scholarly journals Netrin-1 Ameliorates Postoperative Delirium-Like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood-Brain Barrier Permeability

2022 ◽  
Vol 14 ◽  
Author(s):  
Ke Li ◽  
Jiayu Wang ◽  
Lei Chen ◽  
Meimei Guo ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Blood Brain Barrier ◽  
Postoperative Delirium ◽  
Axonal Guidance ◽  
Brain Barrier ◽  
Cell Junction ◽  
Chromosomal Protein ◽  
Neuroprotective Effects ◽  
Aged Mice ◽  
Blood Brain

Postoperative delirium (POD) is a common and serious postoperative complication in elderly patients, and its underlying mechanism is elusive and without effective therapy at present. In recent years, the neuroinflammatory hypothesis has been developed in the pathogenesis of POD, in which the damaged blood-brain barrier (BBB) plays an important role. Netrin-1 (NTN-1), an axonal guidance molecule, has been reported to have strong inflammatory regulatory and neuroprotective effects. We applied NTN-1 (45 μg/kg) to aged mice using a POD model with a simple laparotomy to assess their systemic inflammation and neuroinflammation by detecting interleukin-6 (IL-6), interleukin-10 (IL-10), and high mobility group box chromosomal protein-1 (HMGB-1) levels. We also assessed the reactive states of microglia and the permeability of the BBB by detecting cell junction proteins and the leakage of dextran. We found that a single dose of NTN-1 prophylaxis decreased the expression of IL-6 and HMGB-1 and upregulated the expression of IL-10 in the peripheral blood, hippocampus, and prefrontal cortex. Nerin-1 reduced the activation of microglial cells in the hippocampus and prefrontal cortex and improved POD-like behavior. NTN-1 also attenuated the anesthesia/surgery-induced increase in BBB permeability by upregulating the expression of tight junction-associated proteins such as ZO-1, claudin-5, and occludin. These findings confirm the anti-inflammatory and BBB protective effects of NTN-1 in an inflammatory environment in vivo and provide better insights into the pathophysiology and potential treatment of POD.

scholarly journals Netrin-1 Ameliorates Postoperative Delirium-like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood Brain Barrier Permeability

2020 ◽  
Author(s):  
Ke Li ◽  
Jiayu Wang ◽  
Lei Chen ◽  
Meimei Guo ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Blood Brain Barrier ◽  
Postoperative Delirium ◽  
Axonal Guidance ◽  
Brain Barrier ◽  
Cell Junction ◽  
Chromosomal Protein ◽  
Neuroprotective Effects ◽  
Aged Mice ◽  
Blood Brain

Abstract Background Postoperative delirium (POD) is a common and serious postoperative complication in elderly patients, of which the underlying mechanism is elusive and without effective therapy at present. In recent years, the neuroinflammatory hypothesis has been developed in the pathogenesis of POD. Netrin-1, an axonal guidance molecule, has been reported to have strong inflammatory regulatory and neuroprotective effects.Methods We applied treatment with Netrin-1(45 µg/kg) in aged mice by using the POD model with a simple laparotomy to assess systemic inflammatory, neuroinflammation by detecting interleukin-6 (IL-6), interleukin-10 (IL-10), high mobility group box chromosomal protein-1(HMGB-1) and assessing the reactive states of microglia, permeability of blood-brain barrier (BBB) by detecting cell junction proteins and leakage of dextran, and behavior of the aged mice.Results We found that a single dose of Netrin-1 prophylaxis decreased the expression of IL-6 and HMGB-1, and upregulated the expression of IL-10 in peripheral blood, hippocampus and prefrontal cortex. Nerin-1 reduced activation of microglia cells in the hippocampus and prefrontal cortex and improved the POD-like behavior. Besides, Netrin-1 also attenuated the anesthesia/surgery-induced increase in BBB permeability by up-regulating the expression of tight junction-associated proteins such as ZO-1, claudin-5, and occludin.Conclusions These findings confirm the anti-inflammatory and BBB protective effects of Netrin-1 in an inflammatory environment in vivo and provide better insights into the pathophysiology and potential treatment of POD.

scholarly journals VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Zhezhe Sun ◽  
Mark Nyanzu ◽  
Su Yang ◽  
Xiaohong Zhu ◽  
Kankai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Blood Brain Barrier ◽  
High Mobility ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Nf Kappa B ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Area Of Interest ◽  
Blood Brain

Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

scholarly journals Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0222721 ◽  
Author(s):  
Kazuhito Mietani ◽  
Masahiko Sumitani ◽  
Toru Ogata ◽  
Nobutake Shimojo ◽  
Reo Inoue ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Postoperative Delirium ◽  
Axonal Damage ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals The Neuroprotective Effects of Necrostatin-1 on Subarachnoid Hemorrhage in Rats Are Possibly Mediated by Preventing Blood–Brain Barrier Disruption and RIP3-Mediated Necroptosis

2019 ◽  
Vol 28 (11) ◽  
pp. 1358-1372 ◽  
Author(s):  
Jingsen Chen ◽  
Hanghuang Jin ◽  
Hangzhe Xu ◽  
Yucong Peng ◽  
Liyong Jie ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Brain Barrier ◽  
New Drugs ◽  
Brain Barrier ◽  
Lesion Volume ◽  
Brain Swelling ◽  
Neuroprotective Effects ◽  
Pharmaceutical Therapy ◽  
Blood Brain

Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood–brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.

scholarly journals Polyphenols in Alzheimer’s Disease and in the Gut–Brain Axis

2020 ◽  
Vol 8 (2) ◽  
pp. 199 ◽  
Author(s):  
V. Prakash Reddy ◽  
Puspa Aryal ◽  
Sara Robinson ◽  
Raheemat Rafiu ◽  
Mark Obrenovich ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Polyphenolic Compounds ◽  
Brain Barrier ◽  
Bacterial Metabolism ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Bacterial Metabolites ◽  
Blood Brain

Polyphenolic antioxidants, including dietary plant lignans, modulate the gut–brain axis, which involves transformation of these polyphenolic compounds into physiologically active and neuroprotector compounds (called human lignans) through gut bacterial metabolism. These gut bacterial metabolites exert their neuroprotective effects in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also have protective effects against other diseases, such as cardiovascular diseases, cancer, and diabetes. For example, enterolactone and enterodiol, the therapeutically relevant polyphenols, are formed as the secondary gut bacterial metabolites of lignans, the non-flavonoid polyphenolic compounds found in plant-based foods. These compounds are also acetylcholinesterase inhibitors, and thereby have potential applications as therapeutics in AD and other neurological diseases. Polyphenols are also advanced glycation end product (AGE) inhibitors (antiglycating agents), and thereby exert neuroprotective effects in cases of AD. Thus, gut bacterial metabolism of lignans and other dietary polyphenolic compounds results in the formation of neuroprotective polyphenols—some of which have enhanced blood–brain barrier permeability. It is hypothesized that gut bacterial metabolism-derived polyphenols, when combined with the nanoparticle-based blood–brain barrier (BBB)-targeted drug delivery, may prove to be effective therapeutics for various neurological disorders, including traumatic brain injury (TBI), AD, and PD. This mini-review addresses the role of polyphenolic compounds in the gut–brain axis, focusing on AD.

Sign in / Sign up

Export Citation Format

Share Document