Up-regulation of BMAL1 by epigallocatechin-3-gallate improves neurological damage in SBI rats.

Brain Muscle ARNT-Like Protein 1 (BMAL1) suppresses oxidative stress in brain injury during surgery. Epigallocatechin-3-gallate (EGCG), a monomer in green tea, has been identified as an antioxidant and a potential agonist for BMAL1. In this work, the mechanism by which BMAL1 is regulated was investigated, as well as the therapeutic effect of EGCG on surgically injured rats. The pathological environment after brain injury during surgery was simulated by excising the right frontal lobe of rats. Rats received an intraperitoneal injection of EGCG immediately after surgery. Neurological scores and cerebral edema were recorded after surgery. Fluoro-Jade C staining, TUNEL staining, western blot, and lipid peroxidation analyses were conducted 3 days later. Here we show that the endogenous BMAL1 level decreased after brain injury. Postoperative administration of EGCG up-regulated the content of BMAL1 around the cerebral cortex, reduced the oxidative stress level, reduced neuronal apoptosis and the number of degenerated neurons, alleviated cerebral edema, and improved neurological scores in rats. This suggests that BMAL1 is an effective target for treating surgical brain injury, as well as that EGCG may be a promising agent for alleviating postoperative brain injury.

Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway.

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) constitute a recently discovered bone-marrow-derived cell type useful for dealing with neuroinflammatory disorders. However, these cells are only formed during inflammatory conditions from immature myeloid cells (IMCs) that acquire immunosuppressive activity, thus being commonly gathered from diseased animals. Then, to obtain a more clinically feasible source, we characterized IMCs directly derived from healthy bone marrow and proved their potential immunosuppressive activity under pathological conditions in vitro. We then explored their neuroprotective potential in a model of human cerebellar ataxia, the Purkinje Cell Degeneration (PCD) mouse, as it displays a well-defined neurodegenerative and neuroinflammatory process that can be also aggravated by invasive surgeries. METHODS: IMCs were obtained from healthy bone marrow and co-cultured with activated T cells. The proliferation and apoptotic rate of the later were analyzed with Tag-it Violet. For in vivo studies, IMCs were transplanted by stereotactic surgery into the cerebellum of PCD mice. We also used sham-operated animals as controls of the surgical effects, as well as their untreated counterparts. Motor behavior of mice was assessed by rotarod test. The Purkinje cell density was measured by immunohistochemistry and cell death assessed with the TUNEL technique. We also analyzed the microglial phenotype by immunofluorescence and the expression pattern of inflammation-related genes by qPCR. Parametric tests were applied depending on the specific experiment: one or two way ANOVA and Student's T test. RESULTS: IMCs were proven to effectively acquire immunosuppressive activity under pathological conditions in vitro, thus acting as MDSCs. Concerning in vivo studios, sham-operated PCD mice suffered detrimental effects in motor coordination, Purkinje cell survival and microglial activation. After intracranial administration of IMCs into the cerebellum of PCD mice, no special benefits were detected in the transplanted animals when compared to untreated mice. Nonetheless, this transplant almost completely prevented the impairments caused by the surgery in PCD mice, probably by the modulation of the inflammatory patterns. CONCLUSIONS: Our work comprise two main translational findings: (1) IMCs can be directly used as they behave as MDSCs under pathological conditions, thus avoiding their gathering from diseased subjects; (2) IMCs are promising adjuvants when performing neurosurgery.

Corrigendum: Treatment of surgical brain injury by immune tolerance induced by peripheral intravenous injection of biotargeting nanoparticles loaded with brain antigens.

[This corrects the article DOI: 10.3389/fimmu.2019.00743.].

Rosiglitazone inhibits acyl-CoA synthetase long-chain family number 4 and improves secondary brain injury in a rat model of surgical brain injury.

