Javalgekar et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-024-03167-8(2024) 21:172

Journal of Neuroinflammation

Open Access

REVIEW

Inflammasomes at the crossroads of traumaticbrain injury and post-traumatic epilepsy
Mohit Javalgekar1,2, Bianca Jupp1,2, Lucy Vivash1,2,3, Terence J. O’Brien1,2,3, David K. Wright1,2, Nigel C. Jones1,2,3*† andIdrish Ali1,2,3*†
Abstract
Post-traumatic epilepsy (PTE) is one of the most debilitating consequences of traumatic brain injury (TBI) and is
one of the most drug-resistant forms of epilepsy. Novel therapeutic treatment options are an urgent unmet clinicalneed. The current focus in healthcare has been shifting to disease prevention, rather than treatment, though, notmuch progress has been made due to a limited understanding of the disease pathogenesis. Neuroinflammation
has been implicated in the pathophysiology of traumatic brain injury and may impact neurological sequelae
following TBI including functional behavior and post-traumatic epilepsy development. Inflammasome signaling
is one of the major components of the neuroinflammatory response, which is increasingly being explored for
its contribution to the epileptogenic mechanisms and a novel therapeutic target against epilepsy. This review
discusses the role of inflammasomes as a possible connecting link between TBI and PTE with a particular focus on
clinical and preclinical evidence of therapeutic inflammasome targeting and its downstream effector molecules
for their contribution to epileptogenesis. Finally, we also discuss emerging evidence indicating the potentialof evaluating inflammasome proteins in biofluids and the brain by non-invasive neuroimaging, as potential
biomarkers for predicting PTE development.
Keywords Post-traumatic epilepsy, Traumatic brain injury, Inflammasome, Microglia, NLRP3†

Nigel C. Jones and Idrish Ali contributed equally to this work.

*Correspondence:
Nigel C. Jones
nigel.jones@monash.edu
Idrish Ali
idrish.ali@monash.edu
1
The Department of Neuroscience, School of Translational Medicine,
Monash University, 99, Commercial Road, Melbourne, Australia
2
Department of Neurology, The Alfred Hospital, 99 commercial road,
Melbourne, Australia
3
The University of Melbourne, Parkville, Australia

Neuroinflammation in epilepsy: a role for
inflammasome signaling?
Traumatic brain injury (TBI) occurs after a physicaltrauma to the head or neck, leading to functional andpathological changes in the brain [1]. In addition to
behavioral and psychiatric disorders which are frequentconsequences, one of the most serious chronic sequelae
of TBI is the development of post-traumatic epilepsy(PTE) [2, 3]. Epilepsy is a neurological disease diagnosedby the recurrence of spontaneous epileptic seizures, andPTE specifically refers to epilepsy caused by a preceding TBI. Epileptogenesis refers to the neurobiologicalprocesses that result in the transformation of a healthy
brain into an epileptic brain through complex molecularand functional aberrations that can be triggered by brain
insults such as TBI [4]. The location and severity of TBIs

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Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

are physical characteristics that have a significant impact
on PTE incidence. Increased risk of PTE is linked tolesions in the temporal lobe and penetrating injuries inthe temporal and parietal lobes [5]. For PTE, epileptogenesis often occurs months to years after the precipitating
injury, and this delay period is referred to as the silent,or latent period [6, 7]. During this period, active but currently undetectable, molecular, inflammatory, and structural brain changes occur which ultimately culminate
in the emergence of spontaneous seizures and epilepsy.
This latent period between TBI and the onset of seizures
provides a window for therapeutic anti-epileptogenic
intervention. However, the community has yet to identify
effective interventions that can interrupt this process of
post-traumatic epileptogenesis in humans. In addition,
initiating preventive therapies during this period remains
conceptually challenging because of the lack of predictive
biomarkers that can identify TBI patients at high risk ofdeveloping epilepsy [8–10]. A greater understanding of
the pathophysiological mechanisms driving post-traumatic epileptogenesis may enable the identification of
specific biomarkers of PTE, as well as disease-modifying
therapeutics.
In recent years, neuroinflammation has emerged asa potential mechanism driving secondary brain injury.
Based on the severity of initial trauma, the extent of neuroinflammation greatly enhances the risk of PTE development [11]. Neuroinflammation following TBI involves
the activation and migration of resident glial cells to thesite of injury, and the release of inflammatory mediatorssuch as cytokines and chemokines [12]. The acute phaseof neuroinflammation provides neuroprotection by limiting the spread of damage and clearing cellular debris [13].
However, the ensuing chronic activation of glial cells maylead to further damage to the surrounding tissue aroundthe primary injury area characterized by ionic imbalance, excitatory amino acid release, calcium overload,
generation of reactive oxygen species(ROS), disruptionof the cell membrane, vascular rupture, and ultimately
cell death [14]. The end products derived from dead or
damaged cells constitute Danger-Associated Molecular Patterns (DAMPs) leading to further stimulation of
microglia and astrocytes and secretion of cytokines,
chemokines, adhesion molecules and transcriptional
upregulation of pro-inflammatory factors like NF-κB[15]. In addition, the integrity of the blood-brain barrier
is changed as a direct result of TBI and cytokine signalling leading to the recruitment of peripheral immune
cells such as blood-derived leucocytes, macrophages andserum proteins in brain parenchyma [16]. Altered BBB
permeability has been shown to induce neuronal hyperexcitability possibly via TGF-β receptor-mediated astrocytic serum albumin uptake and extracellular potassium
accumulation [17]. Other studies have shown that BBB

