The influence of LPS on the brain is immense. This webpage contains research articles concerning LPS and the following topics:

LPS produces changes in the amygdala and hippocampus.
LPS produces alterations in serotonin levels.
LPS causes degeneration and reduction in dopamine (DA) neurons
LPS exacerbates hippocampal damage induced by seizures
LPS affects cerebral blood flow
LPS results in degeneration of Myelin
LPS promotes excessive numbers of cholinergic neurons
LPS results in White Matter Damage

Changes in the amygdala and hippocampus.

"Over the past 10 years, high-tech research methods have begun to reveal neurological damage in some autistic individuals. One of the most important findings indicates specific damage in the limbic system, particularly in the amygdala and hippocampus."[20]
[From Steve Edelson, head of ARI]

Experiments that show LPS damaging the amygdala and hippocampus.

View this article in PubMed
1: Neuroimmunomodulation. 2002;10(1):40-6.
Attenuation of LPS-induced changes in synaptic activity in rat hippocampus by Vasogen's Immune Modulation Therapy.

* Nolan Y, * Minogue A, * Vereker E, * Bolton AE, * Campbell VA, * Lynch MA.

Department of Physiology, Trinity College, Dublin, Ireland.

Systemic injection of lipopolysaccharide (LPS) blocks the expression of long-term potentiation in the hippocampus of the rat. This is coupled with increased IL-1beta concentration and c-Jun NH(2)-terminal kinase activity, as well as an increase in the number of cells displaying apoptotic characteristics in the hippocampus. Vasogen's Immune Modulation Therapy (IMT) is a procedure involving intramuscular administration of syngeneic blood which has been exposed ex vivo to elevated temperature, oxidation and ultraviolet light. We report that Vasogen's IMT significantly abrogates these LPS-induced effects with a concomitant increase in the concentration of the anti-inflammatory cytokine IL-10. These data suggest that Vasogen's IMT may play a protective role against the deleterious effects of immune insults in the brain. Copyright 2002 S. Karger AG, Basel PMID: 12207162 [PubMed - indexed for MEDLINE]

The experiment below demonstrates that LPS affects the amygdala.
LPS administration caused a biochemical change in the amygdala: significant increase in CRH mRNA levels in the PVN and CeAMY. (CeAMY is an abriviation for central amygdala. )

To view this article in PubMed
1: Brain Res. 2006 May 17;1089(1):1-9. Epub 2006 May 2.
The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase.

* Akasaka S, * Nomura M, * Nishii H, * Fujimoto N, * Ueta Y, * Tsutsui M, * Shimokawa H, * Yanagihara N, * Matsumoto T.

Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) may be implicated in the biological responses of the central nervous system to immune stimuli. To elucidate the role of iNOS in the hypothalamo-pituitary axis in responses to endotoxemia, using iNOS knockout (KO) mice, we examined the levels of c-fos, a neural activational marker, and corticotropin-releasing hormone (CRH) gene transcription in the paraventricular nucleus (PVN) and central amygdala (CeAMY) during lipopolysaccharide (LPS)-induced endotoxemia. In addition, the serum adrenocorticotropic hormone (ACTH) levels were also examined during endotoxemia. Following the intraperitoneal administration of LPS (1 mg/kg), the levels of the c-fos gene expression significantly increased in the PVN and the CeAMY regardless of the genotype. However, the disruption of the iNOS gene resulted in a significant decrease in the c-fos gene induction in the PVN in comparison to that observed in control mice. LPS administration caused a significant increase in CRH mRNA levels in the PVN and CeAMY regardless of genotype. However, the LPS-induced upregulation of CRH mRNA was significantly attenuated in the PVN of iNOS KO mice in comparison to that in the control mice. In contrast, no such genotype differences in the neural activity or CRH gene transcription were observed in the CeAMY. The serum ACTH responses to LPS were also significantly blunted in the iNOS KO mice in comparison to the control mice. These results suggest that iNOS-derived NO may therefore play a stimulatory role in the activity of the hypothalamo-pituitary axis during endotoxemia.

PMID: 16631135 [PubMed - indexed for MEDLINE]

LPS produces alterations in serotonin levels.

View this article in PubMed
A role for serotonin in lipopolysaccharide-induced anorexia in rats.

* Hrupka BJ, * Langhans W.

Institute of Animal Sciences, Physiology and Animal Husbandry, Swiss Federal Institute of Technology, Schorenstrasse 16, Postfach, 8603, Schwerzenbach, Switzerland.

