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NLRP3 Activation Contributes to Memory Impairment in an Experimental Model of Pneumococcal Meningitis

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Abstract

Bacterial meningitis is considered a life-threatening condition with high mortality rates. In response to the infection, signaling cascades, producing pro-inflammatory mediators trigger an exacerbated host immune response. Another inflammatory pathway occurs through the activation of inflammasomes. Studies highlight the role of the NLR family pyrin domain containing 3 (NLRP3) in central nervous system disorders commonly involved in neuroinflammation. We aimed to investigate the role of NLRP3 and its inhibitor MCC950 on neurochemical, immunological, and behavioral parameters in the early and late stages of experimental pneumococcal meningitis. For this, adult male Wistar rats received an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a placebo. The animals were divided into control/saline, control/MCC950, meningitis/saline, and meningitis/MCC950. Immediately after the meningitis induction, the animals received 140 ng/kg MCC950 via intracisternal injection. For the acute protocol, 24 h after induction, brain structures were collected to evaluate cytokines, NLRP3, and microglia. In the long-term group, the animals were submitted to open field and recognition of new objects tests at ten days after the meningitis induction. After the behavioral tests, the same markers were evaluated. The animals in the meningitis group at 24 h showed increased levels of cytokines, NLRP3, and IBA-1 expression, and the use of the MCC950 significantly reduced those levels. Although free from infection, ten days after meningitis induction, the animals in the meningitis group had elevated cytokine levels and demonstrated behavioral deficits; however, the single dose of NLRP3 inhibitor rescued the behavior deficits and decreased the brain inflammatory profile.

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Data Availability

The datasets generated and analyzed from this current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), USA (TB and VVG); the Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC) (JSG, CJF, AC, DD, FP, and TB), Brazil, and TB has received grants from the Alzheimer's Association (AARGDNTF-19-619645) and the National Institutes of Health/National Institute on Aging (NIH/NIA grant 1RF1AG072491)

Funding

The Alzheimer's Association Grant number AARGDNTF-19–619645 and U.S. National Institute of Health/National Institute on Aging (NIH/NIA Grant (1RF1AG072491-01) (T.B.).

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Authors and Affiliations

  1. Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Jaqueline S. Generoso, Cristiano Julio Faller, Fabricia Petronilho & Tatiana Barichello

  2. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Allan Collodel & Diogo Dominguini

  3. Faillace Department of Psychiatry and Behavioral Sciences, Translational Psychiatry Program, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Carlos Henrique Rocha Catalão, Tatiana Barichello & Vijayasree V. Giridharan

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  1. Jaqueline S. Generoso
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  2. Cristiano Julio Faller
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  3. Allan Collodel
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  8. Vijayasree V. Giridharan
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jaqueline S. Generoso, Vijayasree V. Giridharan, Cristiano Julio Faller, Allan Collodel, Carlos Henrique Rocha Catalão, and Diogo Dominguini. The first draft of the manuscript was written by Jaqueline S. Generoso, Cristiano Julio Faller, Fabricia Petronilho, and Tatiana Barichello, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jaqueline S. Generoso or Vijayasree V. Giridharan.

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All procedures were approved by the Animal Care and Experimentation Committee of UNESC (Brazil) sob protocol 033/2019 and followed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23) revised in 1996.

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Jaqueline S. Generoso and Vijayasree V. Giridharan contributed equally.

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Generoso, J.S., Faller, C.J., Collodel, A. et al. NLRP3 Activation Contributes to Memory Impairment in an Experimental Model of Pneumococcal Meningitis. Mol Neurobiol 61, 239–251 (2024). https://doi.org/10.1007/s12035-023-03549-8

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