Ferroptosis is a recently discovered non-apoptotic form of cellular death. Acyl-CoA synthetase long-chain family number 4 (ACSL4) is necessary for iron-dependent cellular death, and reactive oxygen species (ROS) produced by ACSL4 are the executioners of ferroptosis. Rosiglitazone improves ferroptosis by inhibiting ACSL4. There is no research indicating whether ACSL4 plays a role in cell death after surgical brain injury (SBI). This study aimed to investigate the role of ACSL4 in SBI via the ferroptosis pathway. Ninety male Sprague-Dawley rats were examined using a model of SBI. Subsequently, the inhibitory effect of rosiglitazone on ACSL4 was assessed via western blot, real-time polymerase chain reaction (PCR), immunofluorescence, fluoro-jade C staining, Perl's staining, ROS assay, and neurological scoring. The results showed that compared with the Sham group, the protein levels of ACSL4 and transferrin were significantly increased after SBI. Administration of rosiglitazone significantly reduced neuronal necrosis, iron deposition, brain water content and ROS in brain tissue and ameliorated neurological deficits at 48 h after SBI, which was concomitant with decreased transferrin expression. These findings demonstrate that SBI-induced upregulation of ACSL4 may be partly mediated by the ferroptosis pathway, which can be reversed by rosiglitazone administration.

RGFP966 exerts neuroprotective effect via HDAC3/Nrf2 pathway after surgical brain injury in rats.

Histone deacetylase 3 (HDAC3) restores chromatin nucleosomes to a transcriptional repression state, thereby inhibiting gene expression. Studies have found that HDAC3 expression is upregulated in a variety of pathological states of the central nervous system and related to its neurotoxicity. However, the role of HDAC3 in surgical brain injury (SBI) has not been thoroughly explored. OBJECTIVE: To observe the role of HDAC3 in SBI and the outcome of SBI after its suppression. METHODS: Rat SBI model was used, and intraperitoneal injection of RGFP966 (HDAC3 specific inhibitor) was used to detect the changes of HDAC3 expression and neuronal apoptosis indexes in the surrounding cortex of SBI rats, and the cerebral edema and neurological outcome of rats were observed. RESULTS: The expression of HDAC3 in the peripheral cortex of SBI rats was increased, and RGFP966 inhibited the upregulation of HDAC3 and saved the nerve cells around the damaged area. In addition, RGFP966 increased the expression of anti-oxidative stress proteins such as heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2). At the same time, the expression of apoptotic marker protein cleaved-caspase-3 (cle-caspase-3) was decreased, while the expression level of apoptotic protective marker protein B-cell lymphoma 2 (Bcl-2) was increased. In addition, this research demonstrated that in the RGFP966 rat SBI model, the expression level of antioxidant modifier nuclear factor-erythroid 2-related factor 2 (Nrf2) was increased. CONCLUSION: RGFP966 might activate HDAC3/Nrf2 signaling pathway by inhibiting HDAC3, regulated oxidative stress and nerve cell apoptosis induced by SBI in rat SBI model, reduced brain edema, and had a protective effect on nerve injury. It might be a potential target of SBI pathology.

Effects of Dimethyl Fumarate on the Karnofsky Performance Status and Serum S100ß Level in Newly Glioblastoma Patients: A Randomized, Phase-II, Placebo, Triple Blinded, Controlled Trial: Effect of DMF On the Serum S100ß Level and KPS Score of GBM Patients.

Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy with a low survival without extra logistics. Currently, there is no definitive chemotherapy among the studied options. This study aims to evaluate the neuroprotective effects of dimethyl fumarate (DMF) on surgical brain injuries in patients treated for GBM. Materials and Methods: This randomized, phase II, placebo, triple-blinded, controlled trial was performed on 36 patients with a diagnosis of GBM. All the patients received DMF (240 mg, three-times per day) or placebo (with the same shape and administration route) one week before surgery. Also, patients in both groups after the operation received standard treatments (radiotherapy plus chemotherapy). In addition, Kanofsky's performance status (KPS) score was evaluated at baseline and one month later. Also, serum S100ß was measured 48 hours before and after surgery. Results: There was no significant difference among DMF and control groups with regard to age, gender, and the extent of resections (P˃0.05). The most adverse event in both groups was a headache. Although the serum S100ß level was not markedly changed after surgery, the mean KPS in the DMF group was higher than in the control group after surgery. Conclusion: The DMF could be a possible good regime for the treatment of GBM; however, questions are raised regarding its efficacy and application for the addition to standard treatment.

