Inflammasomes as biomarkers and therapeutic targets in traumatic brain injury and related-neurodegenerative diseases: A comprehensive overview

Kattan, Dania; Barsa, Chloe; Mekhijian, Sarin; Shakkour, Zaynab; Jammoul, Maya; Doumit, Mark; Zabala, María Camila Pareja; Darwiche, Nadine; Eid, Ali H.; Mechref, Yehia; Wang, Kevin; Vaccari, Juan Pablo de Rivero; Pareja, Jennifer C. Muñoz; Kobeissy, Firas

doi:10.1016/j.neubiorev.2022.104969

Cited by 11 publications

(6 citation statements)

References 225 publications

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“…Caspase-1, ASC, and IL-18 levels are increased in patients with PD, suggesting that inflammasome proteins play a role in the inflammatory response. This finding is consistent with previous studies showing that inflammasome proteins are promising biomarkers of the inflammatory response associated with traumatic brain injury [ 53 , 54 , 55 , 56 , 57 , 58 ], stroke [ 59 ], Alzheimer’s disease [ 60 ], multiple sclerosis [ 61 ], macular degeneration [ 62 ], ocular surface damage [ 63 ], male pattern baldness [ 64 ], psoriasis [ 65 ], depression [ 66 ], renal diseases [ 67 ], and non-alcoholic steatohepatitis [ 68 ].…”

Section: Discussionsupporting

confidence: 93%

Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease

Cabrera Ranaldi,

Nuytemans,

Martinez

et al. 2023

Pharmaceuticals

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Parkinson’s disease (PD) is a neurodegenerative disorder marked by the death of dopaminergic neurons in the midbrain, the accumulation of α-synuclein aggregates, and motor deficits. A major contributor to dopaminergic neuronal loss is neuroinflammation. The inflammasome is a multiprotein complex that perpetuates neuroinflammation in neurodegenerative disorders including PD. Increases in inflammasome proteins are associated with worsened pathology. Thus, the inhibition of inflammatory mediators has the potential to aid in PD treatment. Here, we investigated inflammasome signaling proteins as potential biomarkers of the inflammatory response in PD. Plasma from PD subjects and healthy age-matched controls were evaluated for levels of the inflammasome protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin (IL)-18. This was carried out using Simple Plex technology to identify changes in inflammasome proteins in the blood of PD subjects. The area under the curve (AUC) was obtained through calculation of the receiver operating characteristics (ROC) to obtain information on biomarker reliability and traits. Additionally, we completed a stepwise regression selected from the lowest Akaike information criterion (AIC) to assess how the inflammasome proteins caspase-1 and ASC contribute to IL-18 levels in people with PD. PD subjects demonstrated elevated caspase-1, ASC, and IL-18 levels when compared to controls; each of these proteins were found to be promising biomarkers of inflammation in PD. Furthermore, inflammasome proteins were determined to significantly contribute to and predict IL-18 levels in subjects with PD. Thus, we demonstrated that inflammasome proteins serve as reliable biomarkers of inflammation in PD and that inflammasome proteins provide significant contributions to IL-18 levels in PD.

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Section: Discussionsupporting

confidence: 93%

Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease

Cabrera Ranaldi,

Nuytemans,

Martinez

et al. 2023

Pharmaceuticals

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“…Pyroptosis is a specific type of cellular necrosis that is a key driver of inflammation in TBI (40)(41)(42) and can be activated by damageassociated molecular patterns and pathogen-associated molecular patterns recognized by Toll-like receptors and NOD-like receptors on the membranes of neurons and glial cells, which activates inflammasomes, cleaves GSDMD proteins, forms pores on the cell membrane surface, promotes the release of cell contents into the intracellular environment, and causes severe inflammation and cytotoxic edema, thereby exacerbating the inflammatory response and brain tissue edema of neurons and other brain tissue cells (43)(44)(45)(46). Our study showed that the expression of GSDMD, GSDMD-N, caspase-1 p20, and caspase-1 p10 increased and the levels of IL-1β, IL-18, and LDH improved in the brain of TBI mice, suggesting that cell pyroptosis occurred in brain tissue following TBI (Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Zhang,

Huang,

Hang

et al. 2024

Sci. Adv.

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Posttraumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may have beneficial effects on the treatment of secondary brain damage after TBI. Here, a cysteine-alanine-glutamine-lysine peptide–modified β-lactoglobulin (β-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-β-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-β-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-β-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a potential approach for reducing the secondary spread of TBI.

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“…There are a striking number of points in the “neurometabolic cascade of concussion” ( Giza and Hovda, 2001 , 2014 ) where the availability of betaine might attenuate disruption. Betaine would play an osmoregulatory role ( Knight et al, 2017 ) that may aid in osmolality and tonicity changes observed post-concussion ( Kawamata et al, 2007 ; Knight et al, 2017 ; Khatibi et al, 2019 ; Kushwah et al, 2020 ) and protect against inflammatory ( Di Battista et al, 2019 ; Kattan et al, 2023 ), thermoregulatory ( Pegoli et al, 2020 ), and cerebrovascular disruptions ( Kenney et al, 2016 ) associated with concussion and traumatic brain injury. Indeed, existing literature identifies betaine as anti-inflammatory ( Zhao et al, 2018 ; Zhang et al, 2022 ), and links betaine with improved thermoregulation ( Willingham et al, 2020 ) and protection of microvasculature ( van der Vaart et al, 2023 ).…”

Section: Betaine–a Neuroprotective Prophylactic Against Concussion (M...mentioning

confidence: 99%

Making the case for prophylactic use of betaine to promote brain health in young (15–24 year old) athletes at risk for concussion

Knight,

Knight

2023

Front. Neurosci.

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Betaine supplementation in the context of human nutrition, athletic performance, and clinical therapy demonstrate that the osmolyte and methyl donor, betaine, is cytoprotective and beneficial to human health. These studies also demonstrate that betaine supplementation in healthy humans is straight-forward with no reported adverse effects. Here, we explore betaine uptake in the central nervous system (CNS) and contribute to evidence that betaine may be uniquely protective to the brain. We specifically describe the therapeutic potential of betaine and explore the potential implications of betaine on inhibition mediated by GABA and glycine neurotransmission. The influence of betaine on neurophysiology complement betaine’s role as an osmolyte and metabolite and is consistent with clinical evidence of betaine-mediated improvements to cognitive function (reported in elderly populations) and its anti-convulsant properties. Betaine’s therapeutic potential in neurological disorders including epilepsy and neurodegenerative diseases combined with benefits of betaine supplementation on athletic performance support the unique application of betaine as a prophylaxis to concussion. As an example, we identify young athletes (15–24 years old), especially females, for prophylactic betaine supplementation to promote brain health and resilience in a cohort at high risk for concussion and for developing Alzheimer’s disease.

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Inflammasomes as biomarkers and therapeutic targets in traumatic brain injury and related-neurodegenerative diseases: A comprehensive overview

Cited by 11 publications

References 225 publications

Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease

Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury

Making the case for prophylactic use of betaine to promote brain health in young (15–24 year old) athletes at risk for concussion

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