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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurol Disord Stroke. Author manuscript; available in PMC 2016 June 7.
Published in final edited form as:
J Neurol Disord Stroke. 2014 May-Jun; 2(3): 1074.
Published online 2014 February 21.
PMCID: PMC4896636

Disparity among neural injury models and the unfolded protein response


Endoplasmic reticulum stress is activated following both stroke and traumatic brain injury producing reactive oxgygen species, increasing intracellular calcium levels, and inducing inflammation; however, the timing and duration of activation varies between injuries. Preventing the immediate effects of ischemic/reperfusion injury or traumatic brain injury is challenging due to short onset of injury, but mitigating the secondary effects is a therapeutically targetable option. Preventative therapies using pharmacological agents have been utilized in pre-clinical models of neural injury to ameliorate secondary effects such as apoptosis and neurodegeneration. The connection between ER stress activation, apoptosis, and subsequent neurodegeneration has been proposed, but not yet causally linked. Researchers are now pursuing effective treatment strategies to suppress the secondary effects of neural injury in order to mitigate the development of chronic deficits. Secondary effects such as endoplasimic reticulum stress and neuroinflammation can be prevented in pre-clinical models, but the results have yet to translate to meaningful treatment options for patients. Evidence suggests that targeting the right transcription factors, at the right time, will aid in the prevention of apoptosis and neurodegenerative disease development following neural injury. In this review, we examine therapeutic approaches that target secondary injury and how these may correlate to better treatment options for patients.

Keywords: Ischemic stroke, traumatic brain injury, Endoplasmic reticulum stress, Inflammation, Apoptosis, Neurodegeneration


Cellular responses from injury to the central nervous system occur rapidly. Cellular response mechanisms are triggered from a lack of oxygen (stroke) or from mechanical damage (trauma). Each injury type invokes the same type of cellular responses; however, the secondary effects can differ. The secondary biochemical effects can be therapeutically targeted in order to provide patients with valuable treatment options to attenuate further injury. Endoplasmic reticulum (ER) stress has been implicated in a variety of neural injury models including ischemia/reperfusion (I/R) injury [13] and traumatic brain injury (TBI) [46]. Imediately following injury, the ER stress response is activated due to increased intracellular calcium from glutamate signaling. Apoptosis and neurodegeneration can ensue if ER stress activation is prolonged [7, 8]. A theoretical mechanistic diagram proposing a causal link between ER stress and apoptosis with subsequent neurodegeneration has been provided (Figure 1). Pharmacological tools can be used to further study the basis of the proposed connection. This review investigates how the ER stress response differs among the different pre-clinical models of neural injury, and to what extent the secondary effects can be mitigated to prevent chronic impairment.

Figure 1
PERK-mediated ER stress pathway. Link ER stress activation to apoptosis and neurodegeneration. Includes pharmacological tools (Salubrinal and Guanabenz) to manipulate downstream components following TBI.

The main difference between the ER stress response seen in I/R injury compared to TBI is the duration and severity of insult. I/R injury invokes the gradual loss of oxygen to the brain and is an injury of long duration with multiple phases of inflammatory cascades. The injury disrupts Ca2+ homeostasis resulting from the loss of glucose and therefore the brain’s energy supply. TBI on the other hand occurs over a short duration, and is often a more severe injury. The rotational and acceleration/deceleration components commonly tears axons apart leading to a robust gliosis response. The injury can also cause Ca2+ perturbations much like I/R injury; however, the shock wave seems to harm the cell in an energy-independent process. The damage done by TBI makes membranes more permeable to Ca2+ and even to extracellular proteins [9]. In addition, enhanced glutamate-signaling causes a spike in intracellular calcium. The duration of injury as well as severity provides key targets for specific injury-type treatments.