The Reactive Astrocytes After Surgical Brain Injury Potentiates the Migration, Invasion, and Angiogenesis of C6 Glioma.

BACKGROUND: Surgical resection is a key method for glioma treatment. This inherently invasive procedure alters the tumor microenvironment of glioma cells that cannot be removed by surgery. However, few studies have focused on the impact of this microenvironment change on the growth of glioma cells. METHODS: The authors preconstructed a surgical brain injury model, and then C6 glioma cells were transplanted. HE staining was used to observe the general morphology of tumor cells, and immunohistochemistry of MMP-2, MMP-9, GFAP, and CD31 was used to evaluate the invasiveness of glioma cells and activation of astrocytes and calculate microvessel density. In vitro, primary rat astrocytes were exposed to different temperature gradients. The supernatant was made into conditioned medium for culturing C6 glioma cells. The scratch test and transwell test were used to evaluate the migration and invasion of tumor cells. RESULTS: GFAP expression was stronger in surgical brain injury rats, C6 cells implanted in these rats showed stronger expression of MMP-2 and MMP-9, and CD31 was expressed in more microvessels. Astrocytes exposed to high temperatures of 40°C and 43°C expressed stronger GFAP, and C6 cells cultured in their supernatants had stronger scratch healing ability and the ability to cross transwell chambers. CONCLUSIONS: The microenvironment changes caused by surgical brain injury will enhance the migration and invasion of glioma cells and increase the microvessel density in the tumor. This effect may be related to the activation of astrocytes caused by the thermal injury of bipolar coagulation during surgery.

Downregulation of TREM2/NF-кB signaling may damage the blood-brain barrier and aggravate neuronal apoptosis in experimental rats with surgically injured brain.

Surgical brain injury (SBI) is unavoidable in neurosurgery, and could aggravate secondary brain injury. Post-brain injury, multiple inflammatory factors are released, resulting in neuroinflammation and cell apoptosis, with subsequent brain edema and nerve function injury. TREM2, an immune protein mainly expressed in microglia, is an important link for nerve cells to participate in the inflammatory response. TREM2 and nuclear factor кB (NF-кB) are indeed closely associated with the release of inflammatory cytokines following brain injury. This work aimed to determine the inflammatory function of TREM2 in SBI, and to investigate whether TREM2 regulates interleukin-1 beta (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) release through the NF-кB p65 signaling pathway. We established a rat model of SBI, and performed Western blotting (WB), immunofluorescence (IF) and enzyme-linked immunosorbent assay (ELISA) for further analysis. Next, brain edema and neurological score analyses were performed. Finally, whether TREM2 regulating NF-кB p65 signaling affects blood-brain barrier (BBB) permeability and nerve cell apoptosis was examined. We found that post-SBI, TREM2 was upregulated, and inflammation and brain injury were aggravated. After TREM2 downregulation, NF-кB p65 production, inflammation and brain injury were enhanced, suggesting that TREM2 may play a protective role by inhibiting NF-кB p65 production after SBI. Overall, these findings suggest that TREM2 in SBI may have protective effects on postoperative nerve and BBB damage, possibly in part via the NF-κB p65 pathway.

Inhibition of the p­SPAK/p­NKCC1 signaling pathway protects the blood­brain barrier and reduces neuronal apoptosis in a rat model of surgical brain injury.

