Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) is accompanied by chronic neuroinflammation and occurs with greater incidence in postmenopausal women. The increased incidence may be delayed by estrogen replacement therapy (ERT). The authors investigated the interaction of chronic ERT and lipopolysaccharide (LPS)-induced neuroinflammation in the female rat. Ovariectomy did not impair water maze performance; however, addition of chronic ERT or neuroinflammation resulted in an impairment that became exacerbated by the simultaneous occurrence of both conditions. Chronic LPS activated microglia, which was not reduced by ERT. Intact females receiving LPS infusion were not impaired in the water maze and had significantly fewer activated microglia. Results suggest that chronic ERT in postmenopausal women may exacerbate the memory impairment induced by the chronic neuroinflammation associated with AD.
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PMID:Long-term estrogen therapy worsens the behavioral and neuropathological consequences of chronic brain inflammation. 1236 9

Exposure to infectious agents during early postnatal life often alters glucocorticoid responses to stress and immune outcomes in adulthood. The authors examined whether neonatal infection results in memory impairments in adult animals. Rats infected with Escherichia coli (E. coli) as neonates displayed impaired memory for a recently explored context in adulthood. This impairment, however, was only observed in rats that received a peripheral immune challenge (lipopolysaccharide; LPS) immediately following context exposure. Adult rats treated neonatally with E. coli also had decreased hippocampal astrocytes compared with phosphate-buffered saline-treated rats, but displayed increased astrocyte reactivity in the hippocampus and decreased brain interleukin-1beta following lipopolysaccharide. Infection during development appears to alter glia within the hippocampus, which may contribute to altered cytokine responses and memory impairment.
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PMID:Neonatal infection induces memory impairments following an immune challenge in adulthood. 1572 33

We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.
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PMID:Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. 1613 57

Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.
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PMID:Immunity and behavior: antibodies alter emotion. 1640 5

We have reported that exposure to bacteria (Escherichia coli) during the neonatal period in rats is associated with impaired memory for a novel context in adulthood. However, impairment is only observed if a peripheral immune challenge (bacterial lipopolysaccharide (LPS)) is administered immediately following context exposure. The goal of the current study was to more fully characterize this phenomenon. In Experiment 1, memory impairment as a result of neonatal infection and subsequent LPS challenge was observed in juvenile rats, indicating that the changes induced by infection occur early on and are then manifest throughout the lifespan. In Experiment 2, infection in juvenile rats did not lead to LPS-induced memory impairment in adulthood, suggesting there is a critical period for early infection-induced alterations. In Experiments 3 and 4, memory for a novel context was impaired in neonatally infected rats, a task that is dependent on the hippocampus, whereas cued memory for a tone, which does not depend on the hippocampus, was not impaired. Furthermore, long-term, but not short-term contextual memory was impaired in adult rats infected as neonates following an LPS challenge either 24 h before or immediately after conditioning. Finally, in Experiment 5, no neonatal group differences were observed in corticosterone or open field behaviour, suggesting that decreased freezing to a conditioned context reflects impaired memory, and not simply hyperactivity or altered stress reactivity. Taken together, we have demonstrated that neonatal infection results in robust hippocampal-dependent memory impairment following an immune challenge in adulthood using a number of conditioning paradigms.
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PMID:A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats. 1641 67

We have previously demonstrated that bacterial infection (Escherichia coli) in neonatal rats is associated with impaired memory in a fear-conditioning task in adulthood. This impairment, however, is only observed if a peripheral immune challenge (lipopolysaccharide; LPS) is administered around the time of learning. We used a brief separation/handling paradigm to determine if the adult memory impairment associated with neonatal-infection could be prevented. Naturally occurring variations in maternal care promote striking variations in offspring cognitive development, and handling paradigms are used to manipulate the quality and quantity of maternal care. Rats were injected on post natal (P) day 4 with E. coli or PBS, and half from each group were handled for 15 min/day from P4 to 20. All rats were then tested in adulthood. Neonatal handling of rats infected as neonates prevented the increase in microglial cell marker reactivity within the hippocampus, and the exaggerated brain IL-1beta production to LPS normally produced by the infection. Thus, these neural processes were now comparable to levels of non-infected PBS controls. Furthermore, handling completely prevented LPS-induced memory impairment in a context-fear task in adult rats infected as neonates. Finally, neonatal handling dramatically improved spatial learning and memory and decreased anxiety in rats treated early with PBS, but had no beneficial effect on these measures in rats infected as neonates. Taken together, these data suggest that maternal care may profoundly influence neuroinflammatory processes in adulthood, and that infection may also prevent maternal care influences on cognition later in life.
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PMID:Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood. 1712 27

Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.
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PMID:Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. 1717 Jan 37

Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has led to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well-characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/h for 3 weeks) into the fourth ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for 3 weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the water maze task. Cannabinoid receptors 1 were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN-55212-2 on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.
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PMID:Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. 1717 96

Alzheimer's disease (AD) results in an impairment of memory and behavior. It is accepted that amyloid beta (A beta) peptides are responsible for the etiopathology of AD, but the precise signaling pathways leading to the disease have not been elucidated. In this study, we have investigated the role of cyclooxygenase-2 (COX-2) in A beta(1-42)-evoked memory impairment in mice. Moreover, the effect of systemic inflammation on A beta-dependent locomotor and memory disturbances has been evaluated. Twelve-month-old C57Bl6 mice were injected intracerebroventricularly (icv) with A beta(1-42) alone or simultaneously with intraperitoneal (ip) administration of lipopolysaccharide (LPS). Some mice also received COX-2 inhibitor, NS-398. Another group of mice was pretreated with LPS at 4 and 7 months of age, and then injected with A beta(1-42) at 12 months of age. All mice were subjected to behavioral tests one week after A beta administration. COX-2 protein level was analyzed in the hippocampus using immunochemical method. Our data demonstrated that A beta enhanced COX-2 protein level and decreased the locomotion and exploration in mice. Systemic inflammation elevated COX-2 immunoreactivity at an early stage after injection and intensified behavioral disturbances. Moreover, the object recognition in A beta-treated mice was significantly affected compared to control mice. The administration of LPS simultaneously with A beta worsened recognition performance. A COX-2 inhibitor protected mice against memory deficit and locomotor disturbances. In LPS-pretreated animals, A beta induced locomotor disturbances, but had no effect on memory and COX-2 level. Our results indicate that A beta evokes enhancement of COX-2 protein level and memory deficit. Systemic inflammation modulates A beta effect on the brain function. The COX-2 inhibitor protects the brain against A beta-induced memory disturbances.
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PMID:Inhibitor of cyclooxygenase-2 protects against amyloid beta peptide-evoked memory impairment in mice. 1755 94

The number of activated microglia increase during normal aging. Stimulation of endocannabinoid receptors can reduce the number of activated microglia, particularly in the hippocampus, of young rats infused chronically with lipopolysaccharide (LPS). In the current study we demonstrate that endocannabinoid receptor stimulation by administration of WIN-55212-2 (2mg/kg day) can reduce the number of activated microglia in hippocampus of aged rats and attenuate the spatial memory impairment in the water pool task. Our results suggest that the action of WIN-55212-2 does not depend upon a direct effect upon microglia or astrocytes but is dependent upon stimulation of neuronal cannabinoid receptors. Aging significantly reduced cannabinoid type 1 receptor binding but had no effect on cannabinoid receptor protein levels. Stimulation of cannabinoid receptors may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer's disease.
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PMID:Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. 1756 11


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