Endoplasmic Reticulum Function

When the brain is deprived of oxygen from I/R injury, or withstands severe physical injury from TBI, intracellular Ca2+ (IC) and reactive oxygen species (ROS) accumulate in the cytoplasm [10]. These events cause proteins to unfold, and when the ER becomes overwhelmed and struggles to re-fold the unfolded proteins, an ER stress response ensues [11]. In the short-term, the response can promote cell survival through three separate mechanisms: (1) attenuation of global translation, (2) upregulation of stress response genes, and (3) degradation of unfolded proteins [12]. However, when the response is prolonged, from a severe neural injury for example, cells degrade [13], or commit to undergoing apoptosis [14]. Preserving the adaptive response to unfolded proteins while preventing subsequent apoptosis is a topic being heavily investigated in the field of neural injury.

The ER stress response consists of three adaptive arms which include: (1) PKR-like ER kinase (PERK), (2) inositol requiring kinase 1 (IRE1), and (3) activating transcription factor 6 (ATF6). Each arm of the pathway is triggered by the overabundance of unfolded proteins. Distinct downstream components of these arms have different characteristic responses to unfolded proteins [15]. Each pathway is different based on timing and duration, and may overlap with one another. In addition the ER stress response closely correlates with the intrinsic and extrinsic apoptotic pathways [16]. The next step in experimental research is to map out the interplay of these pathways following I/R injury and TBI to determine how they contribute to chronic neurodegenerative diseases in humans.

PERK Pathway

The ER manages unfolded proteins through nuclear-mediated initiation of global translation inhibition. When the unfolded proteins accumulate a chaperone protein, binding immunoglobulin protein (BiP), dissociates from the ER transmembrane protein PERK and subsequently binds to unfolded proteins [17]. BiP can restore protein conformation as a first line defense against protein misfolding [18]. Following BiP dissociation from PERK, PERK autophosphorylates and activates the first arm of the ER stress response [19]. Activated PERK, phosphorylates eukaryotic initiation factor 2 alpha (eIF2α); which is a direct inhibitor of global translation [20]. Inhibiting protein synthesis reduces the number of proteins that must be folded in the ER, and therefore allows the ER to refold damaged proteins after a traumatic event.

Although global translation is inhibited through the phosphorylation of eIF2α, a subset of stress response genes become more actively transcribed [21]. The ER stress response upregulates the following stress response genes: activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and growth arrest and DNA damage inducible agent 34 (GADD34) [22]. ATF4 contains three open reading frames, which only get transcribed after eIF2α has been phosphorylated [23]. Exactly how ATF4 is transcriptionally regulated is currently unknown; however, other well-known transcriptional regulators are being investigated.

Acutely, ATF4 can upregulate BiP and promote protein refolding and cell survival [24]. ATF4 also promotes the translation of GADD34, a regulatory subunit of the Protein Phosphatase 1 (PP1) complex. GADD34 is known to dephosphorylate eIF2α and acts in the pro-survival feedback mechanism [25]. When the ER stress response persists, constituitively active ATF4 triggers pro-apoptotic downstream cascades [26]. In the long-term, ATF4 becomes a transcription factor for CHOP [27], which is known to promote apoptosis [28]. CHOP actively inhibits the anti-apoptotic factor B-cell lymphoma 2 (Bcl-2) [29], and promotes ROS production [30]. The cells that survive the initial injury are those that we seek to protect from secondary injury mechanisms. Upregulating stress response genes that aid in protein refolding, while downregulating stress response genes that promote apoptosis and degeneration are both viable treatment options for patients subject to neurotrauma.

IRE1 Pathway

The second arm of the ER stress response involves the ER transmembrane component IRE1. BiP dissociates from IRE1 when unfolded proteins accumulate, and IRE1 autophosphorylates itself [31]. IRE1 becomes an endonuclease for x-box binding protein 1 (XBP1) by splicing out a 26bp intron from unspliced XBP1. Spliced XBP1 translocats to the nucleus and regulates several cellular functions [32, 33]. The cellular response to XBP1 is dependent on duration of activation much like ATF4. XBP1 can promote cell survival during conditions of oxygen deprivation [34], yet has detrimental responses in other forms of injury [35]. When ER stress is persistent the IRE1 arm can deactivate, and endonuclease activity ceases [31]. As a result, XBP1 is no longer spliced to become a potent transcription factor for pro-survival genes, including BiP [36]. Eventually the cell will undergo apoptosis if the ER stress response does not subside.