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disruption causes epileptiform discharges in rat somatosensory cortex [18] and a direct correlation between the
seizure burden and the extent of BBB damage in TBI
patients and preclinical TBI model [19]. Furthermore, theintroduction of serum protein in the brain through leaky
BBB could initiate alternate pathways like complement
activation while peripheral immune cells such as neutrophils along with the activated glial cells exacerbate theinflammatory cascade [20, 21]. This inflammatory continuum can ultimately result in progressive neuronal loss
and worsening of injury outcomes [22].
Neuroinflammation following an experimental brain
injury can be sustained for at least six months [23]. Persistent neuroinflammation can also influence several
brain processes implicated in epileptogenesis, including neuronal plasticity, neuronal circuit reorganization,
alterations in excitatory and inhibitory neurotransmitter
receptors and ion channels, and changes in the regulationof neuronal transmission [11].
One neuroinflammatory component that may be particularly relevant to PTE is the inflammasome signaling complex. Inflammasomes are protein complexes
generated in neuroinflammatory environments that are
involved in the activation and release of caspase-1 andinflammatory cytokines [24]. Literature has independently shown the significant contribution of inflammasomes in TBI phenotypes and seizure generation [25, 26].
In this review, we bring this literature together to explore
the possible contribution of inflammasomes to PTE. We
first describe the mechanisms of assembly of inflammasome complexes, discuss inflammasome signaling following TBI and the role of key inflammasome mediators
in epileptogenesis. We also summarize clinical and preclinical examples of therapeutic inflammasome targetingand explore the potential of inflammasomes as biomarkers of PTE. For this narrative review, we searched the
PubMed database using combinations of the following
search criteria: inflammasome, activation and assembly,
epileptogenesis, TBI, molecular mechanisms, therapeuticintervention, and biomarker. For the Tables that summarize this literature, we included all original studies thatassessed inflammasome activation in TBI or epilepsy inboth human subjects and model systems. We excluded all
non-original articles such as reviews, letters, books, andconference abstracts.

Assembly of the inflammasome complex
Inflammasomes are a series of cytosolic multimeric
protein complexes made up of sensory receptor andadaptor proteins that, when aligned, activate caspase-1
to stimulate the maturation and release of pro-inflammatory cytokines [24]. Inflammasome complex formation is well-characterized (Fig. 1) and is integral to theinnate immune response. The formation is initiated via

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

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Fig. 1 NLRP3 inflammasome activation following TBI. (1) TBI causes neuronal damage resulting in DAMP generation. (2) DAMPs initiate TLR-mediated
NFκB activation and subsequent expression of the inflammasome gene. (3) Secondary activation signals from DAMPs such as extracellular ATP, and damaged mitochondrial components like ROS, DNA, and cardiolipin lead to inflammasome assembly, activation, and maturation of caspase-1. (4) Synthesis ofmature IL-1β and Gasdermin D by activated caspase-1. 6) Plasma membrane rupture causing pyroptotic cell death by Gasdermin D and release of IL-1β
in extracellular space resulting in persistent inflammatory responseJavalgekar et al. Journal of Neuroinflammation(2024) 21:172

the activation of pattern recognition receptors (PRRs) by
DAMPs such as ATP, mitochondrial DNA and histones
released from dead or damaged neurons. The PRRs of
the innate immune system are categorized into five categories: Absent in melanoma-2 (AIM2)-like receptors(ALRs), toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic
acid-inducible gene-I (RIG-I)-like receptors (RLRs), andC-type lectin receptors (CLRs) [27]. These receptors are
typically expressed on the surface of microglia, the resident brain immune cells, along with peripheral macrophages, monocytes, neutrophils, and other cells involvedin the primary immune defense [24]. A subset of these
PRRs is the intracellular NLR (Nod-like receptor) family consisting of a central nucleotide-binding and oligomerization (NACHT) domain surrounded by C-terminal
leucine-rich repeats (LRRs) and an N-terminal caspaserecruitment domain (CARD) or pyrin (PYD) domain.
The LRRs act as ligand detectors while CARD and PYD
domains interact with adaptor protein during the inflammasome assembly. Apoptosis-associated Speck-like protein containing a CARD (ASC) is the adaptor protein
containing the PYD and CARD domain [28]. To date,the NLR family of inflammasomes is the most extensively studied and members such as NLRP1 and NLRP3
complexes have been implicated in several conditions
associated with neuroinflammation, such as Alzheimer’s
disease, multiple sclerosis, and TBI [29]. The mechanismof inflammasome assembly, activation and downstream
signaling has been illustrated with NLRP3 activation following TBI as an example in Fig. 1.
Upon detecting the danger signals, there is activationof receptor proteins (NLRs) and the recruitment of theadaptor protein ASC. ASC bridges with the upstream
sensor molecule via a homotypic PYD-PYD or CARDCARD interaction to form a sensor-adaptor complex[30]. Following this initial step, the next stage comprisesof recruitment of pro-caspase-1 by the adaptor protein
ASC via CARD interaction completing the inflammasome complex formation [31]. Bioactive caspase-1 thenactivates inflammatory cytokines like Interleukin 1β (IL1β) and Interleukin 18 (IL-18) by cleavage of their inactive precursor forms pro-IL-1β and pro-IL-18. These
activated cytokines in turn can alter the cellular environment through various mechanisms ranging from disruption of intracellular ionic balance to altered blood-brain
barrier (BBB) permeability which may stimulate further
inflammatory cascade [32]. Unlike other inflammasome
complexes, the mechanism of NLRP3 activation is a twostep step process. A priming signal induced by the PRR
such as TLR induces NF-κB mediated transcriptional
upregulation of pro-IL-1β and NLRP3 proteins. A secondary signal such as P2 purinoreceptor 7 (P2 × 7) signaling by extracellular ATP or the damaged mitochondrial

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components such as ROS, DNA and cardiolipin causes
the assembly of individual inflammasome components
to form a mature NLRP3 complex [33]. Some inflammasomes like NLRP1 and NLRC4 can activate caspase-1 bydirectly interacting with the CARD domain of caspase-1
without engaging the adaptor protein ASC [34, 35].
Caspase-1 also induces a characteristic cell death calledpyroptosis by activating the pore-forming protein Gasdermin D [24, 36]. This causes leakage of cytosolic contents through pores formed on the plasma membrane,
further aggravating inflammation (described further
later). Following pyroptotic cell death, ASC oligomers
continue to process IL-1β extracellularly, as well as
stimulate macrophages for further IL-1β release [37]. In
addition, an alternate pathway of inflammasome activation, termed non-canonical activation, causes the activation and release of caspase-11 in murine or caspase-4/5
in human cells [38, 39]. As was previously indicated, theconnection between inflammasome activity and several
CNS disorders has piqued interest in how they may affectthe neuroinflammatory response after TBI and posttrauma sequelae like epilepsy and is discussed in detail in
the following sections.

