Aberrant Dopamine Receptor Signaling Plays Critical Role in the Impairment of Striatal Neurons in Experimental Cerebral Malaria

Kumar, Simhadri Praveen; Babu, Phanithi Prakash

doi:10.1007/s12035-020-02076-0

Cited by 12 publications

(6 citation statements)

References 93 publications

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“…Aberrant activation of neuronal NOX dysregulate dopaminergic neurotransmission mediated motor coordination in Parkinson's disease [103]. Recently, our group elucidated mechanism of dysregulation of dopamine receptor signaling and impairment of striatal medium spiny neurons in ECM [104]. According to various clinical trial reports, children who survived from CM suffer from motor disabilities after ARM treatment [105][106][107][108].…”

Section: Discussionmentioning

confidence: 99%

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

Kumar

Babu

2021

Mol Neurobiol

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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 de cits 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, 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 changes in overall hippocampal neuronal density. Further, expression of NOX2 and NeuN (a neuronal marker) in hippocampal CA1, dentate gyrus was determined using double immuno uorescence 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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Section: Discussionmentioning

confidence: 99%

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

Kumar

Babu

2021

Mol Neurobiol

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“…However, it is not clear whether the IFN-γ response elicited by Lm inoculation will aggravate immunopathology in the context of complicated malaria like CM. Taking advantage of Plasmodium berghei ANKA ( Pb A)-infected C57BL/6 mice, which are a well-known murine model of CM, we showed in this study that live Lm inoculation reduced parasitemia, ECM symptoms, and brain pathology. This effect was associated with enhanced systemic IFN-γ production in the early stage of Pb A infection.…”

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confidence: 65%

Listeria monocytogenes Inoculation Impedes the Development of Brain Pathology in Experimental Cerebral Malaria by Inhibition of Parasitemia

et al. 2022

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Cerebral malaria (CM) is a serious central nervous system dysfunction caused by Plasmodium falciparum infection. In this study, we investigated the effect of Listeria monocytogenes (Lm) inoculation on experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice. Live Lm inoculation inhibited the parasitemia and alleviated ECM symptoms. The protective effect against ECM symptoms was connected with improved brain pathology manifested as a less-damaged blood−brain barrier, decreased parasite sequestration, and milder local inflammation. Meanwhile, Lm inoculation decreased expression of cell adhesion molecules (ICAM-1 and VCAM-1) and accumulation of pathogenic CD8 + T cells in the brain. In keeping with the suppression of parasitemia, there was an upregulation of IFN-γ, IL-12, MCP-1, and NO expression in the spleen by Lm inoculation upon PbA infection. Early treatment with exogenous IFN-γ exhibited a similar effect to Lm inoculation on PbA infection. Taken together, Lm inoculation impedes the development of brain pathology in ECM, and early systemic IFN-γ production may play a critical role in these protective effects.

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“…Also, axonal injury with the accumulation of APP has been reported in postmortem studies of CM patients, both adults and pediatric cases [103][104][105]. Accordingly, the [106]. The dysregulation of the dopaminergic receptors led to the impairment and degeneration of medium spiny neurons [106].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the [106]. The dysregulation of the dopaminergic receptors led to the impairment and degeneration of medium spiny neurons [106]. Findings from neuroimaging studies have demonstrated that the anatomical and functional grouping of dopaminergic neurons in striatum performs a significant role in the execution of cognition and behavioral consequences in young adults [107,108].…”

Section: Discussionmentioning

confidence: 99%

Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria

Wruck

Adjaye

2021

Preprint

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Background: Malaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children. While the majority of falciparum malaria survivors make a full recovery, there are reports of some patients ending up with neurological sequelae. Methods: We performed an analysis of pooled transcriptome data of whole blood samples derived from two studies involving various Plasmodium falciparum infections, comprising mild malaria (MM), non-cerebral severe malaria (NCM) and CM. Pathways and gene ontologies (GOs) elevated in the distinct falciparum infections were identified. Results: Contrary to other research findings, our analysis showed MM share similar biological processes with cancer and neurodegenerative diseases, NCM is associated with drug resistance and glutathione metabolism and CM is correlated with endocannabinoid signaling and non-alcoholic fatty liver disease (NAFLD). GO revealed the terms biogenesis, DNA damage response and IL-10 production in MM, down-regulation of cytoskeletal organization and amyloid-beta clearance in NCM and aberrant signaling, neutrophil degranulation and gene repression in CM. Differential gene expression analysis between CM and NCM showed the up-regulation of neutrophil activation and response to herbicides while regulation of axon diameter was down-regulated in CM. Conclusions: The results of this study have demonstrated that the deleterious effect of falciparum malaria on the brain may not be limited to CM and NCM alone but also MM. However, the severity of neurological deficit in CM might be due to the down-regulation of various genes involved in cellular function through transcriptional repression, axonal dysfunction, dysregulation of signaling pathways and neurodegeneration as a result of inflammation and cellular stress. We anticipate that our data might form the basis for future hypothesis-driven malaria research.

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Aberrant Dopamine Receptor Signaling Plays Critical Role in the Impairment of Striatal Neurons in Experimental Cerebral Malaria

Cited by 12 publications

References 93 publications

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

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

Listeria monocytogenes Inoculation Impedes the Development of Brain Pathology in Experimental Cerebral Malaria by Inhibition of Parasitemia

Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria

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