Inflammatory proteins, including receptor-interacting kinases (e.g., RIP1/RIP3) and cytokines (e.g., interleukin-1 [IL-1], caspases), modulate inflammatory function and regulate forms of cell death such as necroptosis and apoptosis (10–12). Effects of inflammatory mediators are complex, in that they differ based on injury type, location, and chronicity. Even a single, acute TBI can cause sustained inflammatory signaling, measured by interleukin (IL) protein levels (13). A continued inflammatory response may lead to secondary neuronal injury and a decreased likelihood of spontaneous recovery over time, with persistent neuropsychological deficits. Additional injuries may contribute to chronic functional deficits, due to shortened recovery time between injuries and long-term neurodegeneration.

Neurotransmitters can modulate inflammatory responses in brain injury by disrupting pro-inflammatory cytokines, microglial production, and calcium signaling (14). Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively. Glutamate release into the synaptic cleft occurs via calcium influx and intracellular calcium-dependent signaling (15). Once glutamate acts upon post-synaptic neurons, astrocytes collect and convert it to glutamine which is transported back to pre-synaptic neurons (16). Neuronal excitotoxicity due to altered glutamate and GABA receptor expression and function is evident in models of TBI (17, 18).

N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) are glutamate receptors responsible for neuronal influx of calcium in post-synaptic neurons. Table 1 summarizes NMDA and AMPA functions during typical neuronal depolarization and action potential propagation. The net effect of selectively activating these receptors and regulating their post-synaptic densities is to potentiate a non-toxic glutamate response, which promotes synaptic plasticity, long-term potentiation, and learning and memory (17, 19, 20). However, if these receptors are unselectively trafficked to/from key synaptic regions in brain injury, the result is an acute disruption of these signaling processes. In mechanical models of injury, down-regulation of the AMPA GluR2 and NMDA N2A receptors, along with up-regulation of the NMDA N2B receptor, lead to atypical calcium influx resulting in acute excitotoxic cell death (21–23).

Although TBI primarily leads to neocortical cell death, hippocampal vulnerability is also apparent. In a controlled cortical impact (CCI) mouse model of moderate TBI, apoptosis of immature hippocampal neurons was observed 24–72 h after injury (24). Limited inflammatory markers may be observed up to 7 days post-CCI, and necrosis of immature hippocampal neurons was evident for at least 14 days post-injury (25, 26). These results demonstrate hippocampal vulnerability in response to TBI that may clinically present as memory complaints.

Both altered excitatory glutamate signaling and reduced GABA-mediated inhibition contribute to excitotoxicity in brain injury (27). In a mouse CCI model, glutamate expression correlated with epileptiform activity within injured and adjacent cortex in the setting of decreased GABAergic interneurons. Further, there was significant reduction of the GABA_A γ2-subunit in CCI-injured rats with post-traumatic epilepsy (18). In a mouse CCI model of severe TBI, GABA_A δ and GABA_B B2 receptor subunit expression in dentate gyrus granule cells was reduced by 40–43% (24). In contrast, human studies of chronic, repetitive injuries in athletes (closed head injury [CHI] model) found a compensatory increase in GABA_B receptor expression (28). Decreased GABA_A receptor expression disrupts the inhibitory response (29), while increased GABA_B receptor expression, responsible for membrane hyperpolarization, may serve to avoid further depolarization and excitotoxic effects.

AD pathology includes Aβ plaque accumulation and NFT formation, with tau aggregation and hyper-phosphorylation contributing to dysregulated microtubule dynamics and neuronal functioning (30). Necroptosis activation by RIP1/RIP3 kinases was found in postmortem AD brains (31). Elevated levels of inflammatory markers IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were found in postmortem AD and transgenic animal brains, and microglial and astrocytic activation was observed in response to neurotoxic cytokine expression (32–36).