Inflammasomes are activated after TBI
Inflammasomes have been heavily implicated in chronic
neuroinflammation associated with TBI [40]. For example, in the clinical setting, increased expression of inflammasome complex proteins NLRP1, NLRP3 and ASC, aswell as the matured end products active caspase-1, IL-1β
and IL-18 have been consistently reported in the CSF ofadult TBI patients [41–43]. In keeping with findings fromthe adult population, enhanced NLRP3 expression is also
observed in the CSF of children and infants with severe
TBI [44]. Recent clinical trials targeting inflammasomes
in systemic inflammatory conditions, such as COVID19, gout, heart failure and autoimmune diseases havereported improved outcomes and satisfactory safety andefficacy profiles [25]. Studies targeting inflammasomes in
CNS pathologies such as in TBI patients have not beenreported yet but given its potential could be a promisingtherapeutic option.
Consistent with findings from human patients, studies from rodent models of TBI also report elevated brain
expression of inflammasome component proteins [40].
Studies utilizing these animal models have predominantly assessed constitutive roles of inflammasome proteins by gene knockout methods, longitudinal expressionof inflammasome and associated proteins after TBI and
the effects of pharmacological intervention on disease
outcomes. Surprisingly, in a CCI-induced mouse TBI
model, genetic ablation of NLRP3 was shown to exaggerate astrocytic response and cytokine expression
revealing the dual nature of NLRP3 signaling in acuteJavalgekar et al. Journal of Neuroinflammation(2024) 21:172

neuroinflammation [45]. In contrast, NLRP1 inflammasome may not be relevant to outcomes in the mouse CCI
model because gene deletion of NLRP1 or ASC did not
influence functional recovery or contusion volume [27].
Therapeutic interventions to target the elevated inflammasome signaling are categorized as inflammasomeassociated molecule inhibitors, specific pharmacologicalinhibitors, natural compounds, repurposed drugs andbiologics (stem cell-derived vesicles/exosomes). The outcomes of these studies are summarized in Table 1. Unlike
specific inhibitors, the mechanism for indirect inhibitors via natural products and repurposed drugs is largely
unknown. These may be possibly related to the suppression of inflammasome activating signals [46] or the
induction of negative regulators [47]. A novel approach ofusing biologics such as extracellular vesicles derived fromstem cells has also been explored for targeting inflammasome activation after TBI. In a recent study, extracellular
vesicles were isolated from human mesenchymal stem
cell culture (hMSC-EVs) and validated for enrichmentwith microglia modulating miRNAs. Intranasal deliveryof these hMSC-EVs in the CCI mouse model resulted
in both acute and long-term suppression of the NLRP3
inflammasome, as well as improvements in long-termmood and cognitive deficits [48]. In a separate study,
intravenous (IV) administration of adipose-derived stem
cell exosomes (ADSCs-Exo) was found to inhibit NLRP3
inflammasome activity and improve sensorimotor function in a weight drop model of rat TBI [49]. These studies demonstrate the potential of such emerging biologic
therapies for future exploration, for example in PTE
research. However, a causal relationship is difficult toestablish as they may act through different direct mechanisms and alterations in the inflammasome pathway may
be a by-product of such outcomes, but they do provide
additional associative evidence.
Overall, the outcomes from these studies consistently
demonstrate that decreasing inflammasome and component protein expression in the brain after injury reduces
cortical lesion size, which is associated with decreased
inflammatory cytokine expression, and improvements
in neurobehavioral and motor outcomes. However, none
have explored post-traumatic epilepsy as an outcome
measure in these studies. A recent review discussed indetail the specific inhibition of NLRP3 inflammasome in
TBI and the compounds that are promising candidates
for therapeutic targeting of the NLRP3 inflammasome inthis context [40].

Inflammasome signaling in epilepsy: evidence andtherapeutic targeting
Chronic dysregulated inflammation has been heavily implicated in the pathogenesis of acquired focal epilepsy [61, 62]. More recently, specific investigations into

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inflammasome signaling have been conducted, and theirimpact on epileptogenesis assessed. Despite sufficient
literature evidence implicating inflammasome activation in TBI progression and neurobehavioral outcomes,
the role of inflammasome signalling in animal models of
PTE has not been investigated so far and the research todate is mainly focused on preclinical models of acquired
epilepsy. Therefore, we have discussed the pharmacological inhibition of inflammasomes in preclinical epilepsy
models other than PTE and it remains to be investigatedwhether the same results in terms of seizure burden areachieved in animal models of PTE. While most clinicaland preclinical studies of animal models report increased
inflammasome expression which correlates with disease
burden, animal studies have also revealed functional
improvement after pharmacological inhibition of inflammasomes. The clinical and preclinical evidence has been
described in detail as below (See Table 2).
Clinical evidence

Elevated protein levels of NLRP1, NLRP3 and active caspase-1 have been identified in sclerotic hippocampi of
patients with temporal lobe epilepsy when compared tothe healthy non-epileptic control tissues obtained frombiobanks or patients with other disorders [63, 64]. In
another study, NLRP3 inflammasome levels were upregulated in the temporal cortices of patients with temporal lobe epilepsy (TLE) and associated with endoplasmic
reticulum stress (ERS) [65]. This indicates possible crosstalk between inflammasome signaling and other neuroinflammatory mechanisms such as ERS in epilepsy.
Similar alterations in the inflammasome signaling havebeen reported at transcriptome levels, with increased
NLRP1 levels observed in the resected hippocampi of
TLE patients with hippocampal sclerosis highlighting
a possible role of NLRP1 in TLE pathogenesis [66]. In a
study investigating in Chinese patients, NLRP1 polymorphism was found to be associated with an increased riskof epilepsy development. In this study, it was shown thatthe seizure frequency in recruited patients correlatedwith the polymorphism in NLRP1 inflammasome genes[67].
Contrary to other reports of inflammasome signaling
in the brain, a recent study reported a suppressed inflammasome expression in CD3 + and CD14 + peripheral
blood mononuclear cells (PBMC) in patients with mesial
temporal lobe epilepsy and focal epilepsy of unknown
cause. This study evaluated the inflammasome signalingin peripheral immune cells as compared to the evaluation of brain levels and suggests that the brain levels of
inflammasome components may not display a surrogate
marker in the peripheral immune cells, at least in epilepsy patients [68].

