Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury (2025)

Table of Contents
Abstract Introduction Materials and Methods Animal and Experiment Group TBI Model Modified Neurologic Severity Score Brain Water Content Lesion Volume Wire Hanging Test Tissue Processing for Histology Fluoro-Jade B (FJB) Staining Immunofluorescence Western Blot Protein Oxidation Assay Results PRE-084 Decreased the Lesion Volume and Brain Water Content in TBI Model PRE-084 Improved the Neurologic Recovery in TBI Model PRE-084 Attenuated Neurodegeneration and Prevented Microglia Activation After TBI PRE-084 Reduced Nitrosative and Oxidative Stress After TBI Discussion Acknowledgments Compliance with Ethical Standards Conflict of interest References References

Abstract

Traumatic brain injury (TBI) remains a significant clinical problem and contributes to one-third of all injury-related deaths. Activated microglia-mediated inflammatory response is a distinct characteristic underlying pathophysiology of TBI. Here, we evaluated the effect and possible mechanisms of the selective Sigma-1 receptor agonist 2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate (PRE-084) in mice TBI model. A single intraperitoneal injection 10μg/g PRE-084, given 15min after TBI significantly reduced lesion volume, lessened brain edema, attenuated modified neurological severity score, increased the latency time in wire hang test, and accelerated body weight recovery. Moreover, immunohistochemical analysis with Iba1 staining showed that PRE-084 lessened microglia activation. Meanwhile, PRE-084 reduced nitrosative and oxidative stress to proteins. Thus, Sigma-1 receptors play a major role in inflammatory response after TBI and may serve as useful target for TBI treatment in the future.

Keywords: Traumatic brain injury, Sigma-1 receptor, Nitrosative stress, Oxidative stress

Introduction

Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide (Zhao et al. 2012). Despite extensive clinical and basic research, few effective treatments existed to alleviate neuronal damage and patients need long duration for cognitive, motor, and sensory rehabilitation. Moreover, the costs of care after TBI are difficult to predict because of the disability, psychosocial, and emotional sequelaes of injury (Opara et al. 2014).

TBI initiates a series of inflammatory reactions, which includes some interrelated components, release of intracellular products from damaged brain cells, microglia activation, chemokines production, and recruitments of other peripheral inflammatory cells into damaged brain areas. As one of brain-resident cells, microglia plays critical roles in innate immunity and response to brain injury (Aguzzi et al. 2013; Salter and Beggs 2014). After activation, microglia shows morphological transformation from a ramified to ameboid morphology, and secretes many inflammatory mediators, and clears tissue debris by phagocytosis (Gyoneva and Ransohoff 2015). However, activated microglia could impair brain repair and aggravate brain injury (Block et al. 2007; Hu et al. 2015). More and more evidences suggested that activated microglia can release cytotoxic molecules, including pro-inflammatory cytokines TNFα and nitric oxide, which finally lead to neuronal injury after TBI (Yuan et al. 2015). Microglial inhibition can, therefore, protect brain from inflammatory injury (Festoff et al. 2006; Heppner et al. 2005), and is therefore recognized as an important therapeutic strategy against TBI.

Sigma-1 receptors, transmembrane proteins located in the endoplasmic reticulum (Hayashi and Su 2007; Kimura et al. 2013), are widely distributed in the mammalian brain (Pabba et al. 2014) and are involved in many physiological processes including neurotransmitter release, neuronal firing, learning, and memory. Moreover, Sigma-1 receptor ligands are neuroprotective in many types of injuries (Maurice and Su 2009). Considering existence of microglial Sigma-1 receptors (Maurice and Su 2009) and effects Sigma-1 receptors on reducing microglia activation in amyotrophic lateral sclerosis (ALS) mice(Mancuso et al. 2012), we postulate that Sigma-1 receptors are involved in microglia activation after TBI, which further increases neuronal injury.

Here, we treated TBI mice with PRE-084, a selective Sigma-1 receptor agonist, and found that PRE-084 administration significantly attenuates neuronal damage after TBI and accelerates neurological recovery. In addition, PRE-084-mediated neuroprotection involves reduction of reactive microgliosis and decrease of oxidative and nitrosative stress to proteins.

Materials and Methods

All experiments were conducted in accordance with the guidelines of the National Institutes of Health and approved by the Zhengzhou University Animal Care and Use Committee.