Surgical brain injury (SBI) can disrupt the function of the blood­brain barrier (BBB), leading to brain edema and neurological dysfunction. Thus, protecting the BBB and mitigating cerebral edema are key factors in improving the neurological function and prognosis of patients with SBI. The inhibition of WNK lysine deficient protein kinase/STE20/SPS1­related proline/alanine­rich kinase (SPAK) signaling ameliorates cerebral edema, and this signaling pathway regulates the phosphorylation of the downstream Na+­K+­Cl­ cotransporter 1 (NKCC1). Therefore, the purpose of the present study was to investigate the role of SPAK in SBI­induced cerebral edema and to determine whether the SPAK/NKCC1 signaling pathway was involved in SBI via regulating phosphorylation. An SBI model was established in male Sprague­Dawley rats, and the effects of SPAK on the regulation of the NKCC1 signaling pathway on BBB permeability and nerve cell apoptosis by western blotting analysis, immunofluorescence staining, TUNEL staining, Fluoro­Jade C staining, and brain edema and nervous system scores. The results demonstrated that, compared with those in the sham group, phosphorylated (p)­SPAK and p­NKCC1 protein expression levels were significantly increased in the SBI model group. After inhibiting p­SPAK, the expression level of p­NKCC1, neuronal apoptosis and BBB permeability were significantly reduced in SBI model rats. Taken together, these findings suggested that SBI­induced increases in p­SPAK and p­NKCC1 expression exacerbated post­traumatic neural and BBB damage, which may be mediated via the ion­transport­induced regulation of cell edema.

Targeting gut dysbiosis as a means to enhance recovery from surgical brain injury.

BACKGROUND: Surgical brain injury (SBI) impacts roughly 800,000 people who undergo neurosurgical procedures each year. SBI is the result of unavoidable parenchymal damage, vessel disruption, and thermal injury that is an inherent part of all neurosurgical procedures. Clinically, SBI has been associated with postoperative seizures and long-term neurobehavioral deficits. Current therapies are aimed at providing symptom relief by reducing swelling and preventing seizures. However, there are no therapies aimed at reducing the extent of SBI preoperatively. The microbiome-gut-brain axis may serve as a potential target for the development of new preventative therapies due to its extensive involvement in central nervous system function. METHODS: An extensive literature review was conducted to determine whether there is a potential role for dysbiosis treatment in reducing the extent of SBI. RESULTS: Treatment of gut dysbiosis deserves further exploration as a potential means of reducing the extent of unavoidable SBI. Dysbiosis has been correlated with increased neuroinflammation through impaired immune regulation, increased blood-brain barrier permeability, and increased production of reactive metabolites. Recently, dysbiosis has also been linked to acute neurological dysfunction in the postoperative state. Importantly, treatment of dysbiosis has been correlated with better patient outcomes and decreased length of stay in surgical patients. CONCLUSION: Current literature supports the role of dysbiosis treatment in the preoperative setting as a means of optimizing neurological recovery following unavoidable SBI that results from all neurosurgical procedures.

Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat.

Integrated stress response (ISR) contributes to various neuropathological processes and acting as a therapy target in CNS injuries. However, the fundamental role of ISR in regulating microglial polarization remains largely unknown. Currently no proper pharmacological approaches to reverse microglia-driven neuroinflammation in surgical brain injury (SBI) have been reported. Here we found that inhibition of the crucial ISR effector, activating transcription factor 4 (ATF4), using the RNA interference suppressed the lipopolysaccharide (LPS)-stimulated microglial M1 polarization in vitro. Interestingly, counteracting ISR with a small-molecule ISR inhibitor (ISRIB) resulted in a significant microglial M1 towards M2 phenotype switching after LPS treatment. The potential underlying mechanisms may related to downregulate the intracellular NADPH oxidase 4 (NOX4) expression under the neuroinflammatory microenvironment. Notably, ISRIB ameliorated the infiltration of microglia and improved the neurobehavioral outcomes in the SBI rat model. Overall, our findings suggest that targeting ISR exerts a novel anti-inflammatory effect on microglia via regulating M1/M2 phenotype and may represent a potential therapeutic target to overcome neuroinflammation following SBI.

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model.

Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl- cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1ß, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.

Inhibition of LRRK2-Rab10 Pathway Improves Secondary Brain Injury After Surgical Brain Injury in Rats.