ATF6 Pathway

The third ‘defense’ mechanism of the ER is to simply degrade the proteins marked as improper folding. This process occurs through a collection of proteins known as the ER-associated degradation (ERAD) machinery [11]. This mechanism works in conjunction with the proteasome to prevent aberrant protein accumulation and ultimately to prevent cell apoptosis [37]. ATF6 is the first target of the third arm of the ER stress response. Once activated by BiP dissociation, ATF6 transits to the golgi apparatus, is cleaved by site 1 and 2 proteases, and translocates to the nucleus to upregulate genes of ERAD machinery [38]. Initially, the upregulation of ERAD components is protective to cells by helping to decrease the unfolded protein load; however, when their activity persists a neurodegenerative phenotype can manifest [39]. Determining the timing and duration of the different ER stress mechanisms as well as their complex interplay will allow for the development of preventative therapeutic options.

Targeted Approach

Generally, ER stress is a protective compensatory process in the short-term, with persistent ER stress activation being more detrimental to cells over time. Focused therapy must target the underlying ER stress mechanisms that mediate this temporal transition. Understanding the regulation of ATF4 and XBP1 is critical in designing successful therapeutic approaches. Both transcription factors can promote cell survival acutely, but contribute to cell death during chronic activation. Determining the molecular regulators that lead to persistent ER stress activation will open the door for novel modulation of ER stress at extended time points.

ER Stress Response in Models of Ischemic Stroke

Protein aggregation can results when transient cerebral ischemia disrupts blood supply and interrupts energy metabolism [11]. Oxygen deprivation causes the ER to swell due to the accumulation of aberrant proteins [40]. The physical effects of ischemia trigger the ER stress response and inhibit protein synthesis in those affected areas [41, 42]. The ER stress response has been implicated as an important player during transient and focal ischemia [43]. Neural injury is accompanied by an increase in IC. Usually the ER uses Ca2+ pumps to reduce high Ca2+ levels within the cell, but sometimes the Ca2+ load becomes too high for the ER to handle and the overloaded Ca2+ pumps become damaged [44]. Tissues lacking the necessary oxygen from cerebral blood supply are subject to a disruption in Ca2+ homeostasis due to loss of function in the energy-dependent ER Ca2+ efflux pump [45]. Global ischemic stroke increases the expression of BiP. BiP initially triggers robust ER stress activation and cell survival [46]. More focal injury triggers apoptosis. A model of middle cerebral artery occlusion exhibited increased expression of the active form of caspase-12 [47], indicating an ER-dependent apoptotic response. A third model of stroke, bilateral carotid artery occlusion, showed increased expression of CHOP and BiP with a longer transition to apoptosis [29]. Each model shows that stroke upregulates markers of ER stress and subsequently apoptosis, but the transition to apoptotic pathways is dependent on severity of injury. Ongoing therapeutic investigation should focus on energy maintenance, inflammation attenuation, and apoptosis prevention.