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

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Table 1 Inflammasome expression/activity from clinical and preclinical TBI studies along with specific and non-specific NLRP3
inhibitors used in preclinical TBI studies
Clinical studies - TBI
Subjects
Adults with moderate and severe TBI

Tissue/Fluid
CSF

Adults with moderate and severe TBI

CSF and serum

Adults with severe TBI

CSF

Children with severe TBI

CSF

Adults with severe TBI

Resected cortex

Preclinical studies - TBI
Inhibitor
BAY 11-7082(20 mg/kg IP)
Once daily for 4 D.P.T
Anti ASC antibodies (20 µg/kg ICV)
immediately P.T.
MCC950(50 mg/kg IP)
1- and 3-hours P.T.

Observations
Upregulated NLRP1, ASC
and caspase-1 proteins.
Elevated caspase-1 levels inserum on day 2 and 3 post TBI
Upregulated NLRP1, ASC andcaspase-1 proteins.
Increased NLRP3 levels at 0–24, 25–48,
49–72, and > 72 h post-TBI
Upregulation of NLRP3, caspase-1,IL-1β, and IL-18 proteins

Model, species
CCI, rats

Effect on inflammasomes
Decreased protein levels of NLRP3
and caspase-1 in brain at 7 D.P.T.

FPI, rats

Decreased protein levels of caspase-1,IL-1β and NLRP1 at 24 H. P.T.
Decreased brain protein expression of NLRP3
ASC caspase-1and IL-1β at 24 H. P.T.

CCI, mice

JC124(100 mg/kg IP)
0.5, 6, 24 and 30 H.P.T.

CCI, rats

Decreased protein expression of NLRP3,
ASC and caspase-1 in injured brain at 2 D.P.T.

Mangiferin(100 mg/kg IP)
20 min P.T.
Omega-3 fatty acids (100 mg/kg oral
gavage)twice a week for 6 weeks before TBI

Blast-injury, rats

Decreased mRNA and protein levels of NLRP3
andcaspase-1 p20 in brain at 12 and 24 H P.T.
Decreased protein expression of NLRP3,
caspase-1 and IL-1β in the brain at
8 H. P.T.

Apocynin(5 mg/kg IP) Every 24 h for 4 D.P.T.

CCI, rats

Decreased protein expression of NLRP3, ASC,
caspase-1 and IL-1β in the brain at 4 D. P.T.

Oridonin(10 mg/kg IP)
30 min P.T.

Weight Drop,
mice

Decreased brain mRNA and protein levels of
NLRP3,ASC and caspase-1 at 24 H. P.T.

Dexmedetomidine(25 µg/kg IP for 3 D P.T)

CCI, mice

Artesunate(30 mg/kg IP)
1 H.P.T.

CCI, mice

Decreased protein expression of NLRP3
caspase-1
and IL-1β in brain at 3 D.P.T.
Decreased protein expression of NLRP3, ASC
and caspase-1 in brain at 24 H. P.T.

Propofol(50 mg/kg IP)
1 H.P.T.
Pioglitazone(20 mg/kg IP)
Daily till sacrifice (1,3,7,14 days)

Blast injury, rats

CCI, rats

Weight drop,
mice

Decreased brain mRNA and protein levels of
NLRP3
and caspase-1 p20 at 12 H and 24 H P.T.
Decreased brain protein expression of NLRP3
on(3,7 D) caspase-1(1,3,7,14 D) and IL-1β 14 D. P. T

Reference
[41]
[43]
[42]
[44]
[47]

Outcomes
Reference
Improved cognitive func[50]tion and neuron viability at
7 D.P.T.
Reduced contusion volume [51]at 3 D.P.T.
Decreased cerebral oedema [52]and improved
neurological function at 24
and 72 H P.T.
Prevented neurodegenera[53]tion anddecreased lesion volume at
2 D.P.T.
Ameliorated cerebral oe[46]dema and oxidative stress at
12 and 24 H.P.T.
Decreased oedema and cor- [47]tical lesion volume at 3 D
and improved motor andcognitive performance at
11–15-D. P.T.
Decreased lesion size and[54]
neuronal death in injured
cortex at 4 D. P.T.
Decreased oedema and[55]
cortical lesion volume at
24 H P.T,
improved sensory motor
function (2,4,7,14 D.P.T)
Attenuated BBB disruption[50, 56]
and neurological deficit at
3 D.P.T.
Decreased lesion volume,[57]
inhibited apoptosis,
and increased neurotrophic
factors at 24 H. P.T.
Attenuated cortical damage [58]and oxidative
stress at 12 H and 24 H P.T.
Reduced cerebral oedema[59]
and microglial activation at
3 D. P.T.

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

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Table 1 (continued)
Clinical studies - TBI
Subjects
Telmisartan(10 mg/kg PO) 1 h before TBI

Tissue/Fluid
Cryogenic injury,
mice

Observations
Decreased brain mRNA and protein levels of
NLRP3,ASC and caspase-1 at 24 H P.T.

hMSC-EVs
Intra nasal, 90 min P.T.

CCI, mice

Decreased protein expression of NLRP3, ASC,
caspase-1 and IL-1β in brain at 84 D.P.T.

ADSCs-Exo(IV, 24 h before TBI)

Weight drop, rats

Decreased protein expression of NLRP3
and caspase-1 at 24 H P.T.

