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Published on: June 20, 2017
Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo
Vijayasree V Giridharan1, Allan Collodel2, Jaqueline S Generoso2
1Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
Background:
Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment.
Method:
Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated with ceftriaxone. Twenty-four hours and 10 days after meningitis induction, rats were imaged with positron emission tomography (PET) using [11C]PBR28, a specific translocator protein (TSPO) radiotracer, to determine in vivo microglial activation. Following imaging, the expression of TSPO, cardiolipin, and cytochrome c, inflammatory mediators, oxidative stress markers, and glial activation markers were evaluated in the prefrontal cortex and hippocampus. Ten days after meningitis induction, animals were subjected to behavioral tests, such as the open-field, step-down inhibitory avoidance, and novel object recognition tests.
Results:
Both 24-h (acute) and 10-day (long-term) groups of rats demonstrated increased [11C]PBR28 uptake and microglial activation in the whole brain compared to levels in the control group. Although free from infection, 10-day group rats exhibited increased expression levels of cytokines and markers of oxidative stress, microglial activation (IBA-1), and astrocyte activation (GFAP) similar to those seen in the 24-h group. Acute meningitis induction also elevated TSPO, cytochrome c, and caspase-3 levels with no change in caspase-9 levels. Furthermore, upregulated levels of TSPO, cytochrome c, and caspase-3 and caspase-9 were observed in the rat hippocampus 10 days after meningitis induction with a simultaneous reduction in cardiolipin levels. Animals showed a cognitive decline in all tasks compared with the control group, and this impairment may be at least partially mediated by activating a glia-mediated immune response and upregulating TSPO.
Conclusions:
TSPO-PET could potentially be used as an imaging biomarker for microglial activation and long-term cognitive impairment post-meningitis. Additionally, this study opens a new avenue for the potential use of TSPO ligands after infection-induced neurological sequelae.
Insights
Bacterial meningitis causes cognitive impairment due to activated microglia. Positron emission tomography (PET) with [11C]PBR28 can image this microglial activation, offering a potential biomarker for long-term neurological deficits.
Area of Science:
- Neuroscience
- Infectious Diseases
- Radiochemistry
Background:
- Bacterial meningitis is a severe central nervous system (CNS) infection leading to neurological deficits, notably cognitive impairment.
- Activated microglia-induced neuroinflammation is implicated in the long-term cognitive consequences of meningitis.
Purpose of the Study:
- To investigate the association between activated microglia and cognitive impairment following bacterial meningitis.
- To evaluate the utility of translocator protein (TSPO) positron emission tomography (PET) as a biomarker for microglial activation and cognitive deficits.
Main Methods:
- Bacterial meningitis was induced in Wistar rats using Streptococcus pneumoniae.
- In vivo microglial activation was assessed using [11C]PBR28 TSPO-PET imaging at 24 hours and 10 days post-induction.
- Post-mortem analyses included evaluating TSPO, inflammatory mediators, oxidative stress markers, and glial activation markers in brain tissue, alongside behavioral tests.
Main Results:
- Increased [11C]PBR28 uptake and microglial activation were observed in both acute and long-term meningitis groups.
- Long-term survivors exhibited persistent neuroinflammation, oxidative stress, and glial activation, correlating with cognitive decline in behavioral tasks.
- Upregulation of TSPO, cytochrome c, and caspase-3/9, with reduced cardiolipin, was noted in the hippocampus, suggesting mitochondrial dysfunction.
Conclusions:
- TSPO-PET imaging shows potential as a biomarker for assessing microglial activation and predicting long-term cognitive impairment after meningitis.
- The findings suggest that TSPO ligands could be valuable therapeutic or diagnostic tools for managing post-infectious neurological sequelae.