ER Stress Response in Models of Traumatic Brain Injury

Stroke and traumatic brain injury have several shared mechanisms of injury progression. After TBI, inflammatory responses are triggered [48], apoptotic cascades commence [49], and ER stress is induced [5]. Despite these shared mechanisms, there are subtle differences that differentiate both the primary and secondary injuries. TBI triggers rapid changes in glutamate signaling and oxidative stress with long-term sequalae mediated through nuclear factor regulators. The consequence of injury progression has recently been associated with long-term behavioral and pathologic changes within the CNS. Mechanistic progression is also highly dependent upon injury severity. TBI presentation is variable with severe injuries causing loss of consciousness while subconcussive injuries produce limited acute symptoms. The brain’s response to TBI is more globally distributed than stroke with a vast number of perivascular foci. In contrast to the penumbra seen in stroke, pathologic changes are scattered throughout the brain and highly dependent on axonal shearing and gliosis. The molecular mechanisms of TBI are being pursued by a large number of researchers due to the increased awareness of how these changes contribute to chronic neuropsychiatric symptoms [50, 51].

TBI produces an excess of ROS [52] and can cause a large accumulation of IC [53]. Over time TBI can also cause tau hyperphosphorylation through mechanisms that are not completely understood [50]. Although these factors are common among all neural injury models, in TBI models, these factors are activated immediately following injury and have the potential to advance profoundly over time. The cellular repair mechanisms are more drawn out, and may contribute to neurodegenerative disease [13, 54]. How these effects manifest into chronic disease states is an area of ongoing investigation.

The most common cellular response mechanism to be studied following TBI is inflammation, and more specifically how inflammation leads to subsequent apoptosis [55]. The ER stress response has only recently been addressed by TBI investigators because of its new found link to neurodegeneration [56]. The brains of professional athletes and military veterans are currently being examined by new imaging modalities to discover underlying causes behind neuropsychiatric symptoms, such as post-traumatic stress disorder, chronic traumatic encephalopathy, and Alzheimer’s disease (AD). The timing and duration of the ER stress response and how exactly it develops into a neurodegenerative phenotype warrants further investigation.

ER Stress and Neuroinflammation

Neuroinflammation is another downstream cascade resulting from the inability of the ER to suppress the IC surge following neural injury [57]. Both I/R injury and TBI cause an acute upregulation of inflammatory processeses. In particular, the NF-kB inflammation pathway has been shown to be activated after neural injury [58]. Acute activation of NF-kB contributes to the release of anti-inflammatory cytokines. These cytokines attract microglia and astrocytes to the site of injury in order to scavenge dead or severely damaged neurons [59]. However, when NF-kB has been activated over a long period of time, pro-inflammatory cytokines are released and result in detrimental effects. This pathway has recently been linked to ER stress activation [60]. The following subsections review how neuroinflammation is manifested during I/R injury and TBI.


During ischemic stroke and the subsequent reperfusion injury, NF-kB mediates many genes associated with inflammation [58][61]. The ER stress response, in part, regulates NF-kB and thereby inflammation [62]. Attempts have been made to administer anti-oxidants as a therapy to mitigate NF-kB induction of pro-inflammatory cytokines following I/R injury [59]; however, this approach has failed to translate to the clinic. In fact, a direct link between ER stress and reperfusion inflammation has yet to be determined. Because the inflammatory response and ER stress both act in a biphasic manner following ischemic insult [32], additional emphasis should be placed on combination therapy targeting both components during the same phase of activation.


Neuroinflammation is also an important component of TBI exposure [63]. A prominent study showed that overexpression of Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) led to activation of NF-kB [64]. Moreover, TRAF6 activated Akt, which is upstream of NF-kB. Interestingly, NF-κB was attenuated by GADD34 overexpression in a TBI rat model [5]. In contrast to GADD34, downstream markers of the IRE1 arm were shown to be upregulated with TRAF6 overexpression. Such a paradox opens the possibility for counter-regulation of neuroinflammation by targeting arms 1 and 2 of the ER stress response [65]. Therefore, a connection between NF-kB activation and ER stress following TBI is likely and warrants future investigation.

Current work has shown that the ER stress response phosphorylates eIF2α following controlled cortical impact [6]. Consequently, activated eIF2α suppresses the translation of endogenous inhibitors of nuclear factor kappa B (IKB) [66], and thereby indirectly increases the levels of NF-kB. Therefore, it appears that ER stress activation can augment NF-kB activation and promote cell survival in the short term, but the role of NF-kB during prolonged ER stress activation has not been elucidated. Inflammation and ER stress are closely tied through the NF-kB pathway and future work will examine these intricate interconnections.

