(Mercury exposure has been linked to CNS damage.)

12. LPS and mercury exposure:
1: Clin Exp Immunol. 2005 Aug;141(2):238-47.

Bacterial lipopolysaccharide both renders resistant mice susceptible to
mercury-induced autoimmunity and exacerbates such autoimmunity in susceptible
mice.

Abedi-Valugerdi M, Nilsson C, Zargari A, Gharibdoost F, DePierre JW, Hassan M.

Department of Biochemistry and Biophysics, Arrhenius Laboratories for the
Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
abedi@dbb.su.se

The initiation and severity of systemic autoimmune diseases are influenced by a
variety of genetic and environmental factors, in particular bacterial infections
and products. Here, we have employed bacterial lipopolysaccharide (LPS), which
non-specifically activates the immune system, to explore the involvement of
innate immunity in mercury-induced autoimmunity in mice. Following treatment of
mouse strains resistant [DBA/2 (H-2(d))] or susceptible [SJL(H-2(s))] to such
autoimmunity with mercuric chloride and/or LPS or with physiological saline
alone (control), their immune/autoimmune responses were monitored. Resistant
DBA/2 mice were rendered susceptible to mercury-induced autoimmunity by
co-administration of LPS, exhibiting pronounced increases in the synthesis of
IgG1 and IgE, high titres of IgG1 deposits in the kidneys and elevated
circulating levels of IgG1 antibodies of different specificities. Furthermore,
the percentages of the T cells isolated from the spleens of DBA/2 mice exposed
to both mercury and LPS that produced pro-inflammatory cytokines were markedly
increased by in vitro stimulation with phorbol myristate acetate (PMA) and
ionomycin, which was not the case for splenic T cells isolated from mice
receiving mercuric chloride, LPS or saline alone. In addition, exposure of
susceptible SJL mice to mercury in combination with LPS aggravated the
characteristic features of mercury-induced autoimmunity, including increased
synthesis of IgG1 and IgE, the production of IgG1 anti-nucleolar antibodies
(ANolA) and the formation of renal deposits of IgG1. In summary, our findings
indicate that activation of the innate immune system plays a key role in both
the induction and severity of chemically induced autoimmunity.

PMID: 15996188 [PubMed - indexed for MEDLINE]

(Changes in behaviour result from early exposure to LPS. In particular, Parkies react to stress producing situations in such a manner that symptoms are worsened. More intriguingly, Parkies may react to anxiety producing situations by “taking charge” or “assuming responsibility” as a strategy to reduce the anxiety caused by lack of control.)

13. LPS and “Parkinson’s personality”:

1: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5645-50.

Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function
and predisposition to inflammation.

Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, Lightman SL.

Division of Medicine, University of Bristol, Bristol Royal Infirmary Labs,
Marlborough Street, Bristol, BS2 8HW, United Kingdom. N.Shanks@bristol.ac.uk

We have investigated whether exposure to Gram-negative bacterial endotoxin in
early neonatal life can alter neuroendocrine and immune regulation in adult
animals. Exposure of neonatal rats to a low dose of endotoxin resulted in
long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with
elevated mean plasma corticosterone concentrations that resulted from increased
corticosterone pulse frequency and pulse amplitude. In addition to this marked
effect on the development of the HPA axis, neonatal endotoxin exposure had
long-lasting effects on immune regulation, including increased sensitivity of
lymphocytes to stress-induced suppression of proliferation and a remarkable
protection from adjuvant-induced arthritis. These findings demonstrate a potent
and long-term effect of neonatal exposure to inflammatory stimuli that can
program major changes in the development of both neuroendocrine and
immunological regulatory mechanisms.

PMID: 10779563 [PubMed - indexed for MEDLINE]

1: Behav Brain Res. 2004 Sep 23;154(1):63-9.

Endotoxin exposure in early life alters the development of anxiety-like
behaviour in the Fischer 344 rat.

Walker FR, March J, Hodgson DM.

Laboratory of Neuroimmunology, School of Behavioural Sciences, University of
Newcastle, Newcastle 2308, NSW, Australia. rohan.walker@newcastle.edu.au