Excitotoxicity due to dysregulated Ca²⁺-mediated NMDA receptor functioning decreases cell survival (37, 38). Aβ regulates synaptic vesicle release and affects NMDA receptor structure, density, and electrophysiology – ultimately affecting glutamate transmission and resulting in cognitive changes (39–43). In AD patients with severe cognitive deterioration, decreased glutamate and GABA levels were noted in temporal cortex and CSF compared to AD patients with mild cognitive deterioration and age-matched controls (44, 45), and decreased concentrations of GABAergic terminals in cortical neurons adjacent to Aβ plaques were found in AD patients and transgenic AD mouse models (46, 47). These findings suggest impaired receptor function and neurotransmission and an imbalance between excitatory and inhibitory activity in AD.

Inflammatory responses in epilepsy can contribute to recurrent seizures, secondary neuronal injury, and chronic neurodegeneration (2). During focal to bilateral tonic–clonic seizures, cytokines exert effects through increased AMPA receptor density, NMDA-dependent calcium influx, and reduction of GABA_A receptor density, resulting in greater synaptic glutamate and decreased synaptic GABA concentrations (48–51). Excess glutamate increases the likelihood of neuronal depolarization, excitotoxicity, and eventual cell death (52–54), particularly in models of temporal lobe epilepsy (55). Glia rapidly produce interleukins, particularly interleukin-1 beta (IL-1β), postictally. IL-1β enhances neuronal excitability and sustains inflammatory responses (56, 57). Increased IL-1β activity leads to neuronal degeneration in epileptogenic regions, while astrocytes that express its receptor have neuroprotective functions (1, 58). Astrocytes can mediate the effect of IL-1β on hippocampal neurons, contributing to their likelihood of survival. The presence of astrocytes in epileptogenic regions is a compensatory response to excess synaptic glutamate (59, 60). Increased astrocytes in regions of post-ictal neuronal injury suggest IL-1β involvement in the initiation and continuation of local seizure activity (59).

We propose that during a single seizure and mild TBI (Figure 1), excitotoxic depolarization enhances IL-1β signaling and increases NMDA receptor activity, leading to local propagation of excitotoxic depolarization and extracellular glutamate accumulation. This process, along with increased Aβ and cytokine secretion, recruits astrocytes into the synapse (61) to collect glutamate post-seizure. Excess glutamate also recruits microglia to clear cellular debris, remove excess Aβ, and return to neuronal homeostasis (60, 62, 63). If neuronal homeostasis is not achieved, further excitotoxic injury and cell death signaling can occur.

Neuronal damage in TBI, AD, and epilepsy can result from secondary inflammatory responses and neuronal excitotoxicity. Interleukins, particularly IL-1β, are key modulators of pro-inflammatory responses and apoptosis. Additionally, dysregulation of the glutamate-GABA/excitation-inhibition balance leads to excitotoxic injury and neuronal death.

ER stress occurs when there is an imbalance between the ability of the ER to fold proteins and the cellular demand for protein folding (64). In response to ER stress, the UPR signals to either (1) protect the cell by correcting the imbalance between folding ability and demand (65) via the protein kinase R-like ER kinase (PERK) pathway or (2) promote programmed cell death. Cell death occurs via C/EBP homologous protein (CHOP) and Apaf-1-dependent apoptosis or via necroptosis involving RIP1/RIP3-activation and rapid ATP depletion (66–68). Acute UPRs are protective to the cell. Sustained UPRs, however, induce caspase-dependent apoptosis (69), deplete intracellular ATP (70), and induce necrosis (70).

ER stress contributes to neuronal loss in TBI (26, 71, 72), AD (73), and epilepsy (74) and correlates with tau phosphorylation in TBI and AD (75, 76). In a CCI rat model, markers of reactive ER stress were associated with increased tau oligomers and tau kinase (GSK-3β) activation (77). To study the relationship between tau phosphorylation and ER-stress in promoting AD-like pathogenesis, tau phosphorylation was induced in rat cortical neurons, resulting in a UPR response with elevation of p-PERK and other modulator proteins. In the same study, an ER stress inducer enhanced tau phosphorylation at specific sites (75).