Leucine-rich repeat kinase 2 (LRRK2) is considered as a potential target for the treatment of Parkinson's disease. This protein is expressed in the brain and has been associated with various diseases and lysosomal maintenance. Rab10 is a member of the Rab protein GTPase family that has been recently shown to be a kinase substrate of LRRK2. In addition, LRRK2 and its kinase substrate Rab10 constitute a key stress response pathway during lysosomal overload stress. This study aimed to investigate the potential role and mechanism underlying LRRK2 and its kinase substrate Rab10 involving surgical brain injury (SBI). One hundred and forty-four male Sprague-Dawley rats were examined using an SBI model, and some had received the LRRK2-specific inhibitor PF-06447475. Thereafter, western blotting, immunofluorescence, brain water content analysis, neuronal apoptosis assay, and neurological score analysis were conducted. The results showed that after SBI, LRRK2 and phosphorylated Rab10 (p-Rab10) expression in neuronal cells were upregulated, and administration of PF-06447475 significantly reduced neuronal apoptosis, neuroinflammation, and brain water content 12 h after SBI and improved neurological deficit 72 h after SBI, which is related to the decreased expression of LRRK2 and p-Rab10, and the lessening of lysosomal overload stress. Our research suggests that the inhibition of LRRK2 can effectively interfere with the role of p-Rab10 in promoting the secretion of lysosomal hydrolase in lysosomal overload stress after SBI, thereby reducing neuronal apoptosis and inflammation after SBI and playing a major role in brain protection.

Modern Brain Retractors and Surgical Brain Injury: A Review.

Surgical brain injury caused by brain retraction is a well-known consequence of intracranial surgery. Modern retractor designs, particularly since the 1980s, have significantly improved ease of use, improved visibility for surgeons, and minimized retraction-induced injuries, though not yet been entirely eliminated. Today, brain retractors come in a broad range of styles, each with its own pros and cons regarding operational utility and patient safety. Which type is chosen for use depends on the surgical approach, lesion size and depth, cost, and surgeon preference. Traditionally, self-retaining brain retractors with moveable arms and 1 or more attachable blades made from malleable stainless steel or silicone rubber have been the tool of choice; however, recently tubular retraction systems that only require fixation to the head frame and cause less focal pressure damage than older retractors have gained in popularity for some cases. This review aims to address the history of brain retraction and discuss each of the commonly used brain retractor types, as well as some newer and less common varieties especially in terms of the extent of tissue damage typically caused as well as the types of injuries reported by the users.

The potential of Slit2 as a therapeutic target for central nervous system disorders.

Introduction: Slit2 is an extracellular matrix protein that regulates migration of developing axons during central nervous system (CNS) development. Roundabout (Robo) receptors expressed by various cell types in the CNS, mediate intracellular signal transduction pathways for Slit2. Recent studies indicate that Slit2 plays important protective roles in a myriad of processes such as cell migration, immune response, vascular permeability, and angiogenesis in CNS pathologies. Areas covered: This review provides an overview of the diverse functions of Slit2 in CNS disorders and discusses the potential of Slit2 as a therapeutic target. We reviewed preclinical studies reporting the role of Slit2 in various CNS disease models, transgenic animal research, and rodent models that utilized Slit2 as a therapy. Expert opinion: Slit2 exerts a wide array of beneficial effects ranging from anti-migration, blood-brain barrier (BBB) protection, inhibition of peripheral immune cell infiltration, and anti-apoptosis in various disease models. However, a dual role of Slit2 in endothelial permeability has been observed in transgenic animals. Further research on Slit2 will be crucial including key issues such as effects of transgenic overexpression versus exogenous Slit2, function of Slit2 dependent on cellular expression of Robo receptors and the underlying pathology for potential clinical translation.

Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury.

INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model.

