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.
Highlights
Malaria remains one of the most important infectious diseases till date
Our study suggests that overexpression of Nicotinamide Adenine Dinucleotide Phosphate oxidase 2 (NOX2) could result in loss of hippocampal neuronal density and dendritic spines of cornu ammonis-1 (CA1) neurons affecting the spatial working and reference memory during experimental CM (ECM)
We observed that the mice infected Plasmodium berghei ANKA (PbA) showed altered behavior from day 5 such as loss of rearing and exploration (60 seconds for exploring the corners) with an Rapid Murine Come behavior Scale (RMCBS) score of 12 ± 1
Summary
Malaria remains one of the most important infectious diseases till date. About 409,000 deaths were estimated globally in the year 2019, of which 86 % cases were accounted from Africa and India (World malaria report 2020) and 1 % of them progress to cerebral malaria (CM) [1]. CM is a neurodegenerative disease, classified under the severe forms of malaria, caused by the infection of Plasmodium falciparum exhibiting fatal complications such as recurrent seizures, delirium, and coma, leading to death [2]. Loss of cognition and behavior after treatment is one of the salient features of CM. Previous reports show that 25 % of children exhibit long-term cognitive impairment after survival from CM [1]. The mechanism underlying the cognitive decline is not known
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