Pharmacological Tools Used to Research ER Stress Following Neural Injury


The overarching goal in I/R stroke research is to prevent as much secondary injury as possible after an ischemic event. Two strategies have been employed: preserve the penumbra surrounding the necrotic core [67] and equally important extend the treatment window for thrombolytics [68]. Even with successful pre-clinical studies, the treatments that work in rats have not translated well to the clinic. New treatments for stroke (Table 1) are being studied that focus on the ER stress response and inflammation. Combination treatments that address multiple sites on these complicated pathways will likely have better effects than single-target acute acting drugs. Once a stronger connection between ER stress and inflammation has been established, ideal targets can be mapped for regions of shared overlap.

Table 1
Pharmacological tools used to research ER stress in stroke models


The primary effects of TBI are acute cell death from glutamate excitotoxicity. Targeting glutamate-mediated toxicity is limited due to the short onset of initiation. The secondary effects of injury should therefore be the foremost target of therapeutic intervention. Immediate secondary effects include: axonal sheering [69], blood brain barrier disruption [70] and IC accumulation [44]. These effects are common following TBI but can potentially be attenuated by shortening the duration of the response by timely pharmaceutical intervention. Prolonged secondary events can persist and include: ER stress activation [5], apoptosis [55, 71] and inflammation [72]. In the past decade, experimental pharmacologic interventions targeting these secondary events have become prominent.. Although these events are naturally associated with TBI progression, they have a higher potential to be attenuated if the right therapy is implemented. We provide a list of the most frequently used ER stress modulators for TBI research in Table 2. With the recent linkage between ER stress activation and subsequent neurodegeneration [8], the focus of research pharmacotherapy has transitioned towards mitigation of chronic neural decline. While tau toxicity itself is debated, tau is a well-known marker concurrently expressed during neurodegeneration. The ultimate goal is to diminish neurodegeneration by treating secondary TBI pathways early.

Table 2
Pharmacological tools used to research ER stress in TBI models

Docosahexaenoic acid (DHA), an important component of omega-3 fatty acids, has recently garnered attention as an ER stress inhibitor. DHA has been reported to block inositol triphosphate receptor in the ER and therefore prevent IC accumulation and subsequent ER stress activation during ischemic stroke (Begum et al., 2013). A follow up study was conducted by Begum and colleagues (2014), in which they show that DHA attenuates the ER stress response following TBI and also mitigates tau protein phosphorylation. Pre-clinical models are important in order to understand mechanism of intervention, but clinical trials will be necessary to capitalize dosing and timing strategies.

ER-mediated Apoptosis Following Prolonged ER Stress Activation

When unfolded proteins are not properly refolded or degraded, stress response genes are upregulated. These stress response genes activate proteins that proteolytically cleave caspases and therefore lead to programmed cell-death. [7]. Caspase-12 is specific to the endoplasmic reticulum and triggers apoptosis through downstream activation of caspase-3 [73]. Prolonged ER stress inevitably leads to caspase-12 activation and apoptosis in I/R injury models [74]. Models of TBI have also shown upregulation of Caspase-12 mRNA expression [75], indicative of ER stress mediated apoptosis. This ER-mediated caspase activity may also be involved in the pathogenesis of AD [76]. Apoptosis is not purely detrimental to the damaged brain considering the heightened energy demands following I/R injury or TBI. By limiting energy expended on severly damaged cells, the brain can preserve function in remaining cells. Apoptosis can however induce immunoexcitotoxicity leading to glutamate release into the surrounding milieu [77]. Moreover, immunoexcitotoxicity has been implicated in tau hyperphosphorylation and neurodegeneration [78]. Therefore, the long-term effects of apoptotis must be weighed against the benefits of short-term energy conservation when considering therapeutic intervention.

