Zhengqian Li

Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats.

Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-κB signaling, and to explore its association with hippocampal interleukin (IL)-1β levels and anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in IκB kinase and IκB phosphorylation, as well as a reduction in the NF-κB inhibitory protein (IκBα), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-κB p65 nuclear translocation at 6h after isoflurane exposure and hippocampal IL-1β elevation from 1 to 6h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-κB activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1β increase and NF-κB signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal IL-1β, partially via activation of the canonical NF-κB pathway, in aged rats.

Prophylactic angiotensin type 1 receptor antagonism confers neuroprotection in an aged rat model of postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a common geriatric complication, although its exact neuropathogenesis remains elusive. Blockers of the renin-angiotensin system (RAS) ameliorate cognitive deficits in inflammatory brain disorders, with its effects on POCD not yet fully elucidated. The aim of the present study was to investigate regulation of the brain RAS and the effect of angiotensin II receptor type 1 (AT1) inhibition on surgery-induced cognitive impairment in a well-established rat POCD model. We observed upregulation of angiotensin II protein expression and AT1 subtype B transcript levels in the hippocampus after laparotomy, suggesting surgical stress activates the hippocampal RAS in aged rats. Chronic pretreatment with 0.1 mg/kg/day candesartan, an AT1 antagonist, significantly attenuated surgery-induced cognitive deficits in the Morris water maze task without altering blood pressure. Candesartan also decreased hippocampal blood-brain barrier (BBB) permeability. Concomitant with these functional benefits, we observed significant inhibition of hippocampal neuroinflammation, evidenced by decreased glial reactivity and phosphorylation of the NF-κB p65 subunit, as well as marked reductions in interleukin-1β, tumor necrosis factor-α, and cyclooxygenase-2. Our results are the first to show that activation of the brain RAS after surgery contributes to POCD in aged rats. Chronic treatment with low doses of candesartan may elicit blood pressure-independent neuroprotective effects in POCD by improving BBB function and promoting resolution of neuroinflammation.

Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast‐like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)‐21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL‐21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA‐FLS. We found that IL‐21 promoted the migration, invasion and MMP (MMP‐2, MMP‐3, MMP‐9, MMP‐13) production in RA‐FLS. Moreover, IL‐21 induced activation of the phosphoinositide 3‐kinase (PI3K), signal transducer and activator of transcription‐3 (STAT‐3) and extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT‐3 inhibitor STA‐21 and ERK1/2 inhibitor PD98059] attenuated IL‐21‐induced migration and secretion of MMP‐3 and MMP‐9. In conclusion, our results suggest that IL‐21 promotes migration and invasion of RA‐FLS. Therefore, therapeutic strategies targeting IL‐21 might be effective for the treatment of RA.

Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood–brain barrier in aged rats

The underlying mechanism of isoflurane-induced cognitive dysfunction in older individuals is unknown. In this study, the effects of isoflurane exposure on the hippocampal blood-brain barrier (BBB) in aged rats were investigated because it was previously shown that BBB disruption involves in cognitive dysfunction. Twenty-month-old rats randomly received 1.5% isoflurane or vehicle gas as control. Hippocampal BBB ultrastructure was analyzed by transmission electron microscopy and expression of tight junction proteins was measured by western blot analysis. BBB permeability was detected with sodium fluorescein extravasation and further confirmed by immunoglobulin G immunohistochemistry. Spatial learning and memory were assessed by the Morris water maze test. Isoflurane anesthesia resulted in reversible time-dependent BBB ultrastructure morphological damage and significant decreases in expression of the tight junction proteins occludin, which contributed to sodium fluorescein and IgG leakage. Rats with isoflurane exposure also showed significant cognitive deficits in the Morris water maze test. This in vivo data indicate that occludin down-regulation may be one of the mediators of isoflurane-induced hippocampus BBB disruption, and may contribute to hippocampus-dependent cognitive impairment after isoflurane exposure in aged rats.

Melatonin Attenuates Isoflurane-Induced Acute Memory Impairments in Aged Rats

Melatonin is an endogenous hormone with neuroprotective effects. Melatonin levels in elderly patients are reduced after surgeries that require anaesthesia. Whether reduced melatonin levels are important for postoperative cognitive dysfunction (POCD) remains unclear. Here, we investigated the effects of melatonin on cognitive dysfunctions induced by isoflurane and mechanisms underlying these effects. Seventy‐two 20‐month‐old Sprague–Dawley rats were randomly divided into six groups (n = 12). These groups included M1 and M10 groups that received intraperitoneal melatonin at 1 mg/kg or 10 mg/kg, respectively, and an ISO group that received 4 hr of inhaled 2% isoflurane. They also included M1+ISO and M10+ISO groups that received 1 mg/kg or 10 mg/kg of melatonin plus 4 hr of inhaled 2% isoflurane, respectively, and a control group that received an equal volume of saline. Injections were administered daily for 14 consecutive days. Memory was assessed in the Morris water maze. Plasma and hippocampi were harvested to determine melatonin concentrations and MT1/MT2 receptor expression. Rats treated only with isoflurane showed significantly longer latencies in Morris water maze test trials compared with the control group, with shorter time in the probe trial (p < 0.05). Although plasma melatonin levels and MT2 expression in the hippocampus were significantly decreased, MT1 expression was higher in the isoflurane group than in the control group (p < 0.001). However, these parameters did not significantly vary in animals administered melatonin compared with controls. Isoflurane may induce cognitive dysfunction by influencing melatonin and MT1/MT2 levels. Melatonin can improve cognitive dysfunction by normalizing plasma melatonin and its receptor levels.

