Bacterial toxins and PD - Part 1
 

I apologize for the length of this, but it is just bits and bytes after all. I compiled all this a year ago as a follow-up to the work Ron Hutton and I had done on the role of H. pylori bacteria in PD. I was about to post it when the infamous BT collapse occurred and that venue where it might mean anything to someone disappeared. I thought this info had been lost until a couple of hours ago, when I found it hiding in an obscure neighborhood on my hard disk. Rather than let it go to waste I will post it here for any who are interested.

The gist of it is that there is a strong case to be made for inflammation induced by common bacteria as one of the primary causes and aggravating factors for PD. This isn't just academic interest because, if so, then it becomes very important to think about anti-inflammatory therapies both to prevent further damage and, most exciting of all, to lessen symptoms. After all, those diseases that cause inflammation of the brain such as encephalitis have symptoms from that swelling. Why would PD be any different. So, without further ado, I present the "Ben Hur" of reports: :)


Evidence for and implications of endotoxin-induced inflammatory origins of Parkinson’s disease (PD):

Hypothesis: Parkinson’s patients are part of a subset of the population who show a hypersensitivity to the endotoxin lipopolysaccharide (LPS) resulting from neonatal exposure and which results in a chronic inflammatory state in the brain. This inflammatory state results in both longterm damage to the substantia nigra (SN) and, perhaps more importantly, acute symptomology producing the typical Parkinson’s picture.

In addition to providing a plausible framework for the causes and effect leading to PD, this hypothesis explains many seemingly unrelated facts about the condition. Among them are the observed gender difference in PD, the finding of iron in the SN, the geographical limitation of damaged neurons to the SN, the nature of manganese induced parkinsonism, the sleep disturbances common in PD, the amplification of symptoms by stress, the elevated levels of cortisol common in PD, the role of mercury, the problem of mitochondrial function, etc.

In addition, numerous anecdotal reports by patients of temporary remission coinciding with use of drugs with known anti-inflammatory effects are explained by the hypothesis as are similar reports and epidemological data related to non-prescription medicines such as green tea, turmeric, alpha-lipoic-acid, etc.

No other proposed hypothesis for the origins and course of Parkinson’s disease comes close to explaining all of the above. Nor does any offer the hope of such a quick test of the basic concept. Simply reproducing the anecdotal information referred to above would immediately verify the broader principle. Similarly, a move to clinical trials and even actual treatment by way of “off label” use of already approved drugs should allow speedy implementation.

Bacterial toxins - Part 2
 

Evidence and Implications:

(Note: Multiple studies exist in virtually all the following cases. Only a few representative ones are shown. Also note that the dates on these studies indicate that this is relatively new thinking.)

1: Endotoxin (lipopolysaccharide) induced inflammation as primary factor in Parkinson’s disease:

(It should be noted that at least one author has suggested this concept previously without followup study.)

Occupational and Environmental Medicine 2003;60:378
© 2003 BMJ Publishing Group
LETTER
Endotoxin: is it an environmental factor in the cause of Parkinson’s disease?
I Niehaus1 and J H Lange2

1 Lübeck, Germany
2 Envirosafe Training and Consultants, Inc., PO Box 114022, Pittsburgh, PA 15239, USA; john.pam.lange@worldnet.att.net

Keywords: LPS; agriculture; environmental exposure; occupational health; substantia nigra

Occurrence of Parkinson’s disease (PD) has been reported to be associated with environmental factors, notably those associated with employment in the agricultural industry.1 Some have suggested that the agent associated with agriculture is pesticide exposure, although no specific class of pesticide has been identified.2

We suggest that besides pesticides, endotoxin (lipopolysaccaride, LPS) may also be an environmental factor. Endotoxin is a common airborne environmental and occupational contaminate in agricultural3 and other industries.4,5

Endotoxins are part of the outer cell wall of Gram negative bacteria.6 This agent can elicit a multitude of pathophysiological effects, including inflammation, macrophage activation, fever, and septic shock.7,8 The blood-brain barrier can become leaky as a result of sepsis,9 allowing LPS to enter the cerebrospinal fluid.