In human AD autopsy material, PERK correlated with atypical tau phosphorylation (78), and tau interacted with ER proteins leading to neuronal dysfunction and neurotoxicity (79). In epilepsy, the relationship between ER stress and tau phosphorylation is unknown, although relationships between epilepsy and unfolded proteins have been established. A mouse model of epilepsy suggested that acute, reactive ER stress responses may reduce seizure recurrence or severity (80). In resected tissue from patients with epilepsy due to focal cortical dysplasia, however, there were greater accumulations of unfolded proteins and increased levels of CHOP in patients who were not rendered seizure-free (81). Hence, acute, reactive stress responses may be protective, while chronically increased ER stress may contribute to seizure recurrence.

Aβ can trigger ER stress, just as ER stress can promote Aβ formation, leading to excitotoxicity and apoptosis (82–84). While amyloid precursor protein (APP) increases resistance to ER stress-induced apoptosis in specific cell cultures (85), intracellular Aβ counteracts APP by activating ER stress and pre-disposing cells to other pathways of programmed cell death (86). In brain endothelial cells, Aβ increased concentrations of UPR signaling mediators, increased intracellular Ca²⁺, and upregulated pro-apoptotic transcription factors (87). The relationship between Aβ and excitotoxicity is complex, however, in that Aβ also acts directly on the ER stress response protein XBP1 to reduce intracellular Ca²⁺ concentrations and limit excitotoxic injury (88).

Data suggest initial neuroprotective effects of reactive ER stress, activation of the PERK pathway, and APP (89). However, we postulate that sustained, repeated, or anticipatory (i.e., in the face of chronic injury) induction of the ER stress response may increase atypical tau phosphorylation and Aβ concentrations, with deleterious effects. Aβ has both pro-apoptotic and excitotoxic effects, but to limit neural injury, it acts feeds back on the ER stress response to interrupt it. If Aβ fails to halt its excitotoxic effects, and microglia and reactive astrocytes cannot successfully clear toxic tau and Aβ aggregates, neurodegeneration follows.

The AIR pathway is a pro-inflammatory mechanism that minimizes the likelihood of acute excitotoxic effects and cell death. In the AIR pathway, an acute TBI or brief seizure leads to IL-1β formation (108–110, 122), which has multiple effects on NMDA and AMPA receptors (Figure 2), including downregulation of NMDA receptors NR1 and NR2B. Unselective CAMK-II activation, coupled with the IL-1β signaling, promotes atypical calcium influx and excitotoxic glutamate release. As a result, there is an increased probability of cell death unless excess glutamate can be cleared from the synapse. CAMK, however, also recruits astrocytes into the affected region, evidenced by reactive astrocytes and phosphorylated CAMK-II in the hippocampal CA3 region of a kainic acid mouse model (106). The inflow of reactive astrocytes, coupled with increased IL-1 receptor density, clears excess synaptic glutamate (59, 60, 107).

The RIR pathway results in excitotoxity and apoptosis (Figure 3). Recurrent TBI activates -IL-1 precursors, which are cleaved into IL-1β by proteases such as caspase-1 (108–110). Similarly, recurrent seizures, through excitotoxic neuronal depolarization, activate caspase-1 and lead to IL-1β signaling (108–111). IL-1β, however, does not down-regulate NMDA receptors as in AIR. Instead, IL-1β hyper-activates NMDA receptors via GluNR2B subunit phosphorylation in response to chronic injury (112). The resultant increase in NMDA receptor density contributes to atypical calcium influx, prolongs excitatory synaptic enhancement, and propagates pathologic signaling from excess glutamate.

Further, there is decreased GABA_A receptor density (50) and downregulation of the GABA_A receptor δ-subunit (18, 113), contributing to extracellular glutamate accumulation and excitotoxicity (18, 113). AMPA-GluR1 and GluR2 receptors are also down-regulated in response to injury (21–23, 49, 114–116). As a result of AMPA dysregulation, CAMK-II autophosphorylation is impaired and recruitment of proteasomes – highly active enzyme complexes that play a role in cell-cycle progression – into dendritic spines is blocked, resulting in apoptosis (117). Additionally, subsequent phosphorylation at AMPA receptors also indirectly decreases astrocytic recruitment and clearance of excess glutamate (118).