Neurosurgical procedures result in surgically induced brain injury (SBI) that causes postoperative complications including brain edema and neuronal apoptosis in the surrounding brain tissue. SBI leads to the release of cytokines that indirectly cause the stimulation of kynurenine 3-monooxygenase (KMO) and the release of neurotoxic quinolinic acid (QUIN). This study tested a KMO inhibitor, RO 61-8048, to prevent postoperative brain edema and consequent neuronal apoptosis in an in vivo model of SBI. A rodent model of SBI was utilized which involves partial resection of the right frontal lobe. A total of 127 Sprague-Dawley male rats (weight 275-325 g) were randomly divided into the following groups: Sham surgical group, SBI, SBI + DMSO, SBI + RO 61-8048 (10 mg/kg), SBI + RO 61-8048 (40 mg/kg), and SBI + RO 61-8048 (40 mg/kg) + KAT II inhibitor PF-04859989 (5 mg/kg). RO 61-8048 was administered by intraperitoneal injection after SBI. Postoperative assessment at different time points included brain water content (brain edema), neurological scoring, and western blot. SBI increased brain water content (ipsilateral frontal lobe), decreased neurological function, and increased apoptotic markers compared with sham animals. Treatment with RO 61-8048 (40 mg/kg) reduced brain water content and improved long-term neurological function after SBI. RO 61-8048 increased the expression of kynurenic acid while reducing QUIN and apoptotic markers in the surrounding brain tissue after SBI. These neuroprotective effects were reversed by PF-04859989. This study suggests KMO inhibition via RO 61-8048 as a potential postoperative therapy following neurosurgical procedures.

Enhanced Expression of PD-L1 on Microglia After Surgical Brain Injury Exerts Self-Protection from Inflammation and Promotes Neurological Repair.

Neuroinflammation and brain edema are major complications in the pathophysiology of surgical brain injury (SBI). Programmed death-ligand 1 (PD-L1), an immune inhibitory receptor ligand, has been increasingly investigated for inhibition of T cell-mediated immunity and braking inflammatory response. However, the negative immunomodulatory capacity of PD-L1 and their possible mechanism in SBI is not yet clear. This study aimed to evaluate the expression and the role of PD-L1 in a mouse model of SBI induced inflammation and to further study the potential therapeutic effects of PD-L1 on SBI. Here we showed that PD-L1 expression was markedly elevated in the surrounding peri-resection brain tissue post-SBI in vivo. PD-L1 was up-regulated through ERK signal pathway in LPS-treated BV-2 cells in vitro. Furthermore, blockade of the PD-L1 checkpoint using PD-L1 antibody significantly enhanced brain edema, exacerbated apoptosis and increased neurodeficits post-SBI. Moreover, activated PD-1/PD-L1 with PD-L1 protein significantly attenuated the inflammation responses and brain edema post-SBI. These results suggest that enhanced expression of PD-L1 post-SBI exerts self-protection from inflammation and promotes neurological repair. PD-L1 signal may have therapeutic potential for neurodegenerative disorders.

Treatment of Surgical Brain Injury by Immune Tolerance Induced by Peripheral Intravenous Injection of Biotargeting Nanoparticles Loaded With Brain Antigens.

Once excessive, neurological disorders associated with inflammatory conditions will inevitably cause secondary inflammatory damage to brain tissue. Immunosuppressive therapy can reduce the inflammatory state, but resulting infections can expose the patient to greater risk. Using specific immune tolerance organs or tissues from the body, brain antigen immune tolerance treatment can create a minimal immune response to the brain antigens that does not excessively affect the body's immunity. However, commonly used immune tolerance treatment approaches, such as those involving the nasal, gastrointestinal mucosa, thymus or liver portal vein injections, affect the clinical conversion of the therapy due to uncertain drug absorption, or inconvenient routes of administration. If hepatic portal intravenous injections of brain antigens could be replaced by normal peripheral venous infusion, the convenience of immune tolerance treatment could certainly be greatly increased. We attempted to encapsulate brain antigens with minimally immunogenic nanomaterials, to control the sizes of nanoparticles within the range of liver Kupffer cell phagocytosis and to coat the antigens with a coating material that had an affinity for liver cells. We injected these liver drug-loaded nanomaterials via peripheral intravenous injection. With the use of microparticles with liver characteristics, the brain antigens were transported into the liver out of the detection of immune armies in the blood. This approach has been demonstrated in rat models of surgical brain injury. It has been proven that the immune tolerance of brain antigens can be accomplished by peripheral intravenous infusion to achieve the effect of treating brain trauma after operations, which simplifies the clinical operation and could elicit substantial improvements in the future.