Previous research in the rat has demonstrated that neonatal exposure to
bacterial endotoxin alters the level of anxiety-like behaviour displayed in
adulthood. Currently, however, little is known about the emergence and
development of this type of behaviour. Given the ability of neonatal endotoxin
exposure to alter neural substrates involved in regulating anxiety, we tested
the hypothesis that it may also alter the developmental trajectory of
anxiety-like behaviour in the rat. Male Fischer 344 neonatal rats were treated
with endotoxin (0.05 mg/kg lipopolysaccharide from Salmonella enteriditis) or
vehicle on postnatal days 3 and 5. Age related changes in anxiety-like behaviour
were subsequently investigated using the elevated plus maze apparatus at three
developmental time points; adolescence (43 days), adulthood (80 days) and
senescence (400 days). Neonatal endotoxin exposure was found to significantly
increase circulating levels of corticosterone on postnatal days 3 and 5 at 4 h
postadministration (P < 0.05). Additionally, endotoxin exposure was found to
markedly alter anxiety-like behaviour in adulthood and senescence (P < 0.05).
Specifically, adult and senescent endotoxin treated animals displayed
significantly more anxiety-like behaviour than vehicle treated controls.
Interestingly no significant differences in anxiety-like behaviour were observed
between treatment groups during adolescence. These findings highlight the
importance of the early life microbial environment in the development of
emotional behaviour and suggests that neonatal infection may be an important
predictor of susceptibility to anxiety related disorders in adult life.

PMID: 15302111 [PubMed - indexed for MEDLINE]



1: J Endotoxin Res. 2003;9(1):3-24.

Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis.

Beishuizen A, Thijs LG.

Department of Intensive Care, VU University Medical Center, Amsterdam, The
Netherlands. beishuizen@vumc.nl

Endotoxin is considered to be a systemic (immunological) stressor eliciting a
prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The
HPA-axis response after an endotoxin challenge is mainly due to released
cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells,
which in turn stimulate different levels of the HPA axis. Controversy exists
regarding the main locus of action of endotoxin on glucocorticoid secretion,
since the effect of endotoxin on this neuro-endocrine axis has been observed in
intact animals and after ablation of the hypothalamus; however, a lack of LPS
effect has been described at both pituitary and adrenocortical levels. The
resulting increase in adrenal glucocorticoids has well-documented inhibitory
effects on the inflammatory process and on inflammatory cytokine release.
Therefore, immune activation of the adrenal gland by endotoxin is thought to
occur by cytokine stimulation of corticosteroid-releasing hormone (CRH)
production in the median eminence of the hypothalamus, which, in turn stimulates
the secretion of ACTH from the pituitary. Acute administration of endotoxin
stimulates ACTH and cortisol secretion and the release of CRH and vasopressin
(AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of
both immune and HPA function develops, with a crucial role for glucocorticoids
in the modulation of the HPA axis. A single exposure to a high dose of LPS can
induce a long-lasting state of tolerance to a second exposure of LPS, affecting
the response of plasma TNF-alpha and HPA hormones. Although there are gender
differences in the HPA response to endotoxin and IL-1, these responses are
enhanced by castration and attenuated by androgen and estrogen replacement.
Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-alpha and
IL-1ra release and subsequent activation in postmenopausal women. There appears
to be a temporal and functional relation between the HPA-axis response to
endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus,
suggesting a stimulatory role for nitric oxide in modulating the HPA response to
immune challenges.

Publication Types:
Review

PMID: 12691614 [PubMed - indexed for MEDLINE]

(Manganese exposure has long been linked to parkinsonism although the mechanism of action has been unknown.)

14. LPS and manganese-induced parkinsonism:

1: Toxicol Sci. 2005 Mar;84(1):139-48. Epub 2004 Dec 15.

Manganese potentiates in vitro production of proinflammatory cytokines and
nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism.

Filipov NM, Seegal RF, Lawrence DA.

Wadsworth Center, New York State Department of Health, Albany, New York 11201,
USA. filipov@cvm.msstate.edu

Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity
involves activation of microglia and/or astrocytes; as a consequence, neurons
adjacent to the activated microglia may be injured. Mn modulation of
proinflammatory cytokine expression by microglia has not been investigated.
Therefore, the objectives of this research were to (1) assess whether Mn induces
proinflammatory cytokine expression and/or modulates lipopolysaccharide
(LPS)-induced expression of proinflammatory cytokines and (2) investigate
possible mechanisms for such an induction. N9 microglia were exposed in vitro to
increasing concentrations (50-1000 microM) of Mn in the presence or absence of
LPS (10, 100, or 500 ng/ml). After various incubation times (up to 48 h), media
levels of several cytokines and nitric oxide (NO) were determined, as was the
expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase
(LDH) release into the medium and the cellular uptake of Neutral Red were used
as general measures for cytotoxicity. In the absence of LPS, Mn moderately
increased interleukin-6 and tumor necrosis factor alpha (TNF-a) production only
at higher Mn concentrations, which were cytotoxic. At all LPS doses, however,
proinflammatory cytokine production was dose-dependently increased by Mn.
Similarly, LPS-induced NO production and iNOS expression were substantially
enhanced by Mn. Pharmacological manipulations indicated that nuclear factor
kappa B (NFkappaB) activation is critical for the observed enhancement of
cytokine and NO production. Within the context of inflammation, increased
production of proinflammatory cytokines and NO by Mn could be an important part
of the mechanism by which Mn exerts its neurotoxicity.