If the AIR pathway (Figure 2) is unsuccessful in mediating excitotoxicity or if the RIR pathway is activated in chronic injury/seizures (Figure 3), apoptosis (acute programmed cell death) and necrosis (passive cellular degradation and death) result (142). Oxygen free radical production, caspase activation (e.g., caspase-3 and caspase-6), mitochondrial membrane depolarization, and further neurotoxicity occur (143–145). To minimize the possibility of cell death and preserve structural and functional integrity of surrounding neurons, an additional neuro-protective response is needed. We posit that tau signaling pathways first respond to recurrent seizures/injury in attempt to preserve cellular integrity; however, there is a “tipping point” that transitions the mechanism from neuroprotective to injurious – the repeated or sustained induction of an imbalanced ER stress response (specifically, the unfolded protein response [UPR]) and resultant aberrant tau phosphorylation. The ER stress response stimulates tau phosphorylation and continued tau cleavage; further phosphorylation/hyper-phosphorylation of tau promotes a continued UPR response and promotes neurodegeneration. This chronic dysregulation results in a shift from a tau-induced signaling pathway as a compensatory, neuroprotective response – which once reduced cellular dysfunction and restored apoptotic-necrotic dynamics and cellular homeostasis – to an injurious mechanism that is unable to maintain intracellular homeostasis, nor revert to mechanisms of programmed cell death.

In apoptosis, caspase-3 is activated by multiple mechanisms, including inflammatory responses, mitochondrial-based pathways, and an imbalanced ER stress response (119–123) (Figure 4). To divert the cell away from this apoptotic pathway and attempt to restore cellular homeostasis while maintaining structural integrity, caspases and ATP processes that induce apoptosis must be downregulated, TNF-α expression must be promoted, and tau phosphorylation must be induced, in conjunction with ER stress-induced PERK-pathway activation. Decreasing available caspases and apoptotic signaling reduces the likelihood of further neurotoxic depolarization and cell death, while increasing the likelihood that cellular homeostasis is restored (146). Induction of tau phosphorylation via caspase-6 cleavage indirectly reduces apoptotic signaling while preserving cellular integrity; tau also indirectly activates microglia, which are responsible for tau degradation to its non-toxic components.

Both caspase-3 and caspase-6 cleave tau (124–126) at multiple sites, which increases the susceptibility of tau to phosphorylation (9, 126–128). However, increased tau phosphorylation will also decrease caspase-3 activation in a negative feedback loop (122, 129, 130, 147). We posit that although the imbalanced ER stress response induces atypical tau phosphorylation (75), its acute effect is minimal due to this reduction in caspase-3 activation. As caspase-3 activation is required by apoptosis (119–121, 148), we posit that there is a transition from apoptosis to cellular preservation. However, with a halt of apoptotic signaling in the setting of increased tau concentrations, microglial and reactive astrocyte activation via upregulation of TNF-α, pro-inflammatory cytokines (IL-1β, IL-6, IL-12) and enzymes, and co-stimulatory molecules (131, 132) is required to break down tau. Additionally, tau oligomers (o-tau) and aggregates activate microglia to phagocytize tau and process its isoforms into non-toxic components (133–136). The ER stress response also upregulates Ca²⁺-ATPases in microglia, enhancing their capacity for phagocytosis and tau breakdown (149). Tau clearance is crucial to reestablishing cellular homeostasis and re-balancing the ER stress response post-seizure/injury.

We posit that in an acute, mild TBI or brief seizure, tau will assist the cell in reverting to balanced ER stress response signaling and intracellular homeostasis. However, chronic or sustained activation of tau signaling cascades due to severe and/or recurrent injury will eventually transition this mechanism from neuroprotective to injurious (Figure 5). While tau expression benefits microtubule dynamics, overexpression of phosphorylated, cleaved isoforms disrupts microtubule transport and increases the risk of toxic tau aggregates (150). The overexpression of tau, atypical accumulation of p-tau and hp-tau from caspase-3 cleavage and apoptosis inhibition, and tau deposition due to the inability of microglia to successfully break down toxic tau aggregates, could be a result of the cell’s failed attempt to maintain homeostatic microtubule dynamics.