Experimentally, endotoxin has been shown to cause inflammation in the dopaminergic neurones of the substantia nigra, resulting in pathogenesis of PD.10,11 LPS stimulate astrocytes and microglia in the CNS to secrete cytokines such as TNF-{alpha}, IL-6, and IFN-{gamma}.10 Microglial activation preceded the apparent neuronal degeneration.11

One case study12 reported that a 22 year old laboratory worker developed Parkinson’s syndrome, with bradykinesia, rigidity, tremor, and cogwheel phenomenon, three weeks after accidental exposure to 10 µg Salmonella minnesota LPS through an open wound. The LPS caused a chronic inflammation in the nervous system (6600 pg LPS/ml cerebrospinal fluid), which was also characterised by neuralgic pain, polyneuropathy, and encephalopathy, with difficulties in short term memory, learning, and spatial orientation. Damage to the substantia nigra and cerebral cortex was shown by positron emission tomography.

In another case study13 a laboratory worker would have died without medical help because of severe sepsis after a single injection of 1 mg of Salmonella minnesota LPS. This shows the potency of endotoxin in physiological responses.

The case event of PD is supported by animal experimentation.14 Several animal studies10,11,14 have shown that LPS causes damage to the substantia nigra, resulting in PD. These animal investigations support the hypothesis that LPS may be one of the environmental factors that trigger PD. A recent study15 suggests that LPS may be an important contributor to exacerbation of inflammatory disease resulting from particulate matter associated with air pollution. This shows the diverse influences of LPS on physiological systems.

It is suggested that LPS is one of the causes for postencephalitic parkinsonism after encephalitis from Gram negative bacteria. These findings warrant further investigation of this potential environmental factor.

(It should be noted that one of the authors above – Niehaus – was, in fact, also the 22 year old case study mentioned. More detached researchers have also reached similar conclusions.)



1: Ann N Y Acad Sci. 2003 Jun;991:214-28.

The role of glial reaction and inflammation in Parkinson's disease.

Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP.

INSERM U289, Experimental Neurology and Therapeutics, Hopital de la Salpetriere,
75651 Paris Cedex 13, France. hirsch@ccr.jussieu.fr

The glial reaction is generally considered to be a consequence of neuronal death
in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease,
and Parkinson's disease. In Parkinson's disease, postmortem examination reveals
a loss of dopaminergic neurons in the substantia nigra associated with a massive
astrogliosis and the presence of activated microglial cells. Recent evidence
suggests that the disease may progress even when the initial cause of neuronal
degeneration has disappeared, suggesting that toxic substances released by the
glial cells may be involved in the propagation and perpetuation of neuronal
degeneration. Glial cells can release deleterious compounds such as
proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which may act by
stimulating nitric oxide production in glial cells, or which may exert a more
direct deleterious effect on dopaminergic neurons by activating receptors that
contain intracytoplasmic death domains involved in apoptosis. In line with this
possibility, an activation of proteases such as caspase-3 and caspase-8, which
are known effectors of apoptosis, has been reported in Parkinson's disease. Yet,
caspase inhibitors or invalidation of TNF-alpha receptors does not protect
dopaminergic neurons against degeneration in experimental models of the disease,
suggesting that manipulation of a single signaling pathway may not be sufficient
to protect dopaminergic neurons. In contrast, the antiinflammatory drugs
pioglitazone, a PPAR-gamma agonist, and the tetracycline derivative minocycline
have been shown to reduce glial activation and protect the substantia nigra in
an animal model of the disease. Inhibition of the glial reaction and the
inflammatory processes may thus represent a therapeutic target to reduce
neuronal degeneration in Parkinson's disease.

Publication Types:
Review

PMID: 12846989 [PubMed - indexed for MEDLINE]



1: J Neural Transm. 2005 Jan;112(1):111-9. Epub 2004 Mar 19.

Inflammatory process as a determinant factor for the degeneration of substantia
nigra dopaminergic neurons.

Herrera AJ, Tomas-Camardiel M, Venero JL, Cano J, Machado A.

Departamento de Bioquimica, Bromatologia, Toxicologia y Medicina Legal, Facultad
de Farmacia, Universidad de Sevilla, Spain.

