Xiaosheng Tian

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.

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.

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.

Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells.

Hypoxia‐inducible factor (HIF)‐1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF‐1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over‐expression of HIF‐1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF‐1α decreased them. Meanwhile, HIF‐1α was shown to bind to histone deacetylase (HDAC)‐1 and reduced the association of HDAC‐1 with NEP promoter, thus activating NEP gene transcription in a de‐repression way. In summary, our results indicated that hypoxia in the early stages would up‐regulate NEP expression, in which interaction of HIF‐1α and HDAC‐1 may play a role. This study suggested that NEP up‐regulation might be an adaptive response to hypoxia, which was mediated by HIF‐1α binding to HDAC‐1 at the early stage of hypoxia.

High Manganese, A Risk for Alzheimer's Disease: High Manganese Induces Amyloid-β Related Cognitive Impairment

Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimers disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.

Phospholipid transfer protein (PLTP) deficiency accelerates memory dysfunction through altering amyloid precursor protein (APP) processing in a mouse model of Alzheimer's disease

Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in the transport of cholesterol and other lipids in the plasma and peripheral tissues. Recently, elevated amyloid β (Aβ) in young and aged PLTP-deficient brains had been reported. However, the role of PLTP in amyloid precursor protein (APP) processing and Alzheimers disease (AD) pathology remains elusive. Here we first found that deficiency of PLTP accelerated memory dysfunction in APP/PS1ΔE9 AD model mice at the age of 3 months. Further characterization showed that PLTP deficiency increased soluble Aβ peptides, and intracellular accumulation of Aβ was illustrated, which might be due to disrupted APP turnover and the enhanced amyloidogenic pathway. Besides, reduced brain-derived neurotrophic factor (BDNF) was found in PLTP-deficient APP/PS1ΔE9 mice, and the BDNF level was negatively correlated with Aβ42 content, instead of Aβ40 content. In addition, autophagic dysfunction was found in the PLTP-deficient APP/PS1ΔE9 mice. Our data presented a novel model to link phospholipid metabolism to APP processing and also suggested that PLTP played an important role in Aβ metabolism and would be useful to further elucidate functions of PLTP in AD susceptibility.

Impaired synaptic vesicle recycling contributes to presynaptic dysfunction in lipoprotein lipase-deficient mice

Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons, but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study, we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPL-deficient neurons, which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling, which is known to play an important role in maintaining the RRP size in active synapses, is impaired in LPL-deficient neurons. Moreover, lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice; exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from deficient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-deficient neurons.

Lipoprotein lipase deficiency leads to α-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction.

We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.