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

10.21203/rs.3.rs-549894/v1 ◽

2021 ◽

Author(s):

Simhadri Praveen Kumar ◽

Prakash Babu Phanithi

Keyword(s):

Cognitive Impairment ◽

Cerebral Malaria ◽

Cognitive Functions ◽

Reference Memory ◽

Neuronal Morphology ◽

Hippocampal Damage ◽

Experimental Cerebral Malaria ◽

Neuronal Marker ◽

Neuronal Density

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, 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 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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Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria

PLoS Pathogens ◽

10.1371/journal.ppat.1005477 ◽

2016 ◽

Vol 12 (3) ◽

pp. e1005477 ◽

Cited By ~ 9

Author(s):

Brandi D. Freeman ◽

Yuri C. Martins ◽

Oscar B. Akide-Ndunge ◽

Fernando P. Bruno ◽

Hua Wang ◽

...

Keyword(s):

Cognitive Impairment ◽

Cerebral Malaria ◽

Microvascular Dysfunction ◽

Experimental Cerebral Malaria ◽

Endothelin 1

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Faculty Opinions recommendation of Real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718495180.793517736 ◽

2016 ◽

Author(s):

Paul Timpson ◽

Claire Vennin

Keyword(s):

Cerebral Malaria ◽

Real Time ◽

Experimental Cerebral Malaria ◽

Real Time Imaging

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CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽

10.1182/blood-2002-05-1493 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4253-4259 ◽

Cited By ~ 82

Author(s):

Elodie Belnoue ◽

Michèle Kayibanda ◽

Jean-Christophe Deschemin ◽

Mireille Viguier ◽

Matthias Mack ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Cd8 T Cells ◽

Cytokine Production ◽

Wild Type ◽

Experimental Cerebral Malaria ◽

Pathologic Features ◽

Th1 Cytokine ◽

The Brain ◽

Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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Neuroprotective Benefits of Exercise and MitoQ on Memory Function, Mitochondrial Dynamics, Oxidative Stress, and Neuroinflammation in D-Galactose-Induced Aging Rats

Brain Sciences ◽

10.3390/brainsci11020164 ◽

2021 ◽

Vol 11 (2) ◽

pp. 164

Author(s):

Jae-Hoon Jeong ◽

Jung-Hoon Koo ◽

Jang Soo Yook ◽

Joon-Yong Cho ◽

Eun-Bum Kang

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Cognitive Impairment ◽

Nadph Oxidase ◽

Learning And Memory ◽

Oxidase Activity ◽

Mitochondrial Dynamics ◽

Nadph Oxidase Activity ◽

Aging Rats ◽

Positive Effects

Exercise and antioxidants have health benefits that improve cognitive impairment and may act synergistically. In this study, we examined the effects of treadmill exercise (TE) and mitochondria-targeted antioxidant mitoquinone (MitoQ), individually or combined, on learning and memory, mitochondrial dynamics, NADPH oxidase activity, and neuroinflammation and antioxidant activity in the hippocampus of D-galactose-induced aging rats. TE alone and TE combined with MitoQ in aging rats reduced mitochondrial fission factors (Drp1, Fis1) and increased mitochondrial fusion factors (Mfn1, Mfn2, Opa1). These groups also exhibited improved NADPH oxidase activity and antioxidant activity (SOD-2, catalase). TE or MitoQ alone decreased neuroinflammatory response (COX-2, TNF-α), but the suppression was greater with their combination. In addition, aging-increased neuroinflammation in the dentate gyrus was decreased in TE but not MitoQ treatment. Learning and memory tests showed that, contrarily, MitoQ alone demonstrated some similar effects to TE but not a definitive improvement. In conclusion, this study demonstrated that MitoQ exerted some positive effects on aging when used as an isolated treatment, but TE had a more effective role on cognitive impairment, oxidative stress, inflammation, and mitochondria dysfunction. Our findings suggest that the combination of TE and MitoQ exerted no synergistic effects and indicated regular exercise should be the first priority in neuroprotection of age-related cognitive decline.

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A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria

Molecular Neurobiology ◽

10.1007/s12035-016-0226-3 ◽

2016 ◽

Vol 54 (9) ◽

pp. 7063-7082 ◽

Cited By ~ 6

Author(s):

Aline Silva de Miranda ◽

Fátima Brant ◽

Luciene Bruno Vieira ◽

Natália Pessoa Rocha ◽

Érica Leandro Marciano Vieira ◽

...

Keyword(s):

Receptor Antagonist ◽

Cerebral Malaria ◽

Glutamate Receptor ◽

Neuroprotective Effect ◽

Behavioral Outcomes ◽

Glutamate Receptor Antagonist ◽

Experimental Cerebral Malaria

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Cognitive Impairment After Cerebral Malaria in Children: A Prospective Study

PEDIATRICS ◽

10.1542/peds.2006-2027 ◽

2007 ◽

Vol 119 (2) ◽

pp. e360-e366 ◽

Cited By ~ 152

Author(s):

M. J. Boivin ◽

P. Bangirana ◽

J. Byarugaba ◽

R. O. Opoka ◽

R. Idro ◽

...

Keyword(s):

Cognitive Impairment ◽

Prospective Study ◽

Cerebral Malaria ◽

A Prospective Study

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THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

Infection and Immunity ◽

10.1128/iai.02586-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 759-768 ◽

Cited By ~ 9

Author(s):

Sabrina Torre ◽

Sebastien P. Faucher ◽

Nassima Fodil ◽

Silayuv E. Bongfen ◽

Joanne Berghout ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Cerebral Malaria ◽

Functional Coupling ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Proinflammatory Responses ◽

Inflammatory Bowel ◽

Blood Brain Barrier Integrity

We identify anN-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection withPlasmodium bergheiANKA.ThemisI23Nhomozygous mice show reduced CD4+and CD8+T lymphocyte numbers. ECM resistance inP. bergheiANKA-infectedThemisI23Nmice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMISI23Nprotein expression is absent from mutant mice, concurrent with the decreased THEMISI23Nstability observedin vitro. Biochemical studiesin vitroand functional complementationin vivoinThemisI23N/+:Lck−/+doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses inThemisI23Nmice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells.ThemisI23Nmice can be used to study the newly discovered association ofTHEMIS(6p22.33) with inflammatory bowel disease and multiple sclerosis.

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