The NPT process depends upon the ability of the cell to revert to balanced ER stress responses, balanced apoptotic-necrotic dynamics, and intracellular homeostasis. Successful reactive astrocytic phagocytosis of tau and microglial clearance of tau play key roles in restoring intracellular dynamics. We posit that in the setting of sustained or recurrent injury, however, the ability of reactive astrocytes and microglia to break down tau becomes dysregulated. A resultant buildup of intra-microglial toxic tau occurs (99), which inhibits microglial and reactive astrocytic phagocytosis, threatens neuronal integrity, and drives expulsion of toxic tau aggregates from the cell via exosomal packaging and secretion. However, these secreted toxic tau aggregates are misfolded (151) and therefore more resistant to microglial break down. These exosomal tau aggregates have injurious effects (99) due to increased likelihood of exosomal leakage and surrounding neuronal uptake (152, 153). Further, the recurrent or sustained activation of the ER stress response reinforces microglial migration and dysregulation and limits the ability of microglia to actively break down tau. The inter-neuronal spread of toxic tau may mark the initial transition from a neuroprotective to a more widespread injurious process.

The NPT response may be an attempt to preserve cellular integrity, by avoiding further injury from apoptosis through tau phosphorylation and limiting effects of necrosis through astrocytic and microglial involvement. Over time, however, the NPT mechanism will still result in cell death if the underlying chronic pathology remains untreated. Further, with recurrent injury (e.g., repetitive seizures, repeated head trauma), the NPT response will become overwhelmed, and an aberrant, injurious process will ensue. Over time, repeated activation of injurious pathways will require a “last ditch effort” to revert the cell to pro-apoptotic signaling cascades and avoid further transition to a widespread neurodegenerative process, which leaves the question – what is the role of Aβ?

Tau phosphorylation antagonizes apoptotic processes in response to increased ER stress and imbalanced homeostatic dynamics (147). Tau hyperphosphorylation is a reactive response activated when faced with apoptotic cell death (120, 129). The build-up of hp-tau, therefore, could represent a failed neuroprotective mechanism. NFTs, a hallmark of tauopathies, form as a downstream result of the RIR and NPT pathways. In addition to containing hp-tau, NFTs contain active caspase-6, caspase-6-cleaved tau, and Aβ, further supporting that NFTs are the end result of a neuronal degradation pathway – one that initially includes a neuroprotective pathway preferred by the cell over acute apoptotic death (9), but over time, becomes overwhelmed by the accumulation of repeated injuries.

The NPT response suggests that excess tau is phosphorylated in attempts to preserve cellular integrity in the short-term. In response, microglia and reactive astrocytes are triggered to reinstate homeostasis and break down intracellular tau into non-toxic isoforms. However, in the setting of repeated injury, when excess tau phosphorylation exceeds microglial and astrocytic capacity for tau degradation, toxic tau accumulates. This, along with aberrant tau cleavage, aggregation, and hyper-phosphorylation, propagates a dysregulated microglial response. To combat this, the toxic tau must be expelled from the cell and is done so through exosomal packaging and secretion.

We posit that the response mechanism is neuroprotective to the point of halting apoptosis, phosphorylating tau, and clearing tau via microglia and reactive astrocytes, and that it would continue to be neuroprotective if repetitive seizures or head injuries did not (1) lead to Aβ accumulation and its production of toxic tau and (2) outpace the ability to clear tau. Because epilepsy and repeated TBIs are plagued with recurrent cellular injury and ER response activation, however, a buildup of cleaved, phosphorylated, and hyperphosphorylated tau results in toxic tau aggregates. These toxic aggregates are then propagated to surrounding neurons, adversely affecting these neighboring neurons and increasing the likelihood for localized neuronal degeneration. The extracellular leakage of toxic tau also contributes to NFT formation and induces tauopathy-related necrosis, transitioning the mechanism over time from neuroprotective to neurodegenerative.