Reference
Reduced BBB disruption,[60]
decreased lesion volume,and improved neurological
function at 24 H P.T.
Improved long term mood[48]
and cognitive impairment at
63–84 D.P.T.
Improved sensorimotor[49]
function at 7–35 D. P. T

CCI- Controlled Cortical Impact; FPI - Fluid Percussion Injury; hMSC-EVs- human mesenchymal stem cell culture derived extracellular vesicles; ADSCs-Exo- adiposederived stem cell exosomes, D.P.T- Days Post TBI, H.P.T- Hours Post TBI, IP- Intra Peritoneal, IV- Intra Venous, ICV- Intra cerebroventricular, PO- Oral gavage

Preclinical evidence with therapeutic targeting of
inflammasomes

Studies utilizing animal models of epilepsy have shown
beneficial outcomes following therapeutic inhibition
of NLRP3 inflammasomes. The first study to report the
involvement of inflammasomes in epilepsy was performed in a rat model of status epilepticus (SE). SE wasinduced by the electrical stimulation of the amygdala,which led to significant upregulation of NLRP3, caspase-1, and IL-1β in the hippocampus of stimulated
animals at 3 h and peaked at 12 h post-SE. Importantly,
siRNA-mediated knockdown of NLRP3 or caspase-1 wasable to decrease the levels of IL-1β and this was associated with a reduction in frequency and severity of epileptic seizures and hippocampal cell loss [69]. In anotherstudy by this group, siRNA-silencing of NLRP1 and caspase-1 in an amygdala kindling-induced rat TLE model
revealed a significant reduction in neuronal pyroptosis
along with a reduction in the frequency and severity of
epileptic seizures [63]. Activation of the NLRP3 inflammasome is also seen after SE caused by chemo-convulsant. Improved NLRP3 inflammasome activation has
been shown by Zhang et al. to hasten the course of SE
in a rat model of kainic acid-induced SE. In this study,
the direct inhibitor MCC950 substantially attenuated theincreased levels of inflammatory proteins and decreased
hippocampal neuron death by inhibiting NLRP3 [74].
MCC950 selectively inhibits NLRP3 by binding directly
to the NACHT domain of the NLRP3 protein [75]. Similarly, in the pentylenetetrazol (PTZ) kindling model,
seizure severity was decreased, and hippocampal neuronal apoptosis attenuated after treatment with a specific
NLRP3 inhibitor CY-09 [73].
In addition to specific inhibition of NLRP3 inflammasome proteins, some of the compounds with antioxidant
activity have also shown the potential to alter inflammasome signaling in epilepsy models. In two separate studies utilizing the PTZ-induced kindling mouse model,
treatment with amentoflavone, a natural bioflavonoid
compound, and Semaglutide, a type II antidiabetic drug,

was shown to delay PTZ kindling progression alongwith reduced hippocampal neuronal apoptosis andan improvement in spatial learning. The hippocampal
mRNA and protein levels of NLRP3, ASC and caspase-1
were significantly reduced in drug-treated mice as compared to control animals indicating that the neuronal andfunctional deficits post PTZ kindling could be mediatedvia NLRP3 inflammasome activation [70, 71]. In a similar study, administration of Agmatine, an endogenous
amine synthesized from the decarboxylation of L-arginine, was also reported to decrease seizure susceptibility
and delayed latency and duration of generalized seizuresin the PTZ kindling model [72]. In all the above-mentioned studies utilizing natural compounds, the authors
investigated the impact of drug treatment on lipopolysaccharide-induced BV2 microglial cells and showed thatit led to the suppression of inflammasome pathway proteins, which supports the in-vivo findings and the roleof NLRP3 inflammasome pathway in epileptogenesis[70–72].
Evidence for inhibition of caspase-1 has also beenreported to show beneficial outcomes in animal models
of epilepsy. In a mouse model of acute seizures induced
by unilateral intrahippocampal kainic acid injection, systemic administration of VX-765, a caspase-1 inhibitor,
delayed the onset of seizures and reduced the frequency
of convulsive episodes. The same study also reported
chronic outcomes following induction of SE using unilateral intrahippocampal kainic acid injection and observed
dose-dependent and reversible reduction in spontaneous
epileptic activity [76]. Taken together, all these findings
indicate that the inflammasome may represent a promising therapeutic target for the treatment of acquired
epilepsy. As discussed previously, the impact of some of
the antioxidant/natural compounds on inflammasome
signaling may be an associative finding or a consequenceof the suppression of epileptic seizures with unrelated
mechanisms. Therefore, a causal relationship between
these compounds and inflammasome signaling remains
evasive.

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

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Table 2 Inflammasome expression/activity from clinical and preclinical epilepsy studies. Autopsy brain tissues from non-diseased
individuals were used as controls in clinical studies while healthy animals were used as controls in preclinical studies respectively. PTZ- Pentylenetetrazol, SE - status epilepticus
Clinical studies - Epilepsy
Epilepsy typeTissueTemporal lobe epilepsy
Hippocampus
Temporal lobe epilepsy
Hippocampus
Temporal lobe epilepsy
Hippocampus
Temporal lobe epilepsy
Temporal cortexi) Focal epilepsy of unBlood
known causeii) Temporal lobe epilepsy
Epileptic patients withBlood
partial seizures
Preclinical studies - Epilepsy
ModelIntervention
Inflammasome gene knockdown
Amygdala-kindling
NLRP1 and caspase-1 knockinduced SE rats
down with siRNA
infusion by osmotic pump for
6 weeks
Amygdala-kindlinginduced SE rats

NLRP3 and caspase-1 knockdown with siRNA
infusion by osmotic pump for
6 weeks

Natural compounds
PTZ induced kindling mice Amentoflavone(25 mg/kg, PO) Alternate day for
29 days.

PTZ induced kindling mice Semaglutide(L.D- 10 nM/kg,
H.D- 25 nM/kg IP)
Alternate day for 37 days, last on
45th day.
PTZ induced kindling in
Agmatinemice(10 mg/kg, IP) Alternate day for
28 days.

