Cerebral Malaria: Mechanisms of disease and neurological salvage

Summary

Principal Investigator: Mahalia S Desruisseaux
Abstract: DESCRIPTION (provided by applicant): Greater than 20% of individuals with cerebral malaria (CM) suffer from persistent neurological and cognitive deficits long after successful anti-parasitic treatment. These deficits encompass a wide range of neuro-cognitive dysfunction. We have demonstrated in a murine model that CM results in a vasculopathy with increased levels of endothelin- 1 (ET-1), leading to a reduction of cerebral blood flow and a decrease in NAA/Cr ratio in the brains of mice on MRS [2]. Our preliminary data also demonstrate that just as with human disease, mice sustain cognitive dysfunction [42], which persists even after successful eradication of the parasite, as evidenced by significantly impaired performance in object recognition and spatial memory tests. Furthermore, CM mice had significant motor coordination deficits on the balance beam even after successful antiparasitic treatment. These cognitive and motor impairments were still evident on retesting 40 days after resolution of malarial infection. However, they were not accompanied by any significant degree of vascular damage, inflammation or astrogliosis. The lack of obvious pathology after parasitic cure suggests that these long-term neuro- cognitive deficits are the result of potentially reversible biochemical and physiological changes in brains of CM mice subsequent to the decreased blood flow and ischemia during the acute infection. We demonstrated that tau, a protein involved in neurofibrillary tangle formation in Alzheimer's disease, is aberrantly phosphorylated in cortical neurons of infected mice during CM. We believe that the aberrant tau phosphorylation is the end product of an altered signaling in the neurons of infected mice mediated by ET-1. We have found a down-regulation of the PI3K/Akt insulin signaling/ survival pathway in the brains of mice with CM. As a result of decreased Akt activation, the normal inhibition of GSK3 by Akt does not occur and tau becomes aberrantly phosphorylated. In addition, Akt is no longer able to facilitate the translocation of glucose transporters to the cell membranes and the cells are not able to uptake glucose. We propose that as a result of a reduction in cerebral blood flow, there is ischemia and neuronal damage associated with abnormalities in the insulin signaling/ survival pathway. This mechanism likely underlies the cognitive function impairment observed in CM and may yield therapeutic targets for adjunctive therapy in the management of CM. PUBLIC HEALTH RELEVANCE: Malaria is an important cause of morbidity and mortality especially in sub-Saharan Africa where children bear the greatest burden. Cerebral malaria is a form of severe malaria caused mainly by Plasmodium falciparum in humans. This form of malaria is often associated with neurological sequelae including seizures, memory impairment and behavior disturbances. In the mouse model of cerebral malaria, mice are infected with the ANKA strain of Plasmodium berghei and compared to a non cerebral malaria model- mice infected with the NK65 strain of P. berghei. These mice have cognitive dysfunction and other neurological abnormalities not seen with the non cerebral malaria mice. We also have evidence of a reduction in cerebral blood flow in this model. Dysregulation of tau protein which is important in the dementia of Alzheimer's disease and abnormalities in the regulation of Akt- one of the signaling pathways that is important in cell survival and glucose regulation- are also present in the mouse model of malaria. Thus, vascular compromise and alterations in Akt and tau may be important in the pathogenesis of malaria and may provide rational targets of drug therapy to ameliorate the consequences of this infection.
Funding Period: 2011-04-15 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. pmc The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative
    Minxian Dai
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States
    Life Sci 91:687-92. 2012
  2. pmc Cerebral malaria: we have come a long way
    Henry J Shikani
    Division of Parasitology and Tropical Medicine, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
    Am J Pathol 181:1484-92. 2012
  3. pmc Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John s University, Queens, New York, USA
    PLoS ONE 7:e44117. 2012
  4. pmc Imaging of small-animal models of infectious diseases
    Linda A Jelicks
    Department of Physiology and Biophysics and the Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 182:296-304. 2013
  5. pmc Alterations in glucose homeostasis in a murine model of Chagas disease
    Fnu Nagajyothi
    Division of Parasitology and Tropical Medicine, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 182:886-94. 2013
  6. pmc N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth
    Sruthi Sundaram
    Department of Pharmaceutical Sciences, St John s University, Queens, New York 11439, USA
    Am J Pathol 183:422-30. 2013

Research Grants

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
  2. Chemokines in Zambian children with Cerebral Malaria
    Monique F Stins; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative
    Minxian Dai
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States
    Life Sci 91:687-92. 2012
    ....
  2. pmc Cerebral malaria: we have come a long way
    Henry J Shikani
    Division of Parasitology and Tropical Medicine, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
    Am J Pathol 181:1484-92. 2012
    ..The present review highlights information gleaned from these studies, especially in terms of their contributions to the understanding of cerebral malaria...
  3. pmc Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John s University, Queens, New York, USA
    PLoS ONE 7:e44117. 2012
    ..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...
  4. pmc Imaging of small-animal models of infectious diseases
    Linda A Jelicks
    Department of Physiology and Biophysics and the Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 182:296-304. 2013
    ..Imaging studies permit enhanced information through longitudinal studies of the same animal during the infection. Herein, we briefly review recent studies of animal models of infectious disease that have used imaging modalities...
  5. pmc Alterations in glucose homeostasis in a murine model of Chagas disease
    Fnu Nagajyothi
    Division of Parasitology and Tropical Medicine, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 182:886-94. 2013
    ..cruzi-induced hypoglycemia, despite reduced insulin, but elevated glucagon levels. The data establishes a complex, multi-tissue relationship between T. cruzi infection, Chagas disease, and host glucose homeostasis...
  6. pmc N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth
    Sruthi Sundaram
    Department of Pharmaceutical Sciences, St John s University, Queens, New York 11439, USA
    Am J Pathol 183:422-30. 2013
    ..These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders. ..

Research Grants30

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  2. Chemokines in Zambian children with Cerebral Malaria
    Monique F Stins; Fiscal Year: 2013
    ....