Rats consistently reduce their food intake following injection of bacterial lipopolysaccharides (LPS). Because LPS increases CNS serotonin (5-HT) turnover, and because increases in CNS 5-HT turnover are associated with a decrease in food intake, we conducted a series of studies to examine 5-HT's potential role in LPS-induced anorexia. Chronic CNS 5-HT depletion by cisterna magna (CM) administration of 5,7-dihydroxytryptamine (5,7-DHT) failed to attenuate LPS-induced (100 microg/kg, ip) anorexia. In subsequent experiments, LPS was injected at lights out (hour 0) and [8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT)] or N-CBZ-[(8beta)-1,6-dimethylergolin-8-yl]methylamine (metergoline) was injected at hour 5 - the time when LPS-treated rats become anorectic. Food intake was measured during the subsequent 2 h. In LPS-treated rats, 8-OH-DPAT (62.5, 125, or 250 microg/kg, sc) injection increased food intake. In a 2 x 2 factorial arrangement of LPS and 8-OH-DPAT, 125 microg/kg 8-OH-DPAT increased food intake significantly more in LPS-treated rats than in non-LPS-treated rats (significant LPS x 8-OH-DPAT interaction). In LPS-treated rats, 1 and 5 mg/kg metergoline significantly enhanced food intake. However, in a 2 x 2 arrangement of LPS and metergoline, 1 mg/kg metergoline failed to increase food intake in LPS and non-LPS-treated rats in two separate trials. The ability of the 5-HT(1A) receptor agonist 8-OH-DPAT to attenuate LPS-induced anorexia in rats supports a role of 5-HT in LPS-induced anorexia.

PMID: 11267641 [PubMed - indexed for MEDLINE]

Degeneration and reduction in dopamine (DA) neurons
Acute LPS injection produces both a reduction and a degeneration in dopamine (DA) neurons

DOPAMINE Below are some quotes from Wikipedia regarding the role of dopamine neurons in the substantia nigra.
View this article in Wikipedia

"The function of the dopamine neurons in the substantia nigra pars compacta is complex. "

"Dopamine neurons are thought to be involved in learning to predict which behaviours will lead to a reward (for example food or sex). In particular, it is suggested that dopamine neurons fire when a reward is greater than that previously expected; a key component of many reinforcement learning models. This signal can then be used to update the expected value of that action."

"Degeneration of pigmented neurons in this region is the principal pathology that underlies Parkinson's disease.".

" Pathological changes to the dopaminergic neurons of the pars compacta are also thought to be involved in schizophrenia (see the dopamine hypothesis of schizophrenia) and psychomotor retardation sometimes seen in clinical depression."

Article about LPS causing degeneration of dopaminergic neurons in substantia nigra.

View this article in PubMed
1: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006 Aug;26(8):715-8.
[Protective effects of triptolide on the lipopolysaccharide-mediated degeneration of dopaminergic neurons in substantia nigra]

* Li G, * Ma R, * Xu Y.

Department of Neurology, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022.

OBJECTIVE: To study the protective effects of triptolide (Tri) on the lipopolysaccharide (LPS)-mediated degeneration of dopaminergic neurons in substantia nigra. METHODS: Forty SD rats were randomly divided into four groups: the sham group, the LPS model group, the Tri group and the normal saline group, 10 in each group. Fourteen days later, the apomorphine-induced rotational behavior, the content of dopamine (DA) and its metabolites in the striatum of the injured side, the number of tyrosine-hydroxylase (TH) positive neurons and activation of microglia in rats were observed. RESULTS: Injection of LPS in substantia nigra could induce cerebral simulated immunoinflammatory reaction, leading to degeneration of dopaminergic neuron and induce ipsilateral directed rotational behavior of rats, which could be improved by Tri. Moreover, Tri could raise the lowered content of DA and its metabolites as well as the TH positive neurons in striatum, and suppress the activation of microglia significantly (P<0.01). CONCLUSION: Tri could protect the dopaminergic neurons from degeneration due to the inflammation mediated by LPS through inhibiting the activation of microglia.

PMID: 16970095 [PubMed - in process]

Article about LPS causing loss of dopamine (DA) neurons in the SN (substantia nigra ).

View this article in PubMed
1: Glia. 2007 Apr 1;55(5):453-62.
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

* Qin L, * Wu X, * Block ML, * Liu Y, * Breese GR, * Hong JS, * Knapp DJ, * Crews FT.

Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.

dopaminergic (DA) neurons dopamine (DA) neurons

LPS and seizures

While LPS by itself does not produce seizures, it contributes to seizures. A higher percentage of children with ASD have seizures but not all children with ASD have them.
View this article in PubMed
Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain.

* Sankar R,
* Auvin S,
* Mazarati A,
* Shin D.

Division of Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA and Mattel Children's Hospital at UCLA, Los Angeles, CA, USA.