The specific degeneration of dopaminergic neurons in the substantia nigra (SN)
is a pathological hallmark of Parkinson's disease (PD). Although the cause of
chronic nigral cell death in PD and its underlying mechanisms remain elusive,
substantial involvement of inflammatory events has been postulated since
inflammatory features have been described in parkinsonians CNS tissue. We have
developed an animal model of dopaminergic neurons degeneration by the single
intranigral injection of lipopolysaccharide (LPS), an inflammatory compound.
This single injection produced the induction of inflammatory process with the
activation of microglia along with the specific degeneration of dopaminergic
neurons in the SN without affecting neither other neurotransmitter systems nor
other structures of the CNS. Dexamethasone, a potent anti-inflammatory drug
preventing many of the features characterizing pro-inflammatory glial
activation, prevented the loss of dopaminergic cells. We also discuss other
inductors of inflammatory process in relationship to the dopaminergic
degeneration in the SN.

Publication Types:
Review

PMID: 15599609 [PubMed - indexed for MEDLINE]


1: Neurobiol Dis. 2000 Aug;7(4):429-47.

The single intranigral injection of LPS as a new model for studying the
selective effects of inflammatory reactions on dopaminergic system.

Herrera AJ, Castano A, Venero JL, Cano J, Machado A.

Departamento de Bioquimica, Bromatologia, Toxicologia, y Medicina Legal,
Universidad de Sevilla, Calle Prof., Garcia Gonzalez s/n, Sevilla, 41012, Spain.

We have injected lipopolysaccharide (LPS) into the nigrostriatal pathway of rats
in order to address the role of inflammation in Parkinson's disease (PD). LPS
induced a strong macrophage/microglial reaction in Substantia nigra (SN), with a
characteristic clustering of macrophage cells around blood-vessels. The SN was
far more sensitive than the striatum to the inflammatory stimulus. Moreover,
only the dopaminergic neurons of the SN were affected, with no detectable damage
to either the GABAergic or the serotoninergic neurons. The damage to the DA
neurons in the SN was permanent, as observed 1 year postinjection. Unlike the
direct death of dopaminergic neurons caused by agents as MPP(+) or 6-OHDA, LPS
seems to cause indirect death due to inflammatory reaction. Therefore, we
suggest that the injection of a single dose of LPS within the SN is an
interesting model for studying the selective effects of inflammatory reaction on
dopaminergic system and also potentially useful for studying PD. Copyright 2000
Academic Press.

PMID: 10964613 [PubMed - indexed for MEDLINE]


2: Neonatal exposure to lipopolysaccharide (LPS) as specific factor:

(Two pertinent effects have been noted thus far. One is the impact on the physical development of the brain including such effects as reduced neurons in the SN and alterations in the HPA axis. The other is the delayed initiation until adulthood of a hypersensitivity to the LPS.

The concept of microglial cells being “primed” or hypersensitized by previous exposure to LPS introduces the concept of an individual who reacts to even small dose exposures to LPS. This reaction leads to a state of constant inflammation in the brain.)


1: J Neurosci. 2005 Oct 5;25(40):9275-84.

Central and systemic endotoxin challenges exacerbate the local inflammatory
response and increase neuronal death during chronic neurodegeneration.

Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH.

CNS Inflammation Group, School of Biological Sciences, Southampton, Hampshire
SO16 7PX, United Kingdom. C.Cunningham@soton.ac.uk

The contribution of inflammation to the progression of neurodegenerative
diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly
understood. Brain inflammation in animal models of these diseases is dominated
by chronic microglial activation with minimal proinflammatory cytokine
expression. However, these inflammatory cells are "primed" to produce
exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS)
challenges. We show that, using the ME7 model of prion disease, intracerebral
challenge with LPS results in dramatic interleukin-1beta (IL-1beta) expression,
neutrophil infiltration, and inducible nitric oxide synthase expression in the
brain parenchyma of prion-diseased mice compared with the same challenge in
normal mice. Systemic inflammation evoked by LPS also produced greater increases
in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase
transcription in prion-diseased mice than in control mice and induced microglial
expression of IL-1beta. These systemic challenges also increased neuronal
apoptosis in the brains of ME7 animals. Thus, both central and peripheral
inflammation can exacerbate local brain inflammation and neuronal death. The
finding that a single acute systemic inflammatory event can induce neuronal
death in the CNS has implications for therapy in neurodegenerative diseases.

