Browsing by Subject "Neuroinflammation"
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Item Open Access A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.(J Control Release, 2013-10-10) Sinclair, S Michael; Bhattacharyya, Jayanta; McDaniel, Jonathan R; Gooden, David M; Gopalaswamy, Ramesh; Chilkoti, Ashutosh; Setton, Lori ARadiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold.Item Open Access Development of Depot Forming Elastin-Like Polypeptide-Curcumin Drug Conjugates for Sustained Drug Delivery to Treat Neuroinflammatory Pathologies(2013) Sinclair, Steven MichaelNeuroinflammation associated with lumbar radiculopathy and peripheral nerve injury is characterized by locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in local delivery of anti-inflammatory drugs to treat this pathology, as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation.
ELPs are biopolymers capable of thermally-triggered in situ depot formation and have been successfully employed as drug carriers and biomaterials in several applications. A library of ELP-curcumin conjugates were synthesized and characterized. One lead conjugate was shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα and NF-κB with near-equivalent potency compared to free curcumin. When injected into the perineural space via intramuscular (i.m.) injection proximal to the sciatic nerve in mice, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4 days post-injection and decreased systemic exposure of curcumin 3-fold.
The results of this dissertation support the use of ELP as a drug carrier for local perineural drug delivery, and the strategy presented here for drug conjugate development and use of depot-forming ELP-curcumin conjugates represents a novel means of providing sustained treatment of neuroinflammation and pain associated with radiculopathy and peripheral nerve injury.
Item Open Access Dietary Choline, Inflammation, and Neuroprotection Across the Lifespan(2020) Maurer, SaraThe cholinergic system is intricately linked with hippocampal memory. As well, choline is anti-inflammatory in the brain and periphery (Terrando et al., 2011; Rivera et al., 1998). However, few have analyzed the anti-inflammatory properties of choline as an alternate means by which cholinergic manipulations affect hippocampal memory throughout the lifespan. The first aim of this dissertation work sought to determine if dietary choline supplementation protects against the deleterious effects of air pollution in the developing brain. Pregnant mice were given a high-choline diet (approximately 4.5x the choline chloride in the control diet) or a synthetic control diet. As well, dams were exposed to a series of diesel particulate (DEP) or saline vehicle sessions throughout pregnancy. Mice were sacrificed and tissues were collected on embryonic day 18. The activation state of microglia, identified by quantifying morphology using Iba1+ immunohistochemical staining, was examined in the dentate gyrus of the hippocampus (DG), the paraventricular nucleus (PVN) of the hypothalamus, the basolateral amygdala (AMY), and the parietal cortex (PCX). As expected, we found that DEP led to increased microglial activation in the fetal DG in males. Choline supplementation partially prevented this increase in activation. Interestingly, these effects were region-specific: the opposite pattern is seen in the PVN, and no significant diesel effect was seen in the AMY and PCX. These findings suggest that prenatal choline supplementation throughout pregnancy may protect the fetal hippocampus against the neuroinflammation associated with air pollution. To analyze whether the acute effects of dietary choline seen prenatally also occur in adulthood, adult dietary choline supplementation alongside the tibial fracture model of post-operative cognitive dysfunction (POCD) was used. POCD occurs when increased neuroinflammation due to peripheral surgery leads to impairments in cognition. Differences were found in almost hippocampal-dependent behavior, astrocytic activation, and cell proliferation. Differences were time point-specific. In the hippocampus, astrocytic activation, cell proliferation, and hilar granule cells all increased 1 day after surgery, and these increases were blunted by dietary choline. An increase in hippocampal young neurons was found 2 weeks after surgery. However, both were blunted by choline supplementation. At both time points assessed, tibial fracture impaired novel object recognition performance, and dietary choline rescued these impairments. As well, dietary choline supplementation did not mitigate the increase in anxiety-related behavior – specifically implicating hippocampal actions of the nutrient. Because the hippocampal-dependent memory impairment and rescue is not time point-specific, but the neural effects of tibial fracture are each specific to a certain timepoint, the mechanisms of behavior are likely different at each time point. Building upon aim 2, aim 3 explores if perinatal choline supplementation can act via “programming” of the neuroimmune system in development to prevent POCD in adulthood. Perinatal choline supplementation prevented POCD and neuroinflammation due to peripheral surgery, but did not protect against increases in young neurons or hilar neurons. Perinatal choline nutrition, in addition to its already-known neuroprotection, is additionally protective against POCD and its associated neuroinflammation in adulthood. Taken together, this body of work concludes that dietary choline supplementation at various administration dates is protective in neuroinflammatory models in behavior and brain.
Item Open Access MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation.(Journal of neuroinflammation, 2020-08-31) Jiang, Maorong; Li, Ran; Lyu, Jingjun; Li, Xuan; Wang, Wei; Wang, Zhuoran; Sheng, Huaxin; Zhang, Weiguo; Karhausen, Jörn; Yang, WeiBackground
Cardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined.Methods
Mice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated.Results
Using our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced.Conclusions
Our data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.Item Open Access Th17 Cell Pathogenicity Promoted by Integrin α3 During Autoimmune Neuroinflammation(2022) Park, EunchongAutoimmune diseases are caused by dysregulated immune responses against self. Multiple sclerosis (MS) is one such autoimmune disease in which the central nervous system (CNS) is affected by chronic inflammation, and Th17 cells are critical mediators of disease pathogenesis. While targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic Th17 cell migration. Here, we report integrin α3 as a Th17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis, a mouse model of MS. CNS-infiltrating Th17 cells express high integrin α3, the expression of which is induced by transcription factors that are required for Th17 cell specification. The deletion integrin α3 in CD4+ T cells or IL-17A-fate-mapped cells attenuated disease severity. Mechanistically, integrin α3 promoted the polarization, proliferation, and transmigration of Th17 cells, and integrin α3-deficiency enhanced the retention of CD4+ T cells in the perivascular space of the blood-brain barrier. Notably, differential RNA-seq expression analysis revealed that Th17 cells continuously depend on integrin α3 to maintain Th17 cell identity and effector function. The requirement of integrin α3 in Th17 cell pathogenicity suggests integrin α3 as a therapeutic target for MS treatment.