Animal and Experiment Group

C57BL/6 wild-type mice (10–12week, 20–26g, total n=112) were used in this study. The animals were housed under the condition with free access to food and water, 12-h light/dark cycle, the temperature (22.0±0.5°C) and the humidity (55±2%). We used the website Randomization.com (http://www.randomization.com) to separate study groups randomly. Animals were divided into three groups: Sham, TBI+Vehicle, and TBI+PRE-084 group. Saline was used as vehicle and a single intraperitoneal injection 10μg/g PRE-084 or vehicle was given 15min after TBI.

TBI Model

The controlled cortical impact (CCI) model of TBI was induced according to the methods described previously (Zhao et al. 2012). Briefly, after successful anesthetization with isoflurane (4.0% for induction, 2.0% for maintenance) and ventilated with oxygen-enriched air (20%:80%) via a nose cone, a left craniotomy (diameter: 3mm) was made between the bregma and the lambda. Then, we removed the bone flap. Mice were subjected to CCI using a 3-mm flat-tip impounder with the following parameters: impact velocity, 4m/s; the depth, 1mm; and impact duration, 150ms. The skull of the sham animals were just removed without injury. During the surgery, a heating pad was used to maintain the rectal temperature at 37±0.5°C.

Modified Neurologic Severity Score

On days 1, 3, 7, 14, 21, and 28 after TBI, a modified neurologic severity score (mNSS) (Xie et al. 2015) was used to evaluate changes in neurologic functions in a blind manner. This score measures motor, sensory, reflex, and balance of the animal with the scale from 0 to 18.

Brain Water Content

Brain water content, which showed the brain edema, was measured on day 3 after TBI, as described previously (Girgis et al. 2013). In brief, mouse brains were removed after animals were sacrificed by cervical dislocation. Ipsilateral hemispheres were immediately weighed (wet weight), followed by being in an incubator at 100°C for 48h. The samples were then weighed once again to obtain the dry weight. Water content was calculated as Water content (%)=(wet weight−dry weight)/wet weight×100%.

Lesion Volume

Mice brains were removed on day 28 post-TBI and kept in 4% paraformaldehyde overnight and 30% sucrose for 48h in sequence. 30-µm-thick sections were cut in a cryostat and stained with Crystal violet solution. Lesion volumes were quantified with Image J software (NIH, USA) and calculated by integrating sum of the thickness of sections, the damaged areas of each section, and the inter-section distance.

Wire Hanging Test

On day 1, 3, 7, 14, 21, and 28, mice were tested for motor strength, balance, and endurance after TBI. A previously published wire hanging test was used in this test (Chen et al. 2014). 55cm above the table, there is metallic wire between two posts. We put the mice on the wire and recorded the time that the mouse was able to remain suspended. To prevent the mice fall to the table, we put a pillow under the wire.

Tissue Processing for Histology

Anesthetized mice were perfused transcardially with cold 0.1mol/L PBS and 4% paraformaldehyde. Brains were removed, postfixed in 4% paraformaldehyde overnight at 4°C, and then transferred into 30% sucrose in PBS for another 48h. Brains were then frozen and serially cut into 30-μm-thick coronal sections for Crystal violet staining (day 28, n=8/group), FJB staining (day 3, n=6/group), and Iba1 staining (day 3, n=6/group).

Fluoro-Jade B (FJB) Staining

For detecting the neuronal death after PRE-084 treatment in TBI model, FJB staining procedures were conducted at 3days as previously described (Zhao et al. 2014). Briefly, the sections were transferred to a solution of 0.06% potassium permanganate for 30min, then rinsed with dH2O, followed by a 0.0004% F-J B (Histochem, Jefferson, AR, USA) staining solution for 45min. After washing 3×5min in PBS, the brains were placed on a slide warmer (approximately 50°C for 30min) for examination using a fluorescence microscope (Eclipse TE2000-E; Nikon, Tokyo, Japan) at an excitation wavelength of 450–490nm. The number of FJB-positive cells was counted in the 200× microscopic field from 15 randomly selected locations per mouse (5 fields per section×3 sections per mouse) near injury area.

Immunofluorescence

Immunofluorescence was conducted according to the method as previously described (Li et al. 2012). After being blocked by 5% horse serum, brain sections were incubated with mouse anti-Iba1 (1:500, Abcam) at 4°C overnight followed by Alexa Fluor 594-conjugated anti-mouse secondary antibody (1:1000; Molecular Probes, Eugene, OR) for 1h at room temperature. Stained sections were examined with a microscope (Eclipse TE2000-E; Nikon, Tokyo, Japan). Immunofluorescent density of activated microglia of the mice was quantified around the injury area (Yang et al. 2011) from 15 randomly selected locations under 200× microscopic field (5 fields per section×3 sections per mice). Sections were analyzed by an investigator blinded to the experimental cohort.

