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Potential cerebral malaria therapy: intramuscular arteether and vitamin D co-administration

Published online by Cambridge University Press:  21 July 2016

HEMLATA DWIVEDI ,
SUNIL KUMAR SINGH ,
BHAVANA SINGH CHAUHAN ,
SARIKA GUNJAN  and
RENU TRIPATHI
HEMLATA DWIVEDI
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India
SUNIL KUMAR SINGH
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
BHAVANA SINGH CHAUHAN
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India
SARIKA GUNJAN
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India
RENU TRIPATHI*
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India
*
*Corresponding author. Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. E-mail: renu1113@rediffmail.com
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Summary

Cerebral malaria (CM) shows lethality rate of 15–25% despite effective antimalarial chemotherapy. The effective adjunct treatment to counteract the CM pathogenesis is urgently required. In murine CM model, most interventions studied till date are administered before the onset of CM symptoms, which belittle its translational value to human. We studied intramuscular arteether–vitamin D (ART–VD) combination treatment for CM outcome improvement after the onset of neurological symptoms. The intramuscular dose of 50 µg kg−1 VD for 3 days combined with a loading dose of 25 mg kg−1α/β arteether followed by 12·5 mg kg−1 dose for two consecutive days led to significant improvement in survival (73% in combination group vs 29 and 0% in arteether and VD monotherapy, respectively) and clinical recovery. The treatment in all the groups partially restored the blood–brain barrier integrity and reduced the level of serum proinflammatory cytokines tumour necrosis factor-α and interferon-γ. The brain transcripts of inflammatory chemokines viz. CXCL10, CXCL9, CCL4 and CCL5 and T cell migration in the brain microvasculature were significantly diminished in all the treatment groups. ART–VD treatment significantly reduced intercellular cell adhesion molecule-1 expression. Taken together, our findings show that coordinated actions of ART–VD improve the outcome of experimental CM.

Keywords

cerebral malariaarteethervitamin Dadjunct therapyPlasmodium berghei ANKA
Type
Research Article
Information
Parasitology , Volume 143 , Issue 12 , October 2016 , pp. 1557 - 1568
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Copyright
Copyright © Cambridge University Press 2016 

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