PMID: 16207887 [PubMed - indexed for MEDLINE]



1: J Neurochem. 2002 Jun;81(6):1285-97.

Microglial activation-mediated delayed and progressive degeneration of rat
nigral dopaminergic neurons: relevance to Parkinson's disease.

Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B.

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

The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing
evidence has suggested a role for inflammation in the brain in the pathogenesis
of PD. However, it has not been clearly demonstrated whether microglial
activation, the most integral part of the brain inflammatory process, will
result in a delayed and progressive degeneration of dopaminergic neurons in
substantia nigra, a hallmark of PD. We report here that chronic infusion of an
inflammagen lipopolysaccharide at 5 ng/h for 2 weeks into rat brain triggered a
rapid activation of microglia that reached a plateau in 2 weeks, followed by a
delayed and gradual loss of nigral dopaminergic neurons that began at between 4
and 6 weeks and reached 70% by 10 weeks. Further investigation of the underlying
mechanism of action of microglia-mediated neurotoxicity using rat mesencephalic
neuron-glia cultures demonstrated that low concentrations of lipopolysaccharide
(0.1-10 ng/mL)-induced microglial activation and production of neurotoxic
factors preceded the progressive and selective degeneration of dopaminergic
neurons. Among the factors produced by activated microglia, the NADPH
oxidase-mediated release of superoxide appeared to be a predominant effector of
neurodegeneration, consistent with the notion that dopaminergic neurons are
particularly vulnerable to oxidative insults. This is the first report that
microglial activation induced by chronic exposure to inflammagen was capable of
inducing a delayed and selective degeneration of nigral dopaminergic neurons and
that microglia-originated free radicals play a pivotal role in dopaminergic
neurotoxicity in this inflammation-mediated model of PD.

PMID: 12068076 [PubMed - indexed for MEDLINE]

Bacterial toxins - Part 3
 

3: LPS interaction with CNS:

(LPS not only induces inflammation into the brain, it also can interact directly with neurotransmitter activity.)


1: Immunology. 2004 Oct;113(2):224-33.

Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and
enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall
components.

Talreja J, Kabir MH, B Filla M, Stechschulte DJ, Dileepan KN.

Division of Allergy, Clinical Immunology, and Rheumatology, Department of
Medicine, The University of Kansas Medical Center, Kansas City, KS, USA.
jtalreja@kumc.edu

Histamine is a major inflammatory molecule released from the mast cell, and is
known to activate endothelial cells. However, its ability to modulate
endothelial responses to bacterial products has not been evaluated. In this
study we determined the ability of histamine to modulate inflammatory responses
of endothelial cells to Gram-negative and Gram-positive bacterial cell wall
components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the
co-operation between histamine and bacterial pathogens. Human umbilical vein
endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS),
lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of
histamine, and the expression and release of interleukin-6 (IL-6), and NF-kappaB
translocation were determined. The effect of histamine on the expression of mRNA
and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS,
LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6
secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but
it did not stimulate proportional IL-6 release. When HUVEC were incubated with
LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6
production and mRNA expression was noted. HUVEC constitutively expressed TLR2
and TLR4 mRNA and proteins, and these were further enhanced by histamine. The
expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated
with TLR signalling, were unchanged by histamine treatment. These results
demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and
amplifies endothelial cell inflammatory responses to Gram-negative and
Gram-positive bacterial components.

PMID: 15379983 [PubMed - indexed for MEDLINE]



(Sensitized individuals are not only at risk from acute infections but are also exposed to a steady micro-dose of LPS from resident bacteria. In addition to these, there are other chronic exposures.)

4: LPS and dental disease as constant source:

1: Life Sci. 2006 Mar 20;78(17):2012-8. Epub 2005 Nov 14.

Lipopolysaccharide stimulates the production of prostaglandin E2 and the
receptor Ep4 in osteoblasts.