The Inhibitory Effect of Altered Collagen II Peptide on HLA-DRB1-Restricted T-Cell Activation

It has been known that rheumatoid arthritis (RA)‐associated antigenic peptides CII263–272 are coupled with human leucocyte antigen (HLA)‐DRB1 and recognized by T‐cell receptor (TCR), which in turn induced T‐cell proliferation and pathogenesis of RA. Non‐T‐cell‐stimulating type II collagen (CII) peptides might be generated by removing the amino acids responsible for TCR contact and keeping the HLA‐DR‐binding residues intact. In this study, a panel of altered CII peptides (APs) with consecutive or single substitutions of the TCR‐contacting residues were synthesized. Through peptide binding and T‐cell activation assays, we demonstrated that altered CII263–272 peptides with substitution of the TCR‐contacting residues did not or barely induced T‐cell activation; one of the best non‐T‐cell‐stimulating peptide AP268–270 inhibited the binding of wild‐type CII263–272 to HLA‐DR1 and T‐cell activation triggered by wild‐type CII263–272 and HA306–318 in a dose–response manner. These data suggest that removal of the TCR‐contacting residues of CII263–272 leads to HLA‐DRB1 binding and low T‐cell‐stimulating peptides, which could potentially inhibit the T‐cell response induced by HLA‐DRB1‐binding antigenic peptides.

Surgical Stress Induces Brain‐Derived Neurotrophic Factor Reduction and Postoperative Cognitive Dysfunction Via Glucocorticoid Receptor Phosphorylation in Aged Mice

This study explored whether surgical stress‐induced glucocorticoid receptor (GR) phosphorylation is related to postoperative cognitive dysfunction (POCD) in aged individuals. Inhibition of GR activation could be an effective treatment for POCD.

Interleukin‐21 Induces Proliferation and Proinflammatory Cytokine Profile of Fibroblast‐like Synoviocytes of Patients with Rheumatoid Arthritis

Fibroblast‐like synoviocytes (FLS) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) through aggressive proliferation and invasion, and certain proinflammatory cytokines may affect synoviocyte proliferation. To evaluate whether interleukin‐21 (IL‐21) could promote proliferation and proinflammatory cytokine production by RA‐FLS, immunohistochemistry and immunoblotting were performed to observe the expression of IL‐21 receptor (IL‐21R) in synovial tissues and FLS from RA and osteoarthritis (OA) patients. The MTS assay was used to analyse RA‐FLS proliferation. The concentrations of IL‐6 and tumour necrosis factor‐α (TNF‐α) in culture supernatants were determined by enzyme‐linked immunosorbent assay (ELISA). The signalling pathways triggered by IL‐21 were characterized by immunoblotting. IL‐21R was upregulated in the synovial tissues and FLS of RA patients as compared with OA patients. IL‐21 stimulated RA‐FLS proliferation and promoted the production of TNF‐α and IL‐6 and blockade of IL‐21/IL‐21R pathway with IL‐21R.Fc attenuated IL‐21‐induced proliferation and secretion of TNF‐α and IL‐6. Moreover, IL‐21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL‐21‐induced proliferation and secretion of TNF‐α and IL‐6. These results suggest that IL‐21 could promote RA‐FLS proliferation and production of proinflammatory cytokines. Therefore, therapeutic strategies targeting IL‐21 might be effective for the treatment of RA.

Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats

Reversible blood-brain barrier (BBB) disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD). Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), as well as three of their endogenous tissue inhibitors of MMP (TIMP-1, -2, -3), and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II) and Ang II receptor type 1 (AT1) after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1), as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB) activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.

Protective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy

Post-operative cognitive dysfunction (POCD) is a commonly seen postoperative complication in elderly patients and its underlying mechanisms are still unclear. Autophagy, a degradation mechanism of cellular components, is required for cell survival and many physiological processes. Although propofol is one of the most commonly used intravenous anesthetics, investigations into its mechanisms and effects on cognition in aged rodents are relatively scarce. In this study, we evaluate the influence of propofol on learning and memory, and identify the potential role of hippocampal autophagy in propofol-induced cognitive alterations in aged rats. The results demonstrate that 4h propofol exposure significantly impaired cognitive performance through the inhibition of hippocampal autophagy. Diaminodiphenyl sulfone (dapsone, DDS), which was used as an anti-leprosy drug, has been found to have neuroprotective effects. We have previously demonstrated that DDS can improve surgical stress induced depression- and anxiety-like behavior. We therefore aimed to investigate the effects of DDS on propofol-induced cognitive dysfunction and associated hippocampal autophagy responses. Pretreatment with 5mg/kg or 10mg/kg body weight DDS significantly improved the behavioral disorder and upregulated the inhibited autophagic response in aged rats. Our exploration is the first to establish an in vivo link between central autophagy and cognitive dysfunction in aged hippocampus after propofol anesthesia and demonstrate that the prophylactic effect of DDS on the cognitive impairment induced by propofol involves autophagy. These findings may imply a potential novel target for the treatment in patients with propofol anesthesia-induced cognitive impairment.