Western Blot

Ipsilateral hemisphere was rapidly removed from TBI mice at 3h of recovery and time-matched sham-operated mice (n=6/group) after transcardial cold PBS perfusion. Tissues were homogenized and centrifuged at 1000×g for 10min to obtain supernatant as total tissue lysates. Protein concentrations were determined by Pierce BCA protein assay (Thermo Fisher Scientific, Rockeford, IL, USA). 20µg protein samples were separated by 4–12% sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE) electrophoresis and electrotransferred onto PVDF membranes. After being blocked with 5% nonfat milk in PBST for 1h, membranes were probed overnight at 4°C with the anti-nitrotyrosine (1:10000, EMD Millipore, Billerica, MA, USA) or anti-β-actin (1:3000, Santa Cruz Biotech, Dallas, TX, USA). The membranes were then washed and incubated with secondary antibodies conjugated with horseradish peroxidase (1:3000, Santa Cruz Biotech) for 1h. After immunoblotting, bands were scanned and analyzed with Image J software (NIH, USA). Values of optical density were normalized by the value of a sham-operated animal on gels.

Protein Oxidation Assay

Oxidative modification of proteins in ipsilateral hemisphere after TBI was determined with an OxyBlot protein oxidation detection kit (EMD Millipore) for carbonyl groups as described in product instructions. In brief, 50μg protein was denatured with 10% SDS, derivatized to 2, 4-dinitrophenylhydrazone (DNP) by a reaction with 2, 4-dinitrophenylhydrazine (DNPH) for 5min, and separated by 4–12% SDS-PAGE and electrotransferred onto PVDF membranes. Proteins with conjugated DNP residues were detected with polyclonal rabbit antibody DNP used at a concentration of 1:150. Proteins were then detected with goat anti-rabbit HRP-conjugated antibody and ECL.

Results

PRE-084 Decreased the Lesion Volume and Brain Water Content in TBI Model

CCI caused obvious brain injury in mice at day 28. PRE-084 treatment significantly reduced lesion volume from 7.84±0.90mm3 in the vehicle-treated group to 5.17±0.79mm3 (n=6/group, p<0.05, t test; Fig.1a). Brain water content is another important clinical feature of TBI. On day 3 after TBI, the brain water content of the ipsilateral hemisphere was reduced significantly with PRE-084 treatment, compared to that of the vehicle treatment (77.38±1.16% vs. 80.49±0.86%, n=6/group, p<0.05, One-way ANOVA test; Fig.1b).

Fig.1.

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PRE-084 Improved the Neurologic Recovery in TBI Model

No significant difference in mNSS scores between vehicle- or PRE-084-treated animals can be found from day 1 to day 14 after TBI. However, the mNSS scores in the PRE-084-treated animals were lower than those in the vehicle-treated group on day 21 and 28. (n=8/group, p<0.05, Two-way ANOVA test; Fig.1c). The wire hanging test showed similar results. PRE-084 treatment did not change the latency time on day 1 and 3. However, it increased the latency time from day 7 to day 28, compared to that in the vehicle-treated group (n=8/group, p<0.05, Two-way ANOVA test; Fig.1b).

PRE-084 Attenuated Neurodegeneration and Prevented Microglia Activation After TBI

FJB-positive cells were widely located in ipsilateral hemisphere of TBI mice on day 3 of recovery. Compared to that in the vehicle-treated brains, the number of FJB-positive cells in the PRE-084-treated group was decreased from 102.3±13.83 to 64.86±16.84 per ×200 field (n=6/group, p<0.05, t test; Fig.2a).

Fig.2.

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Iba-1 immunostaining was selectively labeled for microglia in control and TBI brains. Most microglia in control brains exhibited small, round, or oval cell bodies with numerous fine branching processes. TBI activated microglia and changed their morphology: increased cell bodies with large, shortened, and extended processes. Iba-1 immunofluorescence intensity was further used to evaluate microglia activation around the injured area. On day 3 post-TBI, PRE-084 attenuated the fluorescence intensity, compared to the vehicle-treated group (n=6/group, p<0.05, One-way ANOVA test; Fig.2b).

PRE-084 Reduced Nitrosative and Oxidative Stress After TBI

3-Nitrotyrosine immunoreactivity and protein carbonyl formation have been used as markers of nitrosative and oxidative stress (Besson et al. 2003; Rodriguez-Rodriguez et al. 2014). Immunoblotting of total tissue lysate from ipsilateral hemisphere at 3h after TBI indicated increased 3-nitrotyrosine immunoreactivity in vehicle-treated mice (n=6, p<0.05, One-way ANOVA test; Fig.3a), which can be significantly reduced by PRE-084 treatment. Oxyblot analysis of carbonyl groups indicated that TBI induced a significant increase at 3h of recovery (n=6, p<0.05, One-way ANOVA test; Fig.3b), similar to the effects on 3-nitrotyrosine. PRE-084 significantly attenuated carbonyl formation at 3h of recovery.