NLRP3 specific inhibitors
PTZ induced kindling in
CY-09
mice
(2.5 mg/kg, IP) Alternate day for
22 daysKainic acid-induced SE inmice

MCC950(10 mg/kg, IP)
Daily for 7 days

Outcomes
Upregulated NLRP1 and caspase-1
Upregulated NLRP3 and NLRP1 inflammasomes
Upregulation of NLRP1 inflammasome
Upregulation of NLRP3 inflammasome
Suppressed or unchanged inflammasome activity

Reference
[63]
[64]
[66]
[65]
[68]

Correlation between NLRP1 polymorphism and partial seizures[67]

Effect on inflammasome

Reference

Outcomes

Decreased protein expression of NLRP1, Attenuated hippocampal
caspase-1
neuronal pyroptosis andand IL-1β in brain at 6 weeks after SE.
reduced seizure frequency andseverity in chronic period
at 6 weeks after SE.
Decreased protein expression of NLRP3, Reduced hippocampal neurocaspase-1
nal loss and decreased
and IL-1β in brain at 6 weeks after SE.
seizure severity and frequency
at 6 weeks after SE.

[63]

Decreased mRNA and protein levels of
NLRP3, ASC and caspase-1
in brain at 24 h after last amentoflavone injection.

Reduced seizure frequency andduration, minimized cognitive
dysfunction,and blocked neuronal apoptosis at 24 h after last amentoflavone injection.
Reduced seizure severity andameliorated cognitive
dysfunction at one week after
last Semaglutide injection[70]

Decreased brin mRNA and protein
levels of NLRP3,
ASC and caspase-1 after treatment end(28 days)

Reduced seizure incidence andduration (from day 14th ),alleviated hippocampal neuronal damage after treatment
end (28 days).

[72]

Decreased the levels of caspase-1 andIL-1β in brain
at 24 h after last CY-09 injection.

Suppressed seizure severity
during the treatment andattenuated hippocampal neuronal loss after treatment end.
Reduced hippocampal neuronal loss after treatment end.

[73]

Decreased mRNA and protein expression of NLRP3, ASC andcaspase-1 in brain at one week after
last Semaglutide injection.

Decreased the levels of caspase-1 andIL-1β in brain
after treatment end.

[69]

[71]

[74]

IP- Intra Peritoneal, IV- Intra Venous, ICV- Intra cerebroventricular, PO- Oral gavage

Downstream mediators of inflammasome signaling
in epileptogenesis
Having listed evidence for the involvement of inflammasome signaling in epilepsy, we next explored how
the downstream signaling partners which can be activated by inflammasome signaling may directly impact

epileptogenesis. In this regard, several potential mechanisms may link the effector molecules of inflammasome
activation, such as caspase-1, Gasdermin and cytokines
including IL-1β and IL-18, to cellular hyperexcitability
and, hence, epileptogenesis (summarized in Fig. 2).

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

Page 9 of 15

Fig. 2 Mechanisms by which NLRP3 inflammasome activation increases the susceptibility to post-traumatic epileptogenesis. (1) TBI causes neuronaldamage resulting in DAMP generation. (2) TBI also causes BBB breakdown resulting in infiltration of peripheral inflammatory cells causing cytokine releaseand further neuronal damage. (3) DAMPs initiate TLR-mediated NFκB activation and subsequent expression of the inflammasome genes within microglia. (4) Synthesis of mature IL-1β and Gasdermin D by activated caspase-1. (5) Plasma membrane rupture causing pyroptotic cell death by Gasdermin
D and release of IL-1β in extracellular space.6) Reduced synaptic density and abnormal synapse formation 7) Alteration of NMDA and GABA receptors
by extracellular IL-1β 8) Imbalance between excitation and inhibition ultimately contributing to epileptogenesis. BBB- blood-brain barrier, DAMP- Damage associated molecular patterns, NMDAR- N-methyl-D-aspartate receptor, AMPAR- α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor,
GABAR- Gamma-aminobutyric acid receptor, GSDMD- Gasdermin D, IL-1β - Interleukin-1βJavalgekar et al. Journal of Neuroinflammation(2024) 21:172

Caspase-1

Conventionally, caspase-1 and other cysteine proteases
have largely been studied in the context of apoptotic pathways [77]. After the discovery of inflammasomes as caspase-1 activating platforms, the focus shifted to exploring
the contribution of caspases in various CNS pathologies.
As a key component of inflammasome signaling, caspase-1 is well placed to influence post-traumatic epilepsy
through the activation of several downstream products,
including, for example, IL-1β, Gasdermin D, and IL-18
another pro-inflammatory cytokine released from a variety of cells such as monocytes, macrophages, and keratinocytes [78]. Some evidence also directly implicatesthis enzyme [79]. For example, initial preclinical studies
reported overexpression of caspase-1 in epileptic conditions and proposed the inhibition of caspase-1 as a novel
anticonvulsant strategy [80]. Subsequent studies reported
the ability of caspase-1 to confer pharmaco-resistance inanimal models of epilepsy, though the exact molecularmechanism remains unknown [81]. Furthermore, caspase-1 appears necessary for certain seizure types such as
febrile seizures, since mice lacking caspase-1 were foundto be resistant to febrile seizure induction [82]. Despite
exploring the therapeutic potential of targeting caspases
in neurodegenerative diseases including epilepsy, a lackof understanding of the basic functions of different caspases has hampered progress towards clinical trials [83,84].
IL-1β signaling