PMID: 15601679 [PubMed - indexed for MEDLINE]

1: Neurochem Int. 2006 Jul;49(1):62-71. Epub 2006 Feb 20.

Manganese modulates pro-inflammatory gene expression in activated glia.

Chen CJ, Ou YC, Lin SY, Liao SL, Chen SY, Chen JH.

Department of Education and Research, Taichung Veterans General Hospital,
Taichung, Taiwan; Institute of Biomedical Sciences, National Chung-Hsing
University, Taichung, Taiwan.

Redox-active metals are of paramount importance for biological functions. Their
impact and cellular activities participate in the physiological and
pathophysiological processes of the central nervous system (CNS), including
inflammatory responses. Manganese is an essential trace element and it is
required for normal biological activities and ubiquitous enzymatic reactions.
However, excessive chronic exposure to manganese results in neurobehavioral
deficits. Recent evidence suggests that manganese neurotoxicity involves
activation of microglia or astrocytes, representative CNS immune cells. In this
study, we assessed the molecular basis of the effects of manganese on the
modulation of pro-inflammatory cytokines and nitric oxide (NO) production in
primary rat cortical glial cells. Cultured glial cells consisted of 85% of
astrocytes and 15% of microglia. Within the assayed concentrations, manganese
was unable to induce tumor necrosis factor alpha (TNF-alpha) and inducible
nitric oxide synthase (iNOS) expression, whereas it potentiated iNOS and
TNF-alpha gene expression by lipopolysaccharide/interferon-gamma-activated glial
cells. The enhancement was accompanied by elevation of free manganese,
generation of oxidative stress, activation of mitogen-activated protein kinases,
and increased NF-kappaB and AP-1 binding activities. The potentiated degradation
of inhibitory molecule IkappaB-alpha was one of underlying mechanisms for the
increased activation of NF-kappaB by manganese. However, manganese decreased
iNOS enzymatic activity possibly through the depletion of cofactor since
exogenous tetrahydrobiopterin reversed manganese's action. These data indicate
that manganese could modulate glial inflammation through variable strategies.

PMID: 16488514 [PubMed - in process]


15. LPS and action of roetenone:

1: J Neurosci. 2003 Feb 15;23(4):1228-36.

Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen
lipopolysaccharide: relevance to the etiology of Parkinson's disease.

Gao HM, Hong JS, Zhang W, Liu B.

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National
Institute of Environmental Health Sciences/National Institutes of Health,
Research Triangle Park, North Carolina 27709, USA.

Parkinson's disease (PD) is characterized by a progressive degeneration of the
nigrostriatal dopaminergic pathway resulting in movement disorders. Although its
etiology remains unknown, PD may be the final outcome of interactions among
multiple factors, including exposure to environmental toxins and the occurrence
of inflammation in the brain. In this study, using primary mesencephalic
cultures, we observed that nontoxic or minimally toxic concentrations of the
pesticide rotenone (0.5 nm) and the inflammogen lipopolysaccharide (LPS) (0.5
ng/ml) synergistically induced dopaminergic neurodegeneration. The synergistic
neurotoxicity of rotenone and LPS was observed when the two agents were applied
either simultaneously or in tandem. Mechanistically, microglial NADPH
oxidase-mediated generation of reactive oxygen species appeared to be a key
contributor to the synergistic dopaminergic neurotoxicity. This conclusion was
based on the following observations. First, inhibition of NADPH oxidase or
scavenging of free radicals afforded significant neuroprotection. Second,
rotenone and LPS synergistically stimulated the NADPH oxidase-mediated release
of the superoxide free radical. Third and most importantly, rotenone and LPS
failed to induce the synergistic neurotoxicity as well as the production of
superoxide in cultures from NADPH oxidase-deficient animals. This is the first
demonstration that low concentrations of a pesticide and an inflammogen work in
synergy to induce a selective degeneration of dopaminergic neurons. Findings
from this study may be highly relevant to the elucidation of the multifactorial
etiology of PD and the discovery of effective therapeutic agents for the
treatment of the disease.

PMID: 12598611 [PubMed - indexed for MEDLINE]


16. LPS and protective role of minocycline:
1: Neurobiol Dis. 2004 Jun;16(1):190-201.

Minocycline reduces the lipopolysaccharide-induced inflammatory reaction,
peroxynitrite-mediated nitration of proteins, disruption of the blood-brain
barrier, and damage in the nigral dopaminergic system.

Tomas-Camardiel M, Rite I, Herrera AJ, de Pablos RM, Cano J, Machado A, Venero
JL.

Departamento de Bioquimica, Bromatologia, Toxicologia y Medicina Legal Facultad
de Farmacia, Universidad de Sevilla, E-41012-Seville, Spain.