The role of Aβ is pivotal in the development of neurodegeneration. Aβ induces tau phosphorylation, contributing to toxic tau aggregates that cannot be cleared by microglia and reactive astrocytes. Additionally, microglia cannot clear the excess Aβ, leading to inflammatory signaling, excitotoxicity, and Aβ plaque accumulation. Microglial and reactive astrocytic dysregulation results in further tau and Aβ leakage that contributes to injury. We posit that, although increased Aβ concentration has a deleterious effect on cellular integrity and microglial functioning, increased Aβ also reactivates preferential apoptotic signaling by targeting NMDA/AMPA receptor functioning, CaMK-II phosphorylation, astrocytic recruitment, and mitochondrial membrane permeability (Figure 6). Because glutamate transmission, apoptosis, and necrotic signaling share related pathways, this Aβ compensatory mechanism cannot differentiate between typical and atypical activation, such that excitotoxicity continues. Recurrent or sustained activation of these mechanisms results in the necrotic cell death seen in tauopathies.

A better understanding of tau deposition lends insight into AD, TBI, and epilepsy pathophysiology and presents possible targets for intervention. Potential approaches include neuroprotection, inhibition of inflammatory processes, and disruption of excitotoxic mechanisms. Trials focused on various portions of these pathways. In animal models of TBI, minocycline and statins demonstrate beneficial anti-inflammatory and neuroprotective properties, limit the expression of pro-inflammatory cytokines, and render cell death-associated astrocytes and microglia inactive (232–234). In vitro and in vivo rat brain TBI and immune system studies identified human-cultured mesenchymal stem cells coupled with purified immune cells as a promising treatment that increases production of anti-inflammatory ILs, while decreasing TNF-α (235–237). IL-34 selectively enhances microglial neuroprotective effects, homeostasis, and neuronal survival by promoting Aβ oligomeric clearance and inducing microglial enzymatic activity. These effects reduce oxidative stress without promoting neurotoxicity (61). Promotion of IL-34 receptor binding or activity may benefit those with recurrent seizures/TBI by enhancing microglial function.

Data regarding NMDA antagonists are mixed. Drugs like amantadine, a weak NMDA antagonist, are commonly used in acute brain injury rehabilitation, although supporting data are limited (238). In some TBI studies, NMDA receptor antagonists lacked efficacy and raised safety concerns (239). A trial of the competitive NMDA antagonist D-CCP-ene for the treatment of intractable focal-onset seizures led to severe adverse events in all eight subjects, including sedation, ataxia, depression, amnesia, and poor concentration (240). Seizure frequency worsened in three subjects and remained unchanged in four subjects; one participant demonstrated improved seizure frequency, yet experienced status epilepticus upon D-CCP-ene withdrawal (240). All subjects withdrew from participation, leading to premature termination of the study. However, in a large, randomized, double-blind, placebo-controlled trial of traxoprodil, an NMDA NR2B subunit antagonist, was found to be well-tolerated in adults with severe TBI; they demonstrated improved Glasgow Coma Scale outcomes 6-months post-injury compared to placebo (241).

In an animal model of hippocampal seizures, MK-801 decreased seizure severity at low doses (242). In 68 patients with super-refractory status epilepticus, ketamine infusions administered for a length of one to four days reduced seizure burden by 50% (243). Upregulated NMDA receptor trafficking in the post-synaptic membrane contributes to super-refractory status epilepticus; NMDA receptor antagonists like MK-801 and ketamine may be effective due to improved penetration of the blood brain barrier and maintain their function even in the presence of increased concentrations of intra-and extra-cellular glutamate (244–246).

Memantine, a low-affinity voltage-dependent uncompetitive NMDA antagonist, approved for use in AD, reduced tau phosphorylation and improved functional outcomes after repetitive mild TBI in adult mice (247). In patients with TLE, memantine improved cognition compared to donepezil (248). In a double-blinded, placebo-controlled trial, once-daily memantine significantly improved episodic memory and quality of life in patients with epilepsy, although confounded by reduced seizure frequency (248, 249). In contrast, in subjects with focal-onset seizures of unchanged frequency, memantine yielded no significant improvement in cognition compared to placebo (250). However, in an open-label extension phase, there were improvements in verbal memory, memory-related quality of life, and executive functioning (250). Overall, NMDA antagonists deserve further study in TBI, AD, and epilepsy (238, 241).