Shoji M, Tanabe N, Mitsui N, Tanaka H, Suzuki N, Takeichi O, Sugaya A, Maeno M.

Department of Oral Health Sciences, Nihon University School of Dentistry,
1-8-13, Kanda Surugadai, Tokyo 101-8310, Japan.

Previous studies have indicated that one of the causes of alveolar bone
destruction with periodontitis is lipopolysaccharide (LPS) from the cell wall of
gram-negative bacteria in plaque, and that prostaglandin E(2) (PGE(2)) is one of
the bone resorption factors that stimulate osteoclast formation through an
intercellular interaction between osteoblasts and osteoclast precursors. The
present study was undertaken to determine the effect of LPS on cell growth,
alkaline phosphatase (ALPase) activity, the production of PGE(2), and the
expression of receptors by PGE(2), cyclooxygenase (COX)-1, and COX-2, using
human osteosarcoma cell line Saos-2 as osteoblasts. The cells were cultured with
0, 1, or 10 microg mL(-1) of LPS for up to 14 days. The production of PGE(2) and
the gene expression of COX-1, COX-2, and PGE(2) receptors, including Ep1, Ep2,
Ep3, and Ep4, were determined using enzyme-linked immunosorbent assay (ELISA)
and real-time reverse transcription-polymerase chain reaction (real-time
RT-PCR), respectively. With the addition of LPS, cell growth and ALPase activity
decreased by day 5 of the culture, while PGE(2) production increased in a
dose-dependent manner throughout the entire 14-day culture period. LPS-reduced
ALP activity and LPS-induced PGE(2) production returned to the control level by
the addition simultaneously with indomethacin. The expression of COX-1, Ep1,
Ep2, and Ep3 receptors decreased on day 14 of the culture, whereas the
expression of COX-2 and Ep4 receptors increased significantly with the addition
of LPS. These results suggest that LPS promotes PGE(2) production by increasing
the expression of COX-2, and that LPS promotes the production of Ep4 receptors
in osteoblasts. These results also indicate that LPS-induced PGE(2) may combine
with osteoblast Ep4 receptors in autocrine or paracrine modes, and may promote
the formation of osteoclasts.

PMID: 16289620 [PubMed - indexed for MEDLINE]


5: LPS and house dust as constant source:
1: Arh Hig Rada Toksikol. 2004 Jun;55(2-3):175-81.

Endotoxin measurement in house dust using the end-point Limulus amoebocyte
lysate method.

Varnai VM, Macan J, Plavec D, Juresa D.

Institute for Medical Research and Occupational Health, Zagreb, Croatia.
vvarnai@imi.hr

Endotoxin is a lipopolysaccharide, a part of gram-negative bacteria cell
membrane commonly present in general and many occupational environments. This
paper describes sample preparation and endotoxin measurement in 16 samples of
house dust from urban homes (Zagreb, Croatia) using end-point chromogenic
Limulus amoebocyte lysate (LAL) bioassay. House dust was collected on cellulose
filters by vacuuming bedroom and living room floors, and was kept frozen until
assayed. Samples were extracted from filters with a 0.05% solution of Tween-20
in endotoxin-free water. Serial dilutions of samples were measured in
duplicates. The linearity of the standard curve was satisfying (r=0.983), as
well as the recovery (92 and 110%) and repeatability (coefficient of variation
from 0 to 8.5%). The endotoxin levels found in the house dust samples ranged
from 4.8 to 200 EU/mg, with the arithmetic mean of 49.5 EU/mg (standard error of
the mean of 12.1 EU/mg), and were in the range of house dust endotoxin values
obtained by other authors.

PMID: 15285466 [PubMed - indexed for MEDLINE]



(Gram-negative bacteria and their exaggerated response to certain antibiotics can result in an acute crisis as endotoxin levels are quickly raised.)

6: LPS and amplification of endotoxin output by targeted bacteria:

1: Folia Microbiol (Praha). 2005;50(2):167-71.

Antibiotic-induced release of inflammatory mediators from bacteria in
experimental Klebsiella pneumoniae-induced sepsis.

Toky V, Sharma S, Bramhne HG, Chhibber S.

