Acetylcholinesterase inhibitors reduce brain and blood interleukin‐1β production

Pollak, Yehuda; Gilboa, Adi; Ben-Menachem, Ofra; Ben‐Hur, Tamir; Soreq, Hermona; Yirmiya, Raz

doi:10.1002/ana.20454

Cited by 94 publications

(74 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The specificity of ARP 26 is supported by the finding that ASP 40 , the C-terminal peptide of AChE-S, failed to induce such effects. Thus, extended granulocytosis reflects cellular consequences unique to the AChE-R variant, compatible with recent reports that AChE-R suppression reduces the levels of proinflammatory cytokines in both rats (45) and Cynomolgus monkeys (46) and not as previously related exclusively to the sympathetic pathways (47).…”

Section: From Cortisol Induction To Ache-r C-terminal Cleavagesupporting

confidence: 88%

Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Grisaru¹,

Pick

Perry

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Glucocorticoid-initiated granulocytosis, excessive proliferation of granulocytes, persists after cortisol levels are lowered, suggesting the involvement of additional stress mediator(s). In this study, we report that the stress-induced acetylcholinesterase variant, AChE-R, and its cleavable, cell-penetrating C-terminal peptide, ARP, facilitate granulocytosis. In postdelivery patients, AChE-R-expressing granulocyte counts increased concomitantly with serum cortisol and AChE activity levels, yet persisted after cortisol had declined. Ex vivo, mononuclear cells of adult peripheral blood responded to synthetic ARP26 by overproduction of hemopoietically active proinflammatory cytokines (e.g., IL-6, IL-10, and TNF-α). Physiologically relevant ARP26 levels promoted AChE gene expression and induced the expansion of cultured CD34+ progenitors and granulocyte maturation more effectively than cortisol, suggesting autoregulatory prolongation of ARP effects. In vivo, transgenic mice overexpressing human AChE-R, unlike matched controls, showed enhanced expression of the myelopoietic transcription factor PU.1 and maintained a stable granulocytic state following bacterial LPS exposure. AChE-R accumulation and the consequent inflammatory consequences can thus modulate immune responses to stress stimuli.

show abstract

Section: From Cortisol Induction To Ache-r C-terminal Cleavagesupporting

confidence: 88%

Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Grisaru¹,

Pick

Perry

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Brain and spinal cord samples collected at various times postinfection were homogenized in PBS and centrifuged for 15 min (300 ϫ g) at 4°C (48). The samples at each time point were then pooled for each genotype (n Ն 4 for each time point), and the levels of IL-1␤, TNF-␣, and IL-6 were determined using mouse IL-1␤, TNF-␣, and IL-6 enzyme immunoassay (EIA) kits (BioSource, Camarillo, CA) according to the manufacturer's recommendations.…”

Section: Methodsmentioning

confidence: 99%

Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

Griffin

2006

J Virol

View full text Add to dashboard Cite

Sindbis virus (SV), an enveloped virus with a single-stranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family. In mice, SV infects neurons and can cause apoptosis of immature neurons. Sphingomyelin (SM) is the most prevalent cellular sphingolipid, is particularly abundant in the nervous systems of mammals, and is required for alphavirus fusion and entry. The level of SM is tightly regulated by sphingomyelinases. A defect in acid sphingomyelinase (ASMase) results in SM storage and subsequent intracellular accumulation of SM. To better understand the role of the SM pathway in SV pathogenesis, we have characterized SV infection of transgenic mice deficient in the ASMase gene. ASMase knockout (ASM-KO) mice were more susceptible to SV infection than wild-type (WT) or heterozygous (Het) animals. Titers of SV were higher in the brains of ASM-KO mice than in the brains of WT mice. More SV RNA was detected by in situ hybridization, more SV protein was detected by immunohistochemistry, and more terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were present in the cortex and hippocampus of ASM-KO mice than in those of WT or Het mice. Interleukin-6 (IL-6), but not IL-1␤ or tumor necrosis factor alpha, was elevated in infected ASM-KO mice compared to levels in WT or Het mice, but studies with IL-6-KO mice and recombinant SV expressing IL-6 showed no role for IL-6 in fatal disease. Together these data indicate that the increase in susceptibility of ASM-KO mice to SV infection was the result of more-rapid replication and spread of SV in the nervous system and increased neuronal death.Sindbis virus (SV), an enveloped virus with a singlestranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family (60). In nature, SV cycles between mosquito and avian vertebrate hosts, producing a lifelong infection in mosquitoes and transient infection in vertebrates. In humans, SV infection can cause fever, rash, and arthritis. In mice, SV causes encephalomyelitis, and neurons in the brain and spinal cord are the primary target cells. The severity of infection in mammals depends on both virus and host factors (20, 32) and makes SV an excellent model to study the pathogenesis of virus-induced encephalomyelitis.Cellular lipids play an important role in several aspects of alphavirus replication, but the roles of specific lipids and their interactions with cellular proteins are not clear (22,53,56). The plasma membranes of eukaryotic cells consist primarily of sphingolipids, glycerophospholipids, and cholesterol (16). Sphingomyelin (SM), comprised of a highly hydrophobic ceramide moiety and a hydrophilic phosphorylcholine head group, is the most prevalent cellular sphingolipid, is particularly abundant in the nervous system, and is often associated with cholesterol (16, 50). Hydrogen bonds and hydrophobic interactions mediate tight interactions between the cholesterol sterol ring system and the ceramide moiety of SM (16,50,54). The lateral association of...

show abstract

“…Whether the same balance between injury and repair applies to functional rather than structural alterations in neurons as a consequence of microglial activation is still unknown. Another strategy that applies to inflammatory processes both at the periphery and in the brain is to dampen cytokine production by enhancing cholinergic neurotransmission (Pollak et al, 2005;Tracey, 2007).…”

Section: Identification Of Possible Targets For Interventionmentioning

confidence: 99%

Identification and treatment of symptoms associated with inflammation in medically ill patients

Dantzer

Capuron

Irwin

et al. 2008

Psychoneuroendocrinology

Self Cite

View full text Add to dashboard Cite

Medically ill patients present with a high prevalence of non-specific comorbid symptoms including pain, sleep disorders, fatigue and cognitive and mood alterations that is a leading cause of disability. However, despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of these symptoms in inflammatory conditions, little has been done to translate this newly acquired knowledge to the clinics and to identify appropriate therapies. In a multidisciplinary effort to address this problem, clinicians and basic scientists with expertise in areas of inflammation, psychiatry, neurosciences and psychoneuroimmunology were brought together in a specialized meeting organized in Bordeaux, France, on May 28-29, 2007. These experts considered key questions in the field, in particular those related to identification and quantification of the predominant symptoms associated with inflammation, definition of systemic and central markers of inflammation, possible domains of intervention for controlling inflammation associated symptoms, and relevance of animal models of inflammation associated symptoms. This

show abstract

Acetylcholinesterase inhibitors reduce brain and blood interleukin‐1β production

Cited by 94 publications

References 19 publications

Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

Identification and treatment of symptoms associated with inflammation in medically ill patients

Contact Info

Product

Resources

About