Alternatively, perampanel is highly selective for AMPA receptors and inhibits AMPA-induced calcium influx in rat cortical neurons (251). Pharmacological dampening of AMPA receptor function eliminated interictal-like activity in human lateral amygdala in vivo, without reducing AMPA receptor densities observed in vitro (252). It is efficacious for treatment of focal-onset seizures with a neutral cognitive profile in adult, geriatric, and pediatric patients (253–255). In a rat CCI model, perampanel preserved neurological function, inhibited apoptosis and microglial activation, reduced brain edema, and preserved blood–brain-barrier functioning post-injury, thereby protecting neuro-vasculature (256). It also reduced brain contusion volume and decreased expression of pro-inflammatory TNF-α and IL-1β (257).

The effects of perampanel on neurological functioning, inflammatory markers, and cognition in patients with AD has yet to be comprehensively studied, outside of isolated case reports. In a case study of an 89 year old woman with severe AD, intractable myoclonic epilepsy, and psychiatric symptoms of circadian rhythm disorder and irritability, perampanel improved both myoclonus and psychiatric symptoms (258). An additional case report demonstrated improved cognitive functioning in a patient with non-convulsive seizures and AD, supporting the case for early administration (259). In transgenic AD mice, inhibition of AMPA receptors by perampanel reduced hippocampal Aβ₄₀ and Aβ₄₂ levels and decreased levels of the soluble peptide APPβ by suppressing β-cleavage of APP (260). Further research is needed into the potential effect of perampanel in targeting Aβ pathology by reducing Aβ production in AD.

Metabotropic glutamate receptors (mGluR) may also be a target of interest in generalized and focal seizures, as the group II and III mGluR agonists may decrease NMDA receptor function and the risk of excitotoxicity. Animal studies showed anticonvulsant effects of the group II mGluR agonist, DCG-IV, in models of limbic and generalized motor seizures (261–263). Anticonvulsant effects were also noted in DBA/2 rodent models using agonists that target group III mGluR₈ and mGluR₄, 4A (L-AP4, RS-4-PPG, and ACPT-1) and the antagonist, MPPG. These agents were not found to affect group I, which contribute to epileptogenesis (264, 265). However, mixed responses to mGluR-based treatments have been noted, with proconvulsant effects of group III agonists (L-AP4 and L-SOP) and the MGluR antagonist, MAP4 (266, 267). Further research is needed into safe and effective therapeutic concentrations of mGluR-targeting agents, as well as their role in seizure activity (266–270).

In our proposed RIR model, upregulation of selected NMDA receptors and downregulation of selected AMPA receptors occurs as a result of neuroinflammation in response to sustained or recurrent injury. As a result, there is an increased likelihood of seizure occurrence and atypically high concentrations of intra-and extra-cellular glutamate. At low doses, NMDA receptor antagonists can reduce seizure severity and frequency, but with mixed results. Higher doses, however, risk significant adverse effects. AMPA receptor antagonists, such as perampanel, may show greater promise due to their potential effects on hyperexcitability, underlying pathophysiology of neurodegenerative disorders, and tolerability. MGluR agonists and antagonists showed varied pro-vs. anti-convulsant effects with limited research into safe and effective therapeutic concentrations. Caution in targeting glutamate receptors is warranted.