ER Stress Manifests into a Neurodegenerative Phenotype

The ER stress response is triggered following injury in order to maintain cellular homeostasis [56]. The ER stress response shuts down protein folding, but if left unchecked these unfolded proteins can have long-term detrimental effects on the cell. Through interaction with BiP and the subsequent activation of the three arms of the ER stress pathway, unfolded proteins push CHOP above threshold [79]. Importantly, CHOP can cleave and activate the pro-apoptotic protein, caspase-12, on the ER membrane [80]. Caspase-12 interacts with apoptosis signal-regulating kinase 1 to facilitate the cleavage of caspase-3 [81]. In addition, ER stress can interact with mitochondria to initiate apoptosis through cytochrome C dissociation [82]. CHOP decreases the anti-apoptotic Bcl-2 within the mitochondria while facilitating the release of ROS [83]. While important in mediating acute injury cascades, the ER stress response is also heavily involved in neurodegenerative disease.

ER stress has recently been linked to chronic diseases such as AD, Parkinson’s disease, ischemic stroke, and prion disorders [84]. In AD patients, ER stress enhances neuronal autophagy and tau hyperphosphorylation [54]. The triggering event for persistent ER stress activation is metabolic dysfunction that leads to aberrant protein accumulation [85]. Parkinson’s disease results in ER stress mediated dopaminergic cell apoptosis [86]. In ischemic stroke, the ER stress response is initially protective but can be detrimental with time [43]. The second arm of the ER stress pathway prevents vascular regeneration, and also triggers apoptosis if the unfolded protein response persists [48, 87]. Prion disease is unique in that the inciting event is a lack of synaptic transport mediated by prion protein accumulation in the ER [88]. Although much is yet to be learned regarding ER stress and neurodegeneration, the therapeutics targeting the ER stress response may limit progression towards neurodegenerative disease.


In summary, ER stress is activated following both I/R injury and TBI. The same pathways are activated, the same inflammatory processes are triggered, and the same apoptotic results ensue. Both injury models produce excess ROS, increased IC levels, and induced inflammation; however, the timing, severity, and duration all vary from model to model. It is difficult to prevent the immediate effects of I/R injury or TBI, but we can attempt to mitigate the secondary effects that follow. Preventative therapies, mostly pharmacological agents, have been employed in pre-clinical models of neural injury. The approach has been to reduce apoptosis and neurodegeneration. The underlying link between ER stress, apoptosis and neurodegeneration is not yet fully understood. Research is now being focused on the most effective treatment strategies to suppress chronic effects resulting from neural injury. Of particular importance is transferring preclinical success to effective treatment options for human care. Evidence suggests that combining therapeutic options that target multiple injury components at the ideal time window will be the most effective strategy going forward.


The authors would like to acknowledge Ryan C. Turner for his helpful insight and knowledge of traumatic brain injury and the ER stress response. Research reported in this publication was supported by the NIGMS of the National Institutes of Health under award number U54GM104942. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Traumatic Brain Injury
Endoplasmic Reticulum
Intracellular Calcium
Reactive Oxygen Species
PKR-like ER kinase
Inositol requiring enzyme 1
Activating transcription factor 6
Binding immunoglobulin protein
eukaryotic initiation factor 2 alpha
Activating transcription factor 4
C/EBP homology protein
Growth arrest and damage inducible agent 34
Protein Phosphatase 1
X-box binding protein 1
TNF Receptor-Associated Factor 6
Protein kinase B
Nuclear Factor Kappa Beta
inhibitors of nuclear factor kappa B
B cell lymphoma 2
ER associated degradation
Alzheimer’s disease
Brain-derived neurotrophic factor
Cocaine and amphetamine regulated transcript
Docosahexaenoic acid


Conflict of Interest

There are no conflicts of interest to report


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