Objective - The extent of neuronal injury in the hippocampus produced by experimental status epilepticus (SE) is age dependent and is not readily demonstrable in many models of neonatal seizures. Neonatal seizures often occur in clinical settings that include an inflammatory component. We examined the potential contributory role of pre-existing inflammation as an important variable in mediating neuronal injury. Materials and methods - Postnatal day 7 (P7) and P14 rat pups were injected with lipopolysaccharide (LPS), 2 h prior to SE induced by lithium-pilocarpine (LiPC). Neuronal injury was assessed by well-described histologic methods. Results - While LPS by itself did not produce any discernible cell injury at either age, this treatment exacerbated hippocampal damage induced by LiPC-SE. The effect was highly selective for the CA1 subfield. Conclusions - Inflammation can contribute substantially to the vulnerability of immature hippocampus to seizure-induced neuronal injury. The combined effects of inflammation and prolonged seizures in early life may impact long-term outcomes of neonatal seizures.

PMID: 17362271 [PubMed - in process]

LPS affects Cerebral blood flow

View this article in PubMed
J Cereb Blood Flow Metab. 2002 Oct;22(10):1262-70.

Cerebral blood flow and oxidative metabolism during human endotoxemia.

Moller K, Strauss GI, Qvist J, Fonsmark L, Knudsen GM, Larsen FS, Krabbe KS, Skinhoj P, Pedersen BK.

Department of Infectious Diseases, University Hospital Rigshospitalet, Copenhagen, Denmark.

The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO reactivity), and 90 minutes after an intravenous bolus of a reference endotoxin. Arterial TNF-alpha peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-alpha, interleukin (IL)-1beta, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-alpha during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism.

PMID: 12368665 [PubMed - indexed for MEDLINE]

Degeneration of Myelin

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Systemic injections of lipopolysaccharide accelerates myelin phagocytosis during Wallerian degeneration in the injured mouse spinal cord.

* Vallieres N, * Berard JL, * David S, * Lacroix S.

Department of Anatomy and Physiology, Laval University, Ste-Foy, Quebec, Canada.

The phagocytic cell response within the injured spinal cord is inefficient, allowing myelin debris to remain for prolonged periods of time within white matter tracts distal to the injury. Several proteins associated with this degenerating myelin are inhibitory to axon growth and therefore prevent severed axons from regenerating. Inflammatory agents such as lipopolysaccharide (LPS) can stimulate both the migration and phagocytic activity of macrophages. Using in situ hybridization, we found that the expression of the LPS membrane receptor, CD14, was enhanced in the mouse dorsal column following a dorsal hemisection. Double labeling studies showed that microglia and macrophages are the two major cell types expressing CD14 mRNA following spinal cord injury (SCI). We therefore tested whether systemic injections of LPS would increase the number and phagocytic activity of macrophages/microglia in the ascending sensory tract (AST) of the mouse dorsal column following a dorsal hemisection. Mice were treated daily via intraperitoneal injections of either LPS or phosphate-buffered saline (PBS). At 7 days post-SCI, greater numbers of activated mononuclear phagocytes were present in the AST undergoing Wallerian degeneration (WD) in LPS-treated animals compared with controls. Animals treated with LPS also exhibited greater Oil Red O staining, which is specific for degenerating myelin and macrophages phagocytosing myelin debris. Myelin clearance was confirmed at 7 days using Luxol Fast Blue staining and on toluidine blue-stained semi-thin sections. These results indicate that it is possible to manipulate the innate immune response to accelerate myelin clearance during WD in the injured mouse spinal cord. (c) 2005 Wiley-Liss, Inc.

PMID: 16206158 [PubMed - indexed for MEDLINE]

This article explains how the lipid A region of gram-negative bacterial lipopolysaccharides (LPS) binds with Myelin basic protein to alter the myelin and produce degeneration.

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1: J Immunol. 1981 Mar;126(3):1030-5.
Binding of bacterial endotoxin (LPS) to encephalitogenic myelin basic protein and modulation of characteristic biologic activities of LPS.

* Raziuddin S, * Morrison DC.

Myelin basic protein, isolated from central nervous system tissue and an inducer of experimental allergic encephalomyelitis in animals, has been demonstrated to form a stable molecular complex with the lipid A region of gram-negative bacterial lipopolysaccharides (endotoxins). This binding of endotoxin with myelin basic protein results in generation of lower m.w. aggregates with decreased isopycnic density. A number of lipid A-induced characteristic properties of endotoxin, such as B lymphocyte proliferative response in C3H/St mice, complement activation of normal human serum, Limulus lysate gelation, and lethal effects in mice, are modified as a result of binding of myelin basic protein with lipopolysaccharides.

PMID: 6161956 [PubMed - indexed for MEDLINE]

Cholinergic Receptors

Read an easy to understand article about cholinergic neurons.
"Cholinergic nicotinic receptors, which have become a hot area for brain researchers, are linked to yet another psychiatric-neurological disorder-autism."