One of the best characterized and most studied of the
IL-1 family members, IL-1β, is produced and secreted
by innate immune cells like monocytes, macrophages in
the periphery and microglia in the brain. As mentioned
in the earlier section, caspase-1 mediates the cleavage ofprecursor pro-IL-1β downstream of inflammasome activation. Though caspase-1 mediated activation is almost
exclusive, IL-1β processing is also carried out by proteases derived from neutrophils or invading pathogens[85]. The matured IL-1β then binds with IL-1R and initiates the transcriptional activation of NF-κB and MAPK,
causing enhanced induction of cytokine and chemokine
synthesis. Additionally, alteration of BBB permeability,
recruitment of peripheral inflammatory cells and oedema
formation have also been reported as extracellularactions of IL-1β post-TBI [86]. One of the direct mechanisms of IL-1β-mediated alteration of BBB permeability
was shown to be the enzymatic degradation of endothelial tight junction proteins in a study conducted in amouse CCI model of TBI [87].
The expression pattern of IL-1β over time may suggest
differential roles in acute and chronic TBI pathophysiology. In a preclinical mild closed head injury model, transient upregulation of IL-1β was found to drive the acutePage 10 of 15

neuroinflammatory response in the early hours after
traumatic brain injury (TBI), while persistent IL-1β levels
were responsible for the behavioural impairment seen at
14 weeks post-injury [88].
As for epilepsy development, chronic upregulationof IL-1β can influence both excitatory and inhibitory
neurotransmission, resulting in hyperexcitability anddecreased seizure threshold [89]. This occurs primarily
due to post-translational modifications of receptor channels such as phosphorylation of the NR2A/B subunitsof the NMDA receptor, and subsequent increase in calcium influx which may lead to neuronal hyperexcitability and cell death [90]. In addition, increased glutamate
discharge from glial cells and decreased astrocytic glutamate uptake are also attributed to IL-1β activity [91,92], an effect mediated by the downregulation of extracellular amino acid transporters [93], which may resultin excessive excitatory neurotransmission. IL-1β has also
been shown to interfere with GABAergic neurotransmission. In a study conducted on hippocampal tissue of TLE
patients, and in rat models of acquired epilepsy, IL-1βtreatment decreased the amplitude of GABA-evokedcurrents [94]. This IL-1β-induced decrease in GABAergictransmission has also been linked with decreased neuronal Cl− influx, as observed in cultured hippocampal neurons [95].
Apart from the altered neurotransmission, IL-1β has
been directly linked with synaptic loss through mechanisms such as NMDA receptor-mediated ubiquitin-proteasome pathway and upregulated P-38/MAPK/COX
2 pathway in rat hippocampal neuronal culture [96].
Moreover, in cultured rat cortical neurons, IL-1β lowered
synaptophysin synthesis via the P-38/MAPK pathway,
indicating a potentially deleterious effect of IL-1β on synaptic proteins [97]. As previously mentioned in the article, activation of the NF-κB and/or P-38/MAPK pathway
can sustain the neuroinflammatory cascade by upregulation of cytokines, including IL-1β [98].
The aforementioned cellular alterations wrought by
IL-1β align with its effects on seizures. For example, preclinical studies have shown that intra-hippocampal injection of IL-1β increased acute seizure activity and lowered
seizure threshold in rodents treated with convulsive
drugs, which subsequently reduced after inhibition of the
IL-1R1 signaling or caspase-1 blockade [76, 80]. Also, in a
separate study, IL-1R1 antagonism was shown to reduce
seizure susceptibility after pro-convulsant treatment ina mouse model of pediatric brain injury [99]. IL-1β canfurther induce microglia and astrocytes creating a positive feedback loop and ultimately evolving into a chronic
unchecked neuroinflammatory response [93]. Overall,
inflammasome-mediated activation of IL-1β is a strong
candidate to influence epileptogenesis after TBI [100].

Javalgekar et al. Journal of Neuroinflammation(2024) 21:172

Gasdermin D-mediated pyroptosis

Pyroptosis is a characteristic inflammatory cell death
triggered by activated caspase-1 downstream of inflammasome activation. This pro-inflammatory nature ofpyroptosis has recently been promoted as an important
target in neurodegenerative disorders, including epilepsy[101]. It is mediated by a family of pore-forming proteins known as the Gasdermins, which are activated by
caspase-1 [102]. Among the Gasdermins, Gasdermin D(GSDMD) remains the most well-studied. Pore formation by GSDMD triggers pyroptotic cell death throughrupture of the plasma membrane and leakage of cytosolic
contents [36, 103], stimulating phagocytosis [104]. The
leakage of inflammatory cytokines, as well as the DAMPs,
from dying cells, attracts further inflammatory mediators, damaging the surrounding cells [105]. In a rat modelof TBI, GSDMD was significantly elevated in the injured
cortex along with microglial localization. The same study
showed that GSDMD knockout ameliorated neurological deficits and its cleavage was mainly driven by NLRP3
inflammasome [106]. Active pyroptosis has been demonstrated in the amygdala kindling-induced rat model, andcomponents of pyroptosis identified in excised temporal
lobe epilepsy specimens suggest this cell death pathway
may be relevant for disease pathogenesis [63]. To further
investigate the role of pyroptosis in epilepsy, a bioinformatics study was conducted to identify a gene set thatwas closely related to human epilepsy and pyroptosis
respectively using a weighted gene co-expression network analysis. The authors observed a close relationshipbetween the gene sets related to human epilepsy and thepyroptosis pathway. Furthermore, using a kainic acidinduced SE model in mice, they observed a significant
upregulation of mRNA and protein levels of GSDMD in
the hippocampus. Although these studies do not explain
the exact molecular mechanism, the engagement ofpyroptosis during epilepsy development was confirmed
and authors suggested that it could be an important target for intervention [107].
Interestingly, alternate inflammatory pathways, such as
cGAS-STING-mediated type-1 interferon (IFN) signaling have been shown to contribute towards the activation of the NLRP3 inflammasome and pyroptosis in a rat
TBI model [108]. Other preclinical TBI studies reporting increased STING-mediated type-1 IFN signaling,
reactive gliosis, and cytokine upregulation corroborate
this finding, with the deficiency of the IFN a/b receptor
effectively ameliorating microgliosis and neurobehavioral
dysfunction [109, 110]. Similarly, transcriptomic analysis of ipsilateral cortical astrocytes of PTE mice showed
the involvement of IFN signaling based on altered gene
expression [111]. Together, these are suggestive of cGASSTING and IFN-1 signaling as potential upstream regulators of NLRP3 and the crosstalk between different

Page 11 of 15

inflammatory pathways which may be relevant to PTE. In
the future, a combinatory approach of utilizing molecularbiology and bioinformatics tools can further our understanding of the contribution of these pathways in epilepsy and other neurodegenerative disorders [108].

