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NADPH Oxidase: a Possible Therapeutic Target for Cognitive Impairment in Experimental Cerebral Malaria

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Abstract

Long-term cognitive impairment associated with seizure-induced hippocampal damage is the key feature of cerebral malaria (CM) pathogenesis. One-fourth of child survivors of CM suffer from long-lasting neurological deficits and behavioral anomalies. However, mechanisms on hippocampal dysfunction are unclear. In this study, we elucidated whether gp91phox isoform of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) (a potent marker of oxidative stress) mediates hippocampal neuronal abnormalities and cognitive dysfunction in experimental CM (ECM). Mice symptomatic to CM were rescue treated with artemether monotherapy (ARM) and in combination with apocynin (ARM + APO) adjunctive based on scores of Rapid Murine Come behavior Scale (RMCBS). After a 30-day survivability period, we performed Barnes maze, T-maze, and novel object recognition cognitive tests to evaluate working and reference memory in all the experimental groups except CM. Sensorimotor tests were conducted in all the cohorts to assess motor coordination. We performed Golgi-Cox staining to illustrate cornu ammonis-1 (CA1) pyramidal neuronal morphology and study overall hippocampal neuronal density changes. Further, expression of NOX2, NeuN (neuronal marker) in hippocampal CA1 and dentate gyrus was determined using double immunofluorescence experiments in all the experimental groups. Mice administered with ARM monotherapy and APO adjunctive treatment exhibited similar survivability. The latter showed better locomotor and cognitive functions, reduced ROS levels, and hippocampal NOX2 immunoreactivity in ECM. Our results show a substantial increase in hippocampal NeuN immunoreactivity and dendritic arborization in ARM + APO cohorts compared to ARM-treated brain samples. Overall, our study suggests that overexpression of NOX2 could result in loss of hippocampal neuronal density and dendritic spines of CA1 neurons affecting the spatial working and reference memory during ECM. Notably, ARM + APO adjunctive therapy reversed the altered neuronal morphology and oxidative damage in hippocampal neurons restoring long-term cognitive functions after CM.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

The authors thank Dr. Nakka Venkata Prasuja for sparing apocynin.

Funding

The authors wish to recognize the financial assistance from the Ministry of Science and Technology, Department of Science and Technology, Govt. of India, DST-CSRI file no. SR/CSRI/196/2016; DST-SERB Core grant, file no. CRG/2020/005021; and Department of Biotechnology, Govt. of India, BT/PR17686/MED/30/1664/2016, and financial support to the University of Hyderabad-IoE by the Ministry of Education, Govt. of India (F11/9/2019-U3(A), and INSPIRE student Fellowship (DST/INSPIRE Fellowship/2013/710), Government of India.

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  1. F-23/71, Neuroscience Laboratory, Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500 046, India

    Simhadri Praveen Kumar & Phanithi Prakash Babu

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SPK designed the hypothesis and experimental methodology. PPB guided and assisted with editing the manuscript.

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Correspondence to Phanithi Prakash Babu.

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All the animal experiments were conducted as per the guidelines of the Committee for the Purpose of Control and Supervision of Experimental Animals (CPCSEA), Government of India (Registration No: 48/1999/CPCSEA), after approval from the Institutional Animal Ethics Committee (UH/IAEC/PPB2014-I/68), University of Hyderabad, India.

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Kumar, S.P., Babu, P.P. NADPH Oxidase: a Possible Therapeutic Target for Cognitive Impairment in Experimental Cerebral Malaria. Mol Neurobiol 59, 800–820 (2022). https://doi.org/10.1007/s12035-021-02598-1

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  • DOI: https://doi.org/10.1007/s12035-021-02598-1

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