Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.

Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.

Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress.

Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.

One-Year Follow-Up Study on Assessing the Range of Segmental Motion and Clinical Outcomes Following Cervical Disc Arthroplasty for Treatment of Severe Cervical Disc Degeneration.

BACKGROUND: Though previous studies have documented various clinical outcomes after cervical arthroplasty for degenerative cervical disc disease, none of them reported the impact of cervical arthroplasty on severe cervical disc degeneration (CDD). METHODS: This retrospective cohort study included severe 40 CDD (C3-C7) patients who underwent single-level cervical arthroplasty using ProDisc-C between January 2017 and December 2019. After surgical intervention, the range of motion (ROM) was determined, whereas clinical outcomes were measured in terms of the Visual Analogue Scale (VAS) and Neck Disability Index (NDI) to evaluate neck pain and disability, respectively. RESULTS: Compared to the mean preoperative ROM (6.57 ± 4.85°), the cervical dynamic ROM was increased 3 months after cervical arthroplasty, and the increment was maintained for at least 1 year. The increased ROM is attributed to the extension and not flexion components. The mean preoperative ROM of 6.57 ± 4.85° significantly increased to 11.67 ± 4.98° (P = 0.0005), 10.05 ± 5.18° (P = 0.0426) and 10.46 ± 4.73° (P = 0.0247) after 3 months, 6 months and 1 year, respectively. The extension ROM also revealed a similar trend. VAS for neck and arm decreased from 7.4 and 6.6 to 1.4 and 1.2, respectively. Consistently, the preoperative mean Neck Disability Index (NDI) score of 27.6 decreased to 14.6. We recorded a case of device subsidence, but without extrusion. CONCLUSIONS: Cervical arthroplasty can improve clinical outcomes and restore ROM in severe CDD patients.

Correlation of Insulin-Like Growth Factor 1 With Cognitive Functions in Mild Traumatic Brain Injury Patients.

Mild traumatic brain injury (mTBI) is a prevalent health concern with variable recovery trajectories, necessitating reliable prognostic markers. Insulin-like growth factor 1 (IGF-1) emerges as a potential candidate because of its role in cellular growth, repair, and neuroprotection. However, limited studies investigate IGF-1 as a prognostic marker in mTBI patients. This study aimed to explore the correlation of IGF-1 with cognitive functions assessed using the Wisconsin Card Sorting Test (WCST) in mTBI patients. We analyzed data from 295 mTBI and 200 healthy control participants, assessing demographic characteristics, injury causes, and IGF-1 levels. Cognitive functions were evaluated using the WCST. Correlation analyses and regression models were used to investigate the associations between IGF-1 levels, demographic factors, and WCST scores. Significant differences were observed between mTBI and control groups in the proportion of females and average education years. Falls and traffic accidents were identified as the primary causes of mTBI. The mTBI group demonstrated worse cognitive outcomes on the WCST, except for the "Learning to Learn" index. Correlation analyses revealed significant relationships between IGF-1 levels, demographic factors, and specific WCST scores. Regression models demonstrated that IGF-1, age, and education years significantly influenced various WCST scores, suggesting their roles as potential prognostic markers for cognitive outcomes in mTBI patients. We provide valuable insights into the potential correlation of IGF-1 with cognitive functions in mTBI patients, particularly in tasks requiring cognitive flexibility and problem solving.

Mesenchymal Stem Cells Overexpressing FGF21 Preserve Blood-Brain Barrier Integrity in Experimental Ischemic Stroke.