Inflammasome proteins as biomarkers of PTE
The discovery of valid predictive and diagnostic biomarkers has emerged as one of the crucial requirements
in PTE research and is highlighted by the International
League against Epilepsy [109]. Considering the far-reaching scope of neuroinflammation in the pathogenesis of
TBI and PTE, proteins like inflammasomes which are an
integral part of this process could be potential biomarkers of not only TBI progression but also of epileptogenesis. Some evidence already supports this potential.
Firstly, multiple clinical studies have reported elevatedexpression of inflammasome components and cytokines
in serum and CSF of patients following TBI [41, 110,111]. One study exploring the potential of inflammasome
signaling as a predictive biomarker of TBI outcomes
showed a higher level of ASC, caspase-1, and NALP-1
in the CSF of TBI patients that was collected within 72 h
post-injury. The levels of these proteins correlated significantly to the worst outcomes based on the Glasgow
outcome scale evaluated at 5-months post-TBI. The levels
were also higher in patients with unfavorable outcomes,
such as severe disability and death, 5-months post-TBI[41]. Recently, brain-derived extracellular vesicles (EV)containing inflammasome proteins have been shown topropagate inflammation after CNS injury [42]. In a stroke
patient study, the expression of serum ASC following EV
isolation was found to be a valid biomarker of stroke asdetermined by ROC analysis (AUC 1), suggesting the significant biomarker potential of inflammasome proteins
and indicating their prospective application in other CNS
disorders such as PTE [112].
Secondly, several investigations have demonstrated
the involvement of inflammasome downstream signalling mediators, such as IL-1β, in post-traumatic consequences such as excitotoxicity and premature neuronal
death, underscoring the possible link between IL-1β andthe risk of PTE [113–115]. One study reported that individuals with a higher CSF/serum ratio of IL-1β one-weekpost-injury had an increased risk of developing PTE.
Moreover, the same study reported that genetic polymorphisms of the IL-1β gene increased the susceptibility ofPTE [113].
Also, apart from the conventional fluid biomarkers,
imaging of neuroinflammation with modalities like Positron Emission Tomography (PET) imaging of translocator protein (TSPO) holds promise as biomarkers forPTE. TSPO is a protein located on the outer mitochondrial membrane and thought to be representative ofJavalgekar et al. Journal of Neuroinflammation(2024) 21:172

inflammatory cell activation/density, has been used toassess neuroinflammation in several neurodegenerative
disorders [116]. An increase in TSPO binding, indicative of enhanced neuroinflammation, is observed in TLE
patients [117] and is predictive for seizure frequency
following an epileptogenic insult in a rodent model of
epilepsy (kainic acid-induced status epilepticus) [118].
Given the contribution of inflammasomes to neuroinflammation, there is understandable interest in developing radiotracers targeting inflammasome proteins such as
NLRP3. For example, a recent study reported the synthesis of a carbon 11 labelled NLRP3 inhibitor N-(5-Chloro2-methoxybenzyl)-N-(4-(N-(prop-2-yn-1-yl)-sulfamoyl)
phenethyl)-2-(thiophene-3-yl)acetamide, which exhibited
rapid BBB penetration and moderate and blockable brain
uptake PET imaging in mice [119].
Though the development of inflammasome-specifictracers seems to be focused on optimizing the leadinflammasome inhibitor compounds for therapeutic purposes, future tracers targeting the component proteinsof inflammasome assembly could provide some novel
insight for predicting the development and outcomeof PTE. The correlation of imaging data with fluid biomarker levels, behavioral comorbidities and seizure frequency and severity can further validate the biomarker
potential of inflammasomes.

Conclusions and future directions
PTE is a relatively common and disabling feature of TBI.
While managing TBI is challenging, understanding thedevelopment and progression of PTE is much more elusive. The lack of effective therapeutic interventions has
prompted the investigation of novel molecular pathways
that lead to the development of PTE. Literature evidence
has suggested that inflammasomes could be drivers ofchronic neuroinflammation and potentially responsible
for the worsening of TBI and initiating epileptogenesis.
Recent clinical and experimental findings have independently demonstrated the upregulation of inflammasome signaling in the pathogenesis following TBI, as
well as their involvement in the development of seizuresand epilepsy. Moreover, the downstream mediators ofinflammasome signaling are strongly implicated in disease development, and inhibition of inflammasomes canimprove outcomes of both conditions in experimental
models. This suggests that inflammasomes may represent
an important therapeutic target for managing neuroinflammation and improving patient outcomes, including
the PTE following TBI. In addition, emerging reportssuggest that inflammasome proteins and downstream
signaling molecules may be useful as potential biomarkers of neuroinflammatory conditions following TBI andearly prediction of post-traumatic complications. Given
that inflammatory processes could also predict the risk

Page 12 of 15

or severity of epilepsy, it is hypothesized that inflammasome components upregulated after TBI could represent
a potential biomarker of PTE. In the future, studies evaluating the therapeutic efficacy of manipulating inflammasome pathways for the development of post-traumatic
after TBI need to be conducted. Furthermore, fluid andneuroimaging markers of inflammasome may have thepotential to predict the risk of PTE and select patientsmost likely to benefit from anti-epileptogenic interventions. Their nature would also better understand direct
molecular mechanisms linking inflammasome activation and epilepsy development. Through a combinationof these strategies, the development of novel pharmacological therapies to modulate the inflammatory response
post-TBI could be applied to the clinical subjects following TBI who are at high risk of developing PTE.
Acknowledgements
Not applicable.
Author contributions
MJ, IA, NJ conceptualization and idea development; MJ writing the first draft,
IA, NJ supervised MJ in generating the draft; IA, NJ, TOB, LV, BJ, DW contributedin editing and development of subsequent drafts.
Funding
IA is funded by US Department of Defence W81XWH-21-1-092.
Data availability
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 5 March 2024 / Accepted: 5 July 2024

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