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.

Worsening of Dizziness Impairment Is Associated with Bone Marrow Kinase on Chromosome X Level in Patients after Mild Traumatic Brain Injury.

Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. Bone marrow kinase on chromosome X (BMX), a member of the TEC family of nonreceptor tyrosine kinases, is up-regulated after traumatic neural injury in a rat model of mTBI. The aim of this investigation was to determine whether BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between 13 and 15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks postinjury. The participant was asssigned to the case group if the subject's complaints of dizziness became worse at the sixth week assessment; otherwise, the participant was assigned to the control group. A receiver operating characteristic curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve for prediction of change in DHI postinjury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score, and 0.66 for functional score. Specificities were between 0.69 and 0.77 for total score and emotional score, respectively. Therefore, BMX demonstrates potential as a candidate serum biomarker of exacerbating dizziness post-mTBI.

Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway.

BACKGROUND: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. METHODS: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. RESULTS: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. CONCLUSION: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.

Pomalidomide Reduces Ischemic Brain Injury in Rodents.

Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM's neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.

Psychometric Evaluation of Anxiety, Depression, and Sleep Quality after a Mild Traumatic Brain Injury: A Longitudinal Study.

Introduction. Over 1 million mild traumatic brain injury (mTBI) cases are reported annually worldwide and may result in cognitive, physical, and emotional deterioration; depression; anxiety; and sleep problems. However, studies on long-term mTBI effects are limited. This study included 440 patients, and regular follow-ups of psychological assessments were performed for 2 years. Four questionnaires, including the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), Beck's anxiety inventory (BAI), and Beck's depression inventory (BDI), were used to evaluate sleep problems, daytime sleepiness, anxiety, and depression, respectively. Results show that BAI and BDI scores considerably improved at the 6th-week, 1st-year, and 2nd-year follow-ups compared to baseline, yet these remained significantly different. In addition, anxiety and depression were prominent symptoms in a select subgroup of patients with poor initial evaluations, which improved over the 2 years. However, the ESS and PSQI scores fluctuated only mildly over the same time span. In conclusion, the mTBI patients showed a gradual improvement of anxiety and depression over the 2 years following injury. While anxiety and depression levels for mTBI patients in general did not return to premorbid status, improvements were observed. Sleep disorders persisted and were consistent with initial levels of distress.

Pomalidomide Ameliorates H2O2-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects.

Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer's disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.

Heart rate variability and serum level of insulin-like growth factor-1 are correlated with symptoms of emotional disorders in patients suffering a mild traumatic brain injury.

OBJECTIVE: Patients who have experienced a mild traumatic brain injury (mTBI) are susceptible to symptoms of anxiety or depression. To explore the potential biomarkers for emotional disorders in mTBI patients, we analyzed the frequency domain of heart rate variability (HRV) and serum concentrations of four neurohormones. METHODS: We assessed mTBI patients on their first visit and follow-up. Symptoms were evaluated by the Beck Anxiety Inventory and the Beck Depression Inventory, respectively. Serum levels of adrenocorticotropic hormone (ACTH), melatonin, cortisol, and insulin-like growth factor (IGF)-1 and HRV follow-ups were measured and compared. RESULTS: mTBI patients were more vulnerable to symptoms of anxiety or depression than healthy controls. Reduced HRV was noted in mTBI patients compared to healthy controls. The mTBI patients demonstrated higher serum levels of ACTH, lower IGF-1 compared to healthy controls. In correlation analysis, only IGF-1 was positively correlated with HRV in mTBI patients. Both HRV and IGF-1 were correlated with symptom of depression while only HRV was correlated with symptom of anxiety in mTBI patients. CONCLUSIONS: We infer that HRV may be more significantly correlated with emotional disorders than is IGF-1 in mTBI patients. SIGNIFICANCE: The study is relevant for specific diagnostic markers in mTBI patients.

The influence of BMX gene polymorphisms on clinical symptoms after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.