Blood-brain barrier (BBB) disruption is a prominent pathophysiological mechanism in stroke. Transplantation of mesenchymal stem cells (MSCs) preserves BBB integrity following ischemic stroke. Fibroblast growth factor 21 (FGF21) has been shown to be a potent neuroprotective agent that reduces neuroinflammation and protects against BBB leakage. In this study, we assessed the effects of transplantation of MSCs overexpressing FGF21 (MSCs-FGF21) on ischemia-induced neurological deficits and BBB breakdown. MSCs-FGF21 was injected into the rat brain via the intracerebroventricular route 24 h after middle cerebral artery occlusion (MCAO) surgery. The behavioral performance was assessed using modified neurological severity scores and Y-maze tests. BBB disruption was measured using Evans blue staining, IgG extravasation, and brain water content. The levels of tight junction proteins, aquaporin 4, and neuroinflammatory markers were analyzed by western blotting and immunohistochemistry. The activity of matrix metalloproteinase-9 (MMP-9) was determined using gelatin zymography. At day-5 after MCAO surgery, intraventricular injection of MSCs-FGF21 was found to significantly mitigate the neurological deficits and BBB disruption. The MCAO-induced loss of tight junction proteins, including ZO-1, occludin, and claudin-5, and upregulation of the edema inducer, aquaporin 4, were also remarkably inhibited. In addition, brain infarct volume, pro-inflammatory protein expression, and MMP-9 activation were effectively suppressed. These MCAO-induced changes were only marginally improved by treatment with MSCs-mCherry, which did not overexpress FGF21. Overexpression of FGF21 dramatically improved the therapeutic efficacy of MSCs in treating ischemic stroke. Given its multiple benefits and long therapeutic window, MSC-FGF21 therapy may be a promising treatment strategy for ischemic stroke.

Delta Cord as a Radiological Localization Sign of Postoperative Adhesive Arachnoiditis: A Case Report and Literature Review.

Postoperative adhesive arachnoiditis is an inflammatory response of the spinal leptomeninges that occurs after surgery and results in scar formation in the avascular nature of the arachnoid layer. Clinical manifestations of postoperative adhesive arachnoiditis include pain, sensory deficits, motor dysfunction, reflex abnormalities, and bladder or bowel impairment. In magnetic resonance imaging scans, signs of postoperative adhesive arachnoiditis can vary; however, some indicators can assist surgeons in locating the lesion accurately and, thus, in planning effective surgical interventions. This paper reports the case of a 37-year-old man with postoperative adhesive arachnoiditis after two surgeries for Chiari I malformation. This case illustrates the progressive development of the "delta cord sign", which refers to the formation of a thick arachnoid band causing the spinal cord to adopt a triangular shape in the axial view. This phenomenon is accompanied by the sequential occurrence of syringomyelia. During intraoperative examination, we identified the presence of the delta cord sign, which had been formed by an arachnoid scar that tethered the dorsal spinal cord to the dura. This discovery enabled us to precisely pinpoint the location of the arachnoid scar and thus provided us with guidance that enabled us to avoid unnecessary exploration of unaffected structures during the procedure. Other localization signs were also reviewed.

Postoperative 30-Day Comparative Complications of Multilevel Anterior Cervical Discectomy and Fusion and Laminoplasty for Cervical Spondylotic Myelopathy: An Evidence in Reaching Consensus.

Although a few large-scale studies have investigated multilevel anterior cervical discectomy and fusion (ACDF) and laminoplasty (LAMP) and their related complications for cervical spondylotic myelopathy (CSM), the optimal surgical intervention remains controversial. Therefore, we compared their 30 days of postoperative complications. Through the 2010-2019 ACS NSQIP Participant Use Data Files, we estimated the risk of serious morbidity, reoperation, readmission, mortality, and other postoperative complications. Initially, propensity score matching (PSM) of the preoperative characteristics of both groups was performed for further analysis. Multivariable logistic regression analysis provided OR and 95% CI for comparative complications. After PSM, 621 pairs of cohorts were generated for both groups. Increased frequency of postoperative complications was observed in the LAMP group, especially for surgical wound infection, no matter whether superficial (ACDF/LAMP = 0%/1.13%, p = 0.0154) or deep wound infection (ACDF/LAMP = 0%/0.97%, p = 0.0309). The mean length of total hospital stays (ACDF/LAMP = 2.25/3.11, p < 0.0001) and days from operation to discharge (ACDF/LAMP = 2.12/3.08, p < 0.0001) were longer, while the hospitalization rate for over 30 days (ACDF/LAMP = 4.67%/7.41%, p = 0.0429) and unplanned reoperation (ACDF/LAMP = 6.12%/9.34%, p = 0.0336) were higher in LAMP. Results also indicated congestive heart failure as a risk factor (adjusted OR = 123.402, p = 0.0002). Conclusively, multilevel ACDF may be a safer surgical approach than LAMP for CSM in terms of perioperative morbidities, including surgical wound infection, prolonged hospitalization, and unplanned reoperation. However, these approaches showed no significant differences in systemic complications and perioperative mortality.

Thalamocortical coherence predicts persistent postconcussive symptoms.

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents' histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.

Brain-derived neurotrophic factor contributes to neurogenesis after intracerebral hemorrhage: a rodent model and human study.