Anti-amyloid monoclonal antibodies, such as lecanemab and aducanumab, represent another treatment approach, possibly as maintenance drugs to slow the progression of cognitive decline over the course of the disease. Lecanemab demonstrated high affinity binding to soluble Aβ, and particularly to Aβ soluble protofibrils, which are seen in early AD (271–273). Approved for use in Alzheimer’s disease (274), lecanemab reduced Aβ markers and moderately slowed cognitive decline over 18 months compared to placebo (271, 272), although its effectiveness has been questioned. In a transgenic mouse model, aducanumab decreased both soluble and insoluble Aβ in a dose-dependent manner (275). To evaluate the safety and efficacy of aducanumab in reducing cognitive decline in patients with MCI and mild AD, two large, double-blind, placebo-controlled studies were conducted. Results indicated that aducanumab was associated with dose-dependent amyloid related imaging abnormalities (ARIA), with cerebral edema and increased risk of intracerebral hemorrhage, particularly in ApoE-ɛ4 carriers (276). Infusion-related reactions and other adverse events (including ARIA) make anti-amyloid antibodies a controversial approach in the setting of uncertain benefits. Lecanemab and aducanumab have not yet been tested in patients with TBI or epilepsy, and safety and efficacy clinical trials for both drugs are on-going.

Reduction of tau levels showed promise in tau-expressing transgenic mice with repetitive mild CHI. Mice were treated with kinase-targeting lithium chloride and R-roscovitine, leading to p-tau reduction that correlated with improved cognition (200, 277). Alternatively, phosphatases dephosphorylate toxic tau into non-toxic isoforms. Phosphatase 2A (PP2A) dephosphorylates hp-tau, but PP2A activity is decreased in AD brain (278, 279). In AD, GSK-3 activation inhibits PP2A (280), and PP2A inhibitory proteins (inhibitor-1 and -2) are upregulated (281). Pharmacological interventions that inhibit GSK-3, such as SAR502250 (282), or support mRNA-based downregulation of PP2A inhibitors-1/2, are promising approaches (281). Drugs for approved for other indications may also be “repurposed” given their effects on tau. Suvorexant, an FDA-approved drug for insomnia, reduces tau phosphorylation at selective sites such as −181 and decreases Aβ concentrations compared to placebo (283); its use should be investigated in other disorders. Angiotensin receptor blockers, FDA-approved for hypertension, have anticonvulsant effects in rats (284–286) and decrease incidence of epilepsy in humans (287), while decreasing CSF t-tau and p-tau in MCI patients (288) and improving cognition in hypertensive older adults with early executive impairment (289) and prodromal AD (290). These results support the need to further investigate the safety and efficacy of tau-targeting drugs in epilepsy.

Based on our proposed mechanism, drugs that impair the PERK pathway would have injurious effects. In a mouse TBI model, for example, inhibition of the PERK signaling pathway by GSK2606414 exacerbated immature cell loss, dendritic loss, and cell death (26).

Conversely, pharmacological upregulation of the PERK pathway may be an effective treatment target to avoid atypical ER stress response activation, reduce tau phosphorylation by ER stress response signaling (75), and mediate tau hyper-phosphorylation and Aβ neurotoxicity (291).

Drugs that target the ER stress response cell death pathways may also aid in the restoration of intracellular homeostasis, apoptotic-necrotic signaling dynamics, and ER folding capacity. In a rat lateral fluid percussion model of TBI, administration of the ER stress response inhibitor, salubrinal, 30 min prior to injury significantly reduced the ER stress response, promoted mitochondrial functioning, and inhibited downstream apoptotic signaling (292). In a mouse model of autosomal dominant lateral TLE, 4-phenylbutyric acid restored LGI1 protein function and reduced seizure susceptibility (293). In a mouse model of epilepsy, taurursodiol also reduced seizure susceptibility and mitigated repeated stress-induced neurodegeneration (294). In reducing seizure susceptibility, the likelihood of repeated or chronic activation of the ER stress response and tau-induced pathways decreases. This benefits the cell by favoring restoration of homeostasis, PERK pathway activation, and tau-involvement for maintenance of cellular dynamics; this also reduces the likelihood of repeated/chronic activation of Aβ, resulting in avoidance of irreversible or long-term neurodegeneration.

The numerous proteins and pathways involved in the brain’s inflammatory response make it challenging to identify the most appropriate target. Development of inflammatory modulators must also consider that acute inflammation can serve to protect neuronal integrity and avoid cell death, while chronic inflammation may decrease the likelihood of maximal recovery and cell survival. Further research is needed to find preventative and therapeutic agents for AD, TBI, and epilepsy.