Background The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. Methods We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. Results NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. Conclusions We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.
: The correlation of neuroinflammation with the development of cerebral vasospasm following subarachnoid hemorrhage has been well documented in the literature; both clinical and pre-clinical. The exact mechanisms by which this process occurs, however, are poorly elucidated. Recent evidence indicates that interleukin-6 is not only an important prognostic biomarker for subarachnoid hemorrhage and subsequent vasospasm development but also an integral component in the progression of injury following initial insult. In this review, we briefly highlight other pathways under investigation and focus heavily on what has been discovered regarding the role of interleukin 6 and cerebral vasospasm following subarachnoid hemorrhage. A proposed mechanistic pathway is highlighted in written and graphical format. A discussion regarding the human correlative findings and initial pre-clinical mechanistic studies is addressed. Finally, in the future investigation section, innovative developments and a clear description of areas warranting further scientific inquiry are emphasized. This review will catalyze continued discovery in this area of emerging significance and aid in the quest for effective vasospasm treatment where limited clinical therapeutics currently exist.
Objective Post-traumatic epilepsy is a devastating complication of traumatic brain injury that has no targeted pharmacological therapy. Previous literature has explored the role of the c-Jun N-terminal kinase (JNK) pathway in epilepsy and the creation of epileptogenic foci by reactive astrogliosis; however, the relationship between reactive astrogliosis and the c-Jun N-terminal kinase signaling pathway in the development of post-traumatic epilepsy has not been thoroughly examined. Methods Four experimental groups, consisting of c57/b16 male mice, were examined: (1) control, (2) traumatic brain injury of graded severity (mild, moderate, severe), (3) sub-convulsive kainic acid alone without traumatic brain injury (15 mg/kg i.p.), and (4) sub-convulsive kainic acid administered 72 h after moderate traumatic brain injury. Modified Racine scale from 1 to 72 h and total beam breaks at 72 h were used to assess seizure activity. Immunohistochemistry and western blot were utilized to examine astrogliosis (GFAP), microglia activation (IBA-1), and phosphorylated JNK in prefrontal cortex samples collected from the contracoup side at 72 h post-injury. Results Astrogliosis, measured by GFAP, was increased after traumatic brain injury and increased commensurately based on the degree of injury. Mice with traumatic brain injury demonstrated a four-fold increase in phosphorylated JNK: p < 0.001. Sub-convulsive kainic acid administration did not increase seizure activity nor phosphorylation of JNK in mice without traumatic brain injury; however, sub-convulsive kainic acid administration in mice with moderate traumatic brain injury did increase phosphorylated JNK. Seizure activity was worse in mice, with traumatic brain injury, administered kainic acid than mice administered kainic acid. Conclusions Reactive astrocytes may have dysfunctional glutamate regulation causing an increase in phosphorylated JNK after kainic acid administration. Future studies exploring the effects of JNK inhibition on post-traumatic epilepsy are recommended.
Breast cancer continues to be a difficult disease to treat due to high rates of metastasis. Metastasis to the brain presents a unique and often overlooked challenge. In this focused review, we discuss the epidemiology of breast cancer and which types frequently metastasize to the brain. Novel treatment approaches are highlighted with supporting scientific evidence. The role of the blood-brain barrier and how it may become altered with metastasis is addressed. We then highlight new innovations for Her2-positive and triple-negative breast cancer. Finally, recent directions for luminal breast cancer are discussed. This review serves to enhance understanding of pathophysiology, spark continued innovation, and provide a user-friendly resource through tables and easy-to-process figures.
Background: Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH.Methods: Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/ myeloid mice were used to show myeloid diapedesis. For SAH, 50 μm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia's modified SAH score were utilized. P < 0.05 was considered significant.Results: IL-6 expression peaked 3 days following SAH (p < 0.05). Human IL-6 was increased in aneurysmal blood (p < 0.05) and in cerebral spinal fluid (p < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade (p < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow (p < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine (p < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade (p < 0.05).
BackgroundMonocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) have been identified separately as key mediators of the aneurysm healing process following coil embolization in the rodent model. The ability of protein coated coils to accelerate this process is currently unknown.To create coils coated with both MCP-1 and OPN to target aneurysm healing.MethodsWe uses a polymer (poly(glycolide-co-caprolactone)) (Rao pharmaceuticals) (CG910) to test whether coils could be dual coated with active proteins with sequential reliable release. Coils were coated with poly-DL-lactic glycolic acid (PLGA), CG910, and subsequently dipped with protein OPN (inner layer for delayed release) and MCP-1 (outer layer for initial release). Release assays were used to measure protein elution from coils over time. To test in vivo feasibility, coated coils were implanted into carotid aneurysms to determine the effect on aneurysm healing.ResultsThe in vitro protein release assay demonstrated, a significant amount of OPN and MCP-1 release within 2 days. Using a 200 µg/µL solution of MCP-1 in phosphate-buffered saline, we showed that CG910 coated coils provide effective release of MCP over time. In the carotid aneurysm model, MCP-1 and OPN coated coils significantly increased tissue ingrowth (74% and 80%) compared with PLGA and CG910 coated coils alone (58% and 53%). To determine synergistic impact of dual coating, we measured ingrowth for MCP-1/OPN coils (63%) as well as overlap coefficients for NOX4 and NFκB with CD31.ConclusionsThis study demonstrates that MCP-1 and OPN coated coils are viable and may promote early aneurysm healing. Dual coated coils may have synergistic benefit given different location of protein interaction measured in vivo. Further work is warranted.
Background and Aim The use of prosthetic knee replacements currently represent an alternative for patients who suffer from severe gonarthrosis. Treatment via the technique of ultrasound-guided percutaneous neuromodulation (US-guided PNM) is a therapeutic alternative worth considering as a new tool in physical therapy for the post-surgical recovery of total knee arthroplasty (TKA). The aim of this study was to evaluate the effectiveness of treatment with US-guided PNM in the post-surgical stage among patients intervened with TKA. Material and Methods Patients were selected between February and May 2017 at the Hospital of Denia and were randomly assigned into two groups. The initial sample was 13 patients. The experimental group (n = 7) received treatment with US-guided PNM plus conventional treatment. The control group (n = 6) only received conventional physiotherapy treatment. Patients in the experimental group received an application of PNM, which consisted of an alternate low frequency current at 10 Hz¸ pulse width 250 μs, with an intensity to the pain threshold. The intervention was performed during four consecutive weeks after hospital discharge. The control group received conventional treatment based on manual therapy, active mobilization and the use of the arthromotor until 115° of knee flexion and 0° knee extension was achieved. The main clinical variables evaluated were pain, measured using the Visual Analog Scale (VAS), quality of life, based on physical and mental components, using the SF12 scale and functional assessment using the Oxford Knee Score. Lastly, pain, stiffness and functional capacity was measured using the WOMAC scale. Results Both groups obtained statistically significant results in the four variables evaluated compared to the pre-surgery stage, however, the changes were more evident in the intervention group (p < 0.05). Furthermore, no significant differences were found in the variables evaluated regarding quality of life between the experimental and control group except for the emotional component of the SF-12 scale, where the result was only significant in the experimental group treated with US-guided PNM (P < 0.05). Regarding the improvement in the health status and decreased pain in the postoperative stage after TKA, no significant differences were observed between groups (p > 0.05). Conclusion The application of the US-guided PNM technique provides greater benefits than conventional therapy for decreasing the post-surgical pain in patients who have undergone knee arthroplasty and for emotional function, evaluated using the SF-12 questionnaire.
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