Background and purpose: Intracerebral hemorrhage (ICH) enhances neurogenesis in the subventricular zone (SVZ); however, the mechanism is not fully understood. We investigated the role of brain-derived neurotrophic factor (BDNF) in post-ICH neurogenesis in a rodent model and in patients with ICH using cerebrospinal fluid (CSF). Methods: A rat model of ICH was constructed via stereotaxic injection of collagenase into the left striatum. Patients with ICH receiving an external ventricular drain were prospectively enrolled. CSF was collected from rats and patients at different post-ICH times. Primary cultured rat neural stem cells (NSCs) were treated with CSF with or without BDNF-neutralized antibody. Immunohistochemistry and immunocytochemistry were used to detect NSC proliferation and differentiation. The BDNF concentration in CSF was quantified using enzyme-linked immunosorbent assays (ELISA). Results: In the rat model of ICH, the percentage of proliferating NSCs and neuroblasts in SVZ was elevated in bilateral hemispheres. The cultured rat NSCs treated with CSF from both rats and patients showed an increased capacity for proliferation and differentiation toward neuroblasts. BDNF concentration was higher in CSF collected from rats and patients with ICH than in controls. Blocking BDNF decreased the above-noted promotion of proliferation and differentiation of cultured NSCs by CSF treatment. In patients with ICH, the BDNF concentration in CSF and the neurogenesis-promoting capacity of post-ICH CSF correlated positively with ICH volume. Conclusion: BDNF in CSF contributes to post-ICH neurogenesis, including NSC proliferation and differentiation toward neuroblasts in a rat model and patients with ICH.

Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.

BACKGROUND: Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs. METHODS: TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions. RESULTS: TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice. CONCLUSION: TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component.

Timing of symptomatic subsequent vertebral compression fracture associated with different demographic factors.

BACKGROUND: Symptomatic subsequent vertebral compression fracture (VCF; SVCF) is a common complication associated with poor outcomes. Accumulating evidence shows that demographic factors and incidences of symptomatic SVCFs differ during different periods after the primary vertebroplasty (VP). PURPOSE: To investigate the incidence and demographic factors of symptomatic SVCFs after the primary VP in different periods using registry data in the Taiwan National Health Insurance Research Database. METHODS: This retrospective cohort study included 28,343 patients aged ≥ 50 years with painful VCF treated with VP from 2002 to 2016. Symptomatic SVCF was defined as SVCF requiring another VP or re-admission. During the 2-year follow-up, 1955 patients received subsequent VP while 1,407 were readmitted. Cox proportional hazard models were used to compare the risks of subsequent VP or readmission. RESULTS: The cumulative incident rate of subsequent VP and re-hospitalization was 0.87 [95% confidence interval (CI), 0.82 ~ 0.92] and 0.62 (95% CI, 0.58 ~ 0.66) per 100 person-months, respectively, within the first 6 months after the primary VP, and it decreased over time. A multiple Cox regression model showed that age, osteopenia or osteoporosis, Charlson comorbidity index (CCI) were significant independent risk factors of subsequent VP or readmission within the first 6 months. CONCLUSIONS: This study demonstrated that the incidence of symptomatic SVCF peaked in the first 6 months after the primary VP. Age, osteoporosis or osteopenia, and CCI were determined to be risk factors in the first 6 months, but only osteoporosis or osteopenia and CCI were risk factors thereafter.

3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-ß levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

Personalized Prediction of Postconcussive Working Memory Decline: A Feasibility Study.