Fig.3.

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Discussion

In the current study, we demonstrate for the first time that systemic administration of highly selective Sigma-1 receptor agonist PRE-084 reduces neurodegeneration, attenuates neurologic deficit, alleviates brain edema, and lessens TBI-induced brain injury. These effects are associated with its reduction on microglia activation and oxidative and nitrosative stress to proteins. In addition, this study provides direct evidence showing the Sigma-1 receptor as a novel therapeutic target in TBI brain injury.

TBI has long been recognized as a leading cause of mortality and permanent neurological disability worldwide (Zhao et al. 2012). Although the pathophysiological processes of TBI are complicated, it is now believed that the primary and secondary neuronal damage are involved in TBI (Corps et al. 2015; Maas et al. 2008).The primary neuronal injury is caused by external mechanical force leading to skull fractures, vascular tearing, brain contusions and lacerations, and intracranial hemorrhages. Secondary neuronal damage is mediated through several interactive pathophysiologic events including disruption of blood– brain barrier, brain edema, cerebral ischemia and reperfusion injury, and inflammation. A growing body of evidences suggests critical roles of TBI-induced cerebral inflammation, including microglia activation, migration and recruitment of peripheral inflammatory cells, and release of inflammatory mediators, in the neuronal injury (Corps et al. 2015; Hinson et al. 2015; Finnie 2013).

Microglia, brain’s resident macrophage, is the main cell type of the innate immune system of the brain. It provides surveillance of the CNS homeostasis and protects the CNS against various pathological insults. In normal and physiological conditions, microglia shows a highly ramified morphology with symmetrically extended and motile process. When activated, they change their morphology to facilitate the migration toward the lesion site and the phagocytosis of cellular debris (Raivich 2005), and produce inflammatory cytokines and reactive oxygen species until weeks to months after TBI (Frugier et al. 2010; Hsieh et al. 2013). Blood–brain barrier and neurons can be disturbed by activated microglia and in turn aggravates brain injury (Thal and Neuhaus 2014; Block et al. 2007; Hu et al. 2015). In the current study, we showed reduced immuno-signals of Iba-1 in PRE-084-treated TBI mice brains, which is in agreement with the previous report that PRE-084 reduced Iba1-positive microglial cells in SOD1-G93A mice (Mancuso et al. 2012). Therefore, PRE-084 reduces neurodegeneration, attenuates neurologic deficit, and attenuates brain edema. On the other hand, effects of PRE-084 may not limit to weaken microglia activation after TBI. It is now known that activated microglia can exist broadly into M1 and M2 types cells. M1 cell is classical activated microglia, which is typified by the production of inflammatory cytokines and reactive oxygen species, while M2 cell shows an anti-inflammatory role and is involved in wound repair and debris clearance (Colton 2009; Gordon 2003). PRE-084 treatment has been shown to modify microglial reactivity and facilitate microglia to exhibit functional restorative M2 phenotypes in ALS mice (Peviani et al. 2014). In the future, we will focus on effects of PRE-084 on levels of some M2 phenotype marker, such as CD206 (Kigerl et al. 2009) in TBI brains.

There are still a lot of works for us to do on the roles of Sigma-1 receptors on microglia in TBI brains. On one hand, it is unclear how Sigma-1 receptors activation affects microglia activation. Furthermore, the morphology of activated microglia cannot be discriminated from that of infiltrating macrophages using standard immunohistochemical techniques (Streit et al. 1999; Loane and Byrnes 2010). We may need to find other methods to differentiate microglia with macrophages after TBI and PRE-084 treatment.

In conclusion, our results showed that Sigma-1 receptors play an important role in inflammatory response after TBI, and pharmacological manipulation of Sigma-1 receptors is a promising strategy in treating TBI patients.

Acknowledgments

This study was supported by Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01030300), 211 Project-phase III of Zhengzhou University-the basic and clinical research of stem cells, Excellent Youth Foundation of Henan Scientific Committee (114100510005), Young Excellent Teachers in University Funded Projects of Henan Province, and Bureau of Science and Technology Development Project from Henan Province (200902310250).

Compliance with Ethical Standards

Conflict of interest

The authors declare no competing financial interests.

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Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury (2025)

References

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