onset of clinical symptoms, and often, much later.…”

Section: Discussionmentioning

confidence: 99%

A Rapid Murine Coma and Behavior Scale for Quantitative Assessment of Murine Cerebral Malaria

et al. 2010

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BackgroundCerebral malaria (CM) is a neurological syndrome that includes coma and seizures following malaria parasite infection. The pathophysiology is not fully understood and cannot be accounted for by infection alone: patients still succumb to CM, even if the underlying parasite infection has resolved. To that effect, there is no known adjuvant therapy for CM. Current murine CM (MCM) models do not allow for rapid clinical identification of affected animals following infection. An animal model that more closely mimics the clinical features of human CM would be helpful in elucidating potential mechanisms of disease pathogenesis and evaluating new adjuvant therapies.Methodology/Principal FindingsA quantitative, rapid murine coma and behavior scale (RMCBS) comprised of 10 parameters was developed to assess MCM manifested in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). Using this method a single mouse can be completely assessed within 3 minutes. The RMCBS enables the operator to follow the evolution of the clinical syndrome, validated here by correlations with intracerebral hemorrhages. It provides a tool by which subjects can be identified as symptomatic prior to the initiation of trial treatment.Conclusions/SignificanceSince the RMCBS enables an operator to rapidly follow the course of disease, label a subject as affected or not, and correlate the level of illness with neuropathologic injury, it can ultimately be used to guide the initiation of treatment after the onset of cerebral disease (thus emulating the situation in the field). The RMCBS is a tool by which an adjuvant therapy can be objectively assessed.

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“…Two different anti-apoptotic approaches - treatment with z-VAD (a pan-caspase inhibitor) and over-expression of Bcl-2 (a gene which prevents the release of apoptotic mediators from the mitochondria) - did not reduce cerebral malaria mortality in mice(79). However, the cytokine erythropoietin, which has anti-apoptotic, anti-inflammatory, vaso-dilating and neurotrophic properties and widespread receptors in the brain has shown greater promise.…”

Section: Strategies For Improved Neuro-cogntive Outcomementioning

confidence: 99%

Cerebral Malaria: Mechanisms of Brain Injury and Strategies for Improved Neurocognitive Outcome

et al. 2010

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Cerebral malaria is the most severe neurological complication of infection with Plasmodium falciparum. With over 575,000 cases annually, children in sub-Saharan Africa are the most affected. Surviving patients have an increased risk of neurological and cognitive deficits, behavioral difficulties and epilepsy making cerebral malaria a leading cause of childhood neuro-disability in the region. The pathogenesis of neuro-cognitive sequelae is poorly understood: coma develops through multiple mechanisms and there may be several mechanisms of brain injury. It is unclear how an intravascular parasite causes such brain injury. Understanding these mechanisms is important to develop appropriate neuro-protective interventions. This paper examines possible mechanisms of brain injury in cerebral malaria, relating this to the pathogenesis of the disease and explores prospects for improved neuro-cognitive outcome.

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Failure of Two Distinct Anti-apoptotic Approaches to Reduce Mortality in Experimental Cerebral Malaria

Cited by 14 publications

References 22 publications

Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria

Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria

A Rapid Murine Coma and Behavior Scale for Quantitative Assessment of Murine Cerebral Malaria

Cerebral Malaria: Mechanisms of Brain Injury and Strategies for Improved Neurocognitive Outcome

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