Neuroinflammation trajectories precede cognitive impairment after experimental meningitis—evidence from an in vivo PET study

Giridharan, Vijayasree V.; Collodel, Allan; Generoso, Jaqueline S.; Scaini, Giselli; Wassather, Rico; Selvaraj, Sudhakar; Hasbun, Rodrigo; Dal‐Pizzol, Felipe; Petronilho, Fabrícia; Barichello, Tatiana

doi:10.1186/s12974-019-1692-0

Cited by 22 publications

(13 citation statements)

References 60 publications

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“…Microglial cells are highly specialized tissue macrophages of the CNS [34], and the dysregulation of this cell type triggers neuropsychiatric, neurodegenerative, and neuroinflammatory diseases [35]. Using positron emission tomography (PET) imaging with [ 11 C]PBR28, a radiotracer ligand that binds to 18-KDa translocator protein (TSPO), we identified in vivo microglia activation 10 days after meningitis induction [36] . Similarly, in this research strategy, microglia cells (IBA-1 and CD11B) were activated at 10 days after meningitis induction concomitant with an increase in RAGE and Aβ 1-42 expression in the PFC and hippocampus of meningitis survivor rats.…”

Section: Discussionmentioning

confidence: 99%

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis

et al. 2021

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Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood-brain barrier (BBB) and by increasing the receptor for advanced glycation end product (RAGE) expression in the brain, which causes glial cell activation, leading to cognitive impairment. To test our hypothesis, 60-day-old Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a control group and were treated with a RAGE-specific inhibitor (FPS-ZM1) in saline. The rats also received ceftriaxone 100 mg/kg intraperitoneally, bid, and fluid replacements. Experimental pneumococcal meningitis triggered BBB disruption after meningitis induction, and FPS-ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF-α and IL-1β in the prefrontal cortex (PFC); high expression levels of RAGE, amyloid-β (Aβ 1-42 ), and microglial cell activation in the PFC and hippocampus; and memory impairment, as evaluated by the open-field, novel object recognition task and Morris water maze behavioral tasks. Targeted RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ 1-42 , inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats. The sequence of events generated by pneumococcal meningitis can persist long after recovery, triggering neurocognitive decline; however, RAGE blocker attenuated the development of brain inflammation and cognitive impairment in experimental meningitis.

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Section: Discussionmentioning

confidence: 99%

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis

et al. 2021

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“…According to the manufacturer’s instructions, the protein estimation was performed using a Micro BCA ® protein assay kit for the sample submitted for immunoblotting, cytokine assay, and ELISA (Thermo Fischer Scientific, MA, USA) [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

A crosstalk between gut and brain in sepsis-induced cognitive decline

Giridharan

Generoso

Lence

et al. 2022

J Neuroinflammation

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Background Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors. Methods To test our hypothesis, adult Wistar rats were subjected to cecal–ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory. Results Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group. Conclusions Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.

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“…The BBB transport and glymphatic clearances are interdependent mechanisms, and the dysfunction of these mechanisms can difficult the solute clearance [36]. The BBB permeability or disruption facilitates the migration of peripheral immune cells and inflammatory mediators into the CSF, increasing the production of cytokines, chemokines, reactive oxygen and nitrogen species, and neurotoxic molecules that contribute to glial cell activation and consequent neuroinflammation [6, 7, 8, 9]. Pre-clinical studies of bacterial meningitis have demonstrated that the BBB breakdown is associated with cognitive impairment [37, 38], and when the proteolytic enzymes like matrix metalloproteinases (MMPs) were blocked cognitive dysfunction could be prevented [39, 40].…”

Section: Discussionmentioning

confidence: 99%

“…The inflammation triggered by the host immune response leads to the recruitment of peripheral immune cells into the brain and the cerebrospinal fluid (CSF) in a tentative to eliminate the invasive pathogens [6]. The inflammatory mediators which are released in the brain during the infection include cytokines, chemokines, reactive oxygen and nitrogen species, and neurotoxic molecules that contribute to the activation of the microglial cells, initiating neuroinflammation [7, 8, 9]. All these waste products, including host-derived debris, and the invading pathogen itself along with any secreted toxins, are released in the CSF and in the brain parenchyma and must be efficiently cleared from the brain to regain CNS homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis

Generoso

Thorsdottir

Collodel

et al. 2022

Preprint

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BACKGROUND: Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. The brain is separated from the systemic circulation by the blood-brain barrier (BBB), and meningitis triggers the host immune response increasing the BBB permeability, allowing peripheral immune cells to reach the cerebrospinal fluid (CSF), and increasing debris production. The glymphatic system is a glial-dependent clearance pathway that drives the exchange of compounds between the brain parenchyma and the CSF regulating the waste clearance away from the brain. Aquaporin-4 (AQP4)-water channels on astrocytic end feet regulate the solute transport of the glymphatic system. METHODS AND RESULTS: Wistar rats, either subjected to pneumococcal meningitis or to artificial-CSF (sham), received Evans blue albumin (EBA) intracisternal. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the brain without consistently releasing the EBA into the bloodstream compared to the sham non-infected group. Through western blot and immunofluorescence microscopy analysis using rat CSF and brain tissue sections, an increased accumulation of pneumococci was detected over time in the CSF, and because of a loss of drainage between CSF and brain interstitial space, such bacterial accumulation was not observed in the brain parenchyma. Western blot analysis for Iba1, TMEM119 and IFN-Ɣ in rat brain homogenates and NSE in serum showed increased neuroinflammation and neuronal damage in the brain over time during pneumococcal infection. Neurological impairment upon neuronal cell damage caused by meningitis with a malfunctioning glymphatic system was also demonstrated through open-field behavioral tests comparing rats from sham and meningitis groups. Lastly, protein expression analysis of AQP4 revealed no differences in AQP4 between the brains of the rats from the meningitis group and those from the sham non-infected rats. Importantly, confocal microscopy analysis showed a detachment of the astrocytic end feet from the BBB vascular endothelium with consequent misplacement of AQP4-water channels. CONCLUSIONS: These findings clearly indicate that pneumococcal meningitis decreases the glymphatic system's functionality, increasing the neurotoxic waste debris in the brain ultimately leading to brain-wide neuroinflammation and neuronal damage. Finally, our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the BBB vascular endothelium, which leads to a misplacement of AQP4 with consequent the loss of the AQP4-water channel's functionality.

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Neuroinflammation trajectories precede cognitive impairment after experimental meningitis—evidence from an in vivo PET study

Cited by 22 publications

References 60 publications

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis

A crosstalk between gut and brain in sepsis-induced cognitive decline

Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis

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