Read a research article about cholinergic neurons.

Article that links LPS to cholinergic neurons.

View this article in PubMed
1: Pediatr Res. 2007 Jan;61(1):15-20.
Toll-like receptor ligands and CD154 stimulate microglia to produce a factor(s) that promotes excess cholinergic differentiation in the developing rat basal forebrain: implications for neurodevelopmental disorders.

* Ni L, * Acevedo G, * Muralidharan B, * Padala N, * To J, * Jonakait GM.

Federated Department of Biological Sciences, NJ Institute of Technology and Rutgers University, Newark, NJ 07102, USA.

Maternal inflammation plays a role in the etiology of certain neurodevelopmental disorders including autism and schizophrenia. Because maternal inflammation can lead to activation of fetal microglia, we have examined effects of inflamed microglia on cultured neural progenitors from rat embryonic septal region and basal forebrain. These cells give rise to cholinergic neurons projecting to cortex and hippocampus. Microglia stimulated with lipopolysaccharide (LPS), peptidoglycan, Poly I:C and CD154 produce conditioned media (CM) that promotes excessive numbers of cholinergic neurons and levels of choline acetyltransferase (ChAT) activity 6-8 times that of untreated cultures. Expression of the neural-specific transcription factor MATH1 increases substantially within 1 h of plating in LPS-CM. Untreated cultures do not attain equivalent levels until 6 h. By contrast, expression of glial-related transcription factors in LPS-CM-treated cultures never attains the elevated levels of untreated cultures. LPS-CM-treated clones derived from individual progenitors labeled with a LacZ-expressing retrovirus showed >2.5-fold increase in the percentage of cholinergic cells compared with untreated clones. Thus, CM from activated microglia prompts excess cholinergic differentiation from undifferentiated progenitors suggesting that microglial inflammation during critical stages can lead to aberrant brain development.

PMID: 17211134 [PubMed - indexed for MEDLINE]

White Matter Damage and LPS

Problems with white matter in the brains of ASD kids are currently attracting much attention both in research and in the media.

View a news release about white matter and autism

View an article in Discover Magazine about white matter and autism
Harvard professor Herbert is quoted as saying: "Each child’s path to autism may be distinct but they may share common inflammatory abnormalities". She has shown through morphometric brain imaging that white matter—which carries impulses between neurons—is larger in children with autism.

“It was the most absolutely outstanding piece of information in all the brain data I looked at,” Herbert recalls of the years 2001 and 2002, when she was analyzing this brain imaging data. “People were saying, don’t look at the white matter, look at the cerebral cortex, but I knew we had an important finding.”

Articles that shows the connection between LPS and white matter injury:

1: Ment Retard Dev Disabil Res Rev. 2002;8(1):30-8.
Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults.

* Hagberg H, * Peebles D, * Mallard C.

Perinatal Center, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Goteberg, Sweden.

White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.

PMID: 11921384 [PubMed - indexed for MEDLINE]

View this article in PubMed
Long-term changes in blood-brain barrier permeability and white matter following prolonged systemic inflammation in early development in the rat.

* Stolp HB, * Dziegielewska KM, * Ek CJ, * Potter AM, * Saunders NR.

Department of Pharmacology, University of Melbourne, Parkville, VIC 3010, Australia.

Epidemiological evidence in human fetuses links inflammation during development with white matter damage. Breakdown of the blood-brain barrier has been proposed as a possible mechanism. This was investigated in the present study by inducing a prolonged inflammatory response in newborn rats, with intraperitoneal injections of lipopolysaccharide (LPS; 0.2 mg/kg) given at postnatal (P) day 0, P2, P4, P6 and P8. An acute phase response was present over the whole period of injections. Changes in blood-brain barrier permeability were determined for small (sucrose and inulin) and large (protein) molecules. During and immediately after the inflammatory response, plasma proteins were detected in the brain only within white matter tracts, indicating an increased permeability of the blood-brain barrier to protein during this period. The alteration in permeability to protein was transient. In contrast, the permeability of the blood-brain barrier to 14C-sucrose and 14C-inulin was significantly higher in adult animals that had received serial LPS injections during development. Adult animals receiving a single 1 mg/kg LPS injection at P0 showed no alteration in blood-brain barrier permeability to either small or larger molecules. A significant decrease in the volume of CNPase immunoreactive presumptive white matter tracts occurred in the external capsule and corpus callosum at P9. These results demonstrate that a prolonged systemic inflammatory response in the early postnatal period in rats causes size selective increases in blood-brain barrier permeability at different stages of brain development and results in changes in white matter volume.

PMID: 16324115 [PubMed - indexed for MEDLINE]