Concussion, also known as mild traumatic brain injury (mTBI), commonly causes transient neurocognitive symptoms, but in some cases, it causes cognitive impairment, including working memory (WM) deficit, which can be long-lasting and impede a patient's return to work. The predictors of long-term cognitive outcomes following mTBI remain unclear, because abnormality is often absent in structural imaging findings. Previous studies have demonstrated that WM functional activity estimated from functional magnetic resonance imaging (fMRI) has a high sensitivity to postconcussion WM deficits and may be used to not only evaluate but guide treatment strategies, especially targeting brain areas involved in postconcussion cognitive decline. The purpose of the study was to determine whether machine learning-based models using fMRI biomarkers and demographic or neuropsychological measures at the baseline could effectively predict the 1-year cognitive outcomes of concussion. We conducted a prospective, observational study of patients with mTBI who were compared with demographically matched healthy controls enrolled between September 2015 and August 2020. Baseline assessments were collected within the first week of injury, and follow-ups were conducted at 6 weeks, 3 months, 6 months, and 1 year. Potential demographic, neuropsychological, and fMRI features were selected according to their significance of correlation with the estimated changes in WM ability. The support vector machine classifier was trained using these potential features and estimated changes in WM between the predefined time periods. Patients demonstrated significant cognitive recovery at the third month, followed by worsened performance after 6 months, which persisted until 1 year after a concussion. Approximately half of the patients experienced prolonged cognitive impairment at the 1-year follow up. Satisfactory predictions were achieved for patients whose WM function did not recover at 3 months (accuracy = 87.5%), 6 months (accuracy = 83.3%), and 1 year (accuracy = 83.3%) and performed worse at the 1-year follow-up compared to the baseline assessment (accuracy = 83.3%). This study demonstrated the feasibility of personalized prediction for long-term postconcussive WM outcomes based on baseline fMRI and demographic features, opening a new avenue for early rehabilitation intervention in selected individuals with possible poor long-term cognitive outcomes.

99mTc-TRODAT-1 SPECT Revealed That Striatal Dopamine Transport Availability Significantly Decreases in Late Mid-Aged Healthy Taiwanese and Then Remains Stable.

OBJECTIVES: Neuroimaging studies in the past 20 years have documented an age-related decline in striatal dopamine transporters (DATs), which is a marker of dopaminergic neurodegeneration; however, concerns about ethnic variations in the decline in DAT with age have not been addressed. The purpose of this study was to assess the rate of striatal DAT loss in healthy Taiwanese adults using kit-based 99mTc-TRODAT-1, a radioligand for DAT SPECT. PATIENTS AND METHODS: Fifty healthy subjects (mean age ± SD, 63 ± 12 years; range, 30-80 years) were studied. 99mTc-TRODAT-1 was prepared from a lyophilized kit. Brain DAT SPECT imaging was acquired between 165 and 195 minutes postinjection (~740 MBq or 20 mCi) using a dual-head camera equipped with fan-beam collimators (Helix SPX; GE). Specific uptake in the striatum (ST), caudate nucleus (CA), and putamen (PU) were calculated from reconstructed transaxial slices at the level of maximal striatal activity. Occipital cortices were used as reference areas. Data were presented as specific binding ratios. RESULTS: Age had a significant moderate to large negative effect on striatal DAT, which declined by -25.7% ± 6.10% between the ages of 30 and 80 years, equivalent to 6.4% loss per decade. The rates of decline in the CA and PU were 6.9% and 7.3% per decade, respectively. CONCLUSIONS: This study suggests ethnic variations may not significantly affect the age-related decline in DAT. The data generated in this study could also be used as a reference to estimate DAT loss/occupancy in patients with DAT-related diseases.

Screening for Poor Self-Reported Sleep Quality at 12 Weeks in Post-Mild Traumatic Brain Injury Patients Using the HF-Age-Gender (HAG) Index.

To identify a screening tool for poor self-reported sleep quality at 12 weeks according to non-invasive measurements and patients' characteristics in the first week after mild traumatic brain injury (mTBI), data from 473 mTBI participants were collected and follow-ups were performed at 12 weeks. Patients with previous poor self-reported sleep quality prior to the injury were excluded. Patients were then divided into two groups at 12 weeks according to the Pittsburgh Sleep Quality Index based on whether or not they experienced poor sleep quality. The analysis was performed on personal profiles and heart rate variability (HRV) for 1 week. After analyzing the non-invasive measurements and characteristics of mTBI patients who did not complain of poor sleep quality, several factors were found to be relevant to the delayed onset of poor sleep quality, including age, gender, and HRV measurements. The HRV-age-gender (HAG) index was proposed and found to have 100% sensitivity (cut-off, 7; specificity, 0.537) to predicting whether the patient will experience poor sleep quality after mTBI at the 12-week follow-up. The HAG index helps us to identify patients with mTBI who have no sleep quality complaints but are prone to developing poor self-reported sleep quality. Additional interventions to improve sleep quality would be important for these particular patients in the future.

Mesenchymal Stem/Stromal Cell Therapy in Blood-Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects.

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood-brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile.

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain-gut-microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain-gut-microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.

3,6'-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury.

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.

CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation.

Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.