We have evaluated the potential neuroprotectant activity of minocycline in an
animal model of Parkinson's disease induced by intranigral injection of
lipopolysaccharide. Minocycline treatment was very effective in protecting
number of nigral dopaminergic neurons and loss of reactive astrocytes at 7 days
postlesion. Evaluation of microglia revealed that minocycline treatment highly
prevented the lipopolysaccharide-induced activation of reactive microglia as
visualized by OX-42 and OX-6 immunohistochemistry. Short-term RT-PCR analysis
demonstrated that minocycline partially prevented the lipopolysaccharide-induced
increases of mRNA levels for interleukin-1alpha and tumor necrosis factor-alpha.
In addition, lipopolysaccharide highly induced protein nitration as seen by
3-nitrotyrosine immunoreactivity in the ventral mesencephalon. Minocycline
treatment strongly diminished the extent of 3-nitrotyrosine immunoreactivity. We
also found a direct correlation between location of IgG immunoreactivity-a
marker of blood-brain barrier disruption-and neurodegenerative processes
including death of nigral dopaminergic cells and reactive astrocytes. There was
also a precise spatial correlation between disruption of blood-brain barrier and
3-nitrotyrosine immunoreactivity. We discuss potential involvement of
lipopolysaccharide-induced formation of peroxynitrites and cytokines in the
pathological events in substantia nigra in response to inflammation. If
inflammation is proved to be involved in the ethiopathology of Parkinson's
disease, our data support the use of minocycline in parkinsonian patients.

PMID: 15207276 [PubMed - indexed for MEDLINE]


17. LPS and protective action of green tea:

1: J Neurosci Res. 2004 Dec 1;78(5):723-31.

(-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial
activation and protects against inflammation-mediated dopaminergic neuronal
injury.

Li R, Huang YG, Fang D, Le WD.

Health Science Center, Shanghai Institute for Biological Science, Chinese
Academy of Science, Shanghai Second Medical University, Shanghai, Peoples
Republic of China.

Microglial activation is believed to play a pivotal role in the selective
neuronal injury associated with several neurodegenerative disorders, including
Parkinson's disease (PD) and Alzheimer's disease. We provide evidence that
(-)-epigallocatechin gallate (EGCG), a major monomer of green tea polyphenols,
potently inhibits lipopolysaccharide (LPS)-activated microglial secretion of
nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) through the
down-regulation of inducible NO synthase and TNF-alpha expression. In addition,
EGCG exerted significant protection against microglial activation-induced
neuronal injury both in the human dopaminergic cell line SH-SY5Y and in primary
rat mesencephalic cultures. Our study demonstrates that EGCG is a potent
inhibitor of microglial activation and thus is a useful candidate for a
therapeutic approach to alleviating microglia-mediated dopaminergic neuronal
injury in PD.

PMID: 15478178 [PubMed - indexed for MEDLINE]


18. LPS and iron in PD:

1: Neuroscience. 2005;135(3):829-38. Epub 2005 Sep 13.

Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in
glia of the rat substantia nigra and induces locomotor deficits.

Zhang J, Stanton DM, Nguyen XV, Liu M, Zhang Z, Gash D, Bing G.

Department of Anatomy and Neurobiology, 310 Whitney Hendrickson Building,
University of Kentucky, Chandler Medical Center, 800 Rose Street, Lexington, KY
40536-0098, USA.

Increasing evidence suggests that abnormal iron handling may be involved in the
pathogenesis of Parkinson's disease. The present study investigates the role of
iron and the iron-storage protein ferritin in inflammation-induced degeneration
of dopaminergic neurons of the substantia nigra pars compacta. Injection of
lipopolysaccharide into the globus pallidus of young and middle-aged rats
substantially decreased tyrosine hydroxylase immunostaining in substantia nigra
pars compacta four weeks after injection. Loss of tyrosine hydroxylase
expression was accompanied by increased iron and ferritin levels in glial cells
of the substantia nigra pars reticulata. Despite greater increases in nigral
iron levels, ferritin induction was less pronounced in older rats, suggesting
the regulation of ferritin was compromised with age. Automated movement tracking
analyses showed that young rats recovered from LPS-induced locomotor deficits
within four weeks, yet older rats failed to improve on measures of speed and
total distance moved. Intrapallidal lipopolysaccharide injection also increased
expression of alpha-synuclein and ubiquitin in tyrosine hydroxylase-positive
neurons of the substantia nigra pars compacta. These results suggest that
pallidal inflammation significantly increases stress on dopamine-containing
neurons in the substantia nigra pars compacta. Alterations in nigral iron levels
and protein handing may increase the vulnerability of nigral neurons to
degenerative processes.

PMID: 16165292 [PubMed - indexed for MEDLINE]