Department of Microbiology, Panjab University, 160 014 Chandigarh, India.
kltoky@yahoo.com

In a fibrin-clot model of sepsis, developed in mice, treatment with the
antibiotics ceftazidime (Cfz) and ofloxacin (Ofl) caused significant (p < 0.01)
release of endotoxin and TNF-alpha after 4.5 h when compared with control
(untreated) and amikacin (Ami) treated group. Except for control group, the
level of bacteremia declined in all three antibiotic-treated groups. The results
suggest that antibiotic therapy, irrespective of the agent used, results in an
increase in endotoxin levels in vivo. The amount of endotoxin liberated by Ami
was much smaller than with Cfz and Ofl therapy, which makes it an appropriate
agent for the treatment of sepsis. An increase in the level of TNF-alpha along
with endotoxin is suggestive of increased inflammatory response.

PMID: 16110923 [PubMed - indexed for MEDLINE]

Bacterial toxins - Part 4
 

(H. pylori, due to its’ ubiquitous nature, its’ capacity to generate large amounts of endotoxin, and its known link to PD, is a prime candidate.)

7: Helicobacter pylori:
1: FEMS Immunol Med Microbiol. 2005 May 1;44(2):129-35.

Role of inflammation in gastrointestinal tract in aetiology and pathogenesis of
idiopathic parkinsonism.

Dobbs SM, Dobbs RJ, Charlett A, Bjarnason IT.

Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College,
London SE5 8AF, UK.

Idiopathic parkinsonism (IP) is a common disorder, conventionally regarded as
neurodegenerative. Its cardinal features, poverty and slowness of movement,
muscle rigidity, postural abnormality and a characteristic tremor, are
associated with loss of dopaminergic neurones in the substantia nigra of the
brain. Genetic factors explain only a minority of cases, and a common toxic
environmental insult remains elusive. We propose that IP is a systemic disorder
resulting from a ubiquitous peripheral infection, and that only the tip of the
iceberg comes to diagnosis. There is evidence for inflammatory/immune activation
peripherally and in the brain. We have used statistical modelling to explore
links with non-specific and specific systemic markers of inflammation/infection
in IP probands, and explore whether their partners and siblings have a frank or
pre-presentation parkinsonian state. Critical to this approach is continuous
objective measures of the facets of IP. Hypotheses on causality and mechanism
are based on the statistical models. There is pathological and clinical evidence
for direct involvement of the gastrointestinal tract in IP. The candidacy of
Helicobacter pylori infection as a trigger event or driving infection is
relatively high. We have found that eliminating infection in late parkinsonism
with cachexia, a stage usually considered intractable, can result in a U-turn.
However, eradication therapy may not provide a complete solution. Persistence of
antibody against cytotoxin-associated antigen (CagA), increases the predicted
probability of being labelled as having parkinsonism. Evidence for autoimmunity
and immunocompromise is used to build schemes for the natural history. We
conclude that current classifications of neuropsychiatric disease may not prove
the best with respect to defining sub-clinical disease, prophylaxis or halting
progression.

Publication Types:
Review

PMID: 15866206 [PubMed - indexed for MEDLINE]



(Other bacteria and viruses have been linked to PD although the exact mechanism is not known. An inflammatory action would explain the association.)

8. Nocardia:
1: Braz J Med Biol Res. 2004 Apr;37(4):539-48. Epub 2004 Mar 23.

Nocardia otitidiscaviarum (GAM-5) induces parkinsonian-like alterations in
mouse.

Diaz-Corrales FJ, Colasante C, Contreras Q, Puig M, Serrano JA, Hernandez L,
Beaman BL.

Laboratorio de Fisiologia de la Conducta, Facultad de Medicina, Universidad de
Los Andes, Merida, Venezuela.

Parkinson's disease, a major neurodegenerative disorder in humans whose etiology
is unknown, may be associated with some environmental factors. Nocardia
otitidiscaviarum (GAM-5) isolated from a patient with an actinomycetoma produced
signs similar to Parkinson's disease following iv injection into NMRI mice. NMRI
mice were infected intravenously with a non-lethal dose of 5 x 10(6) colony
forming units of N. otitidiscaviarum (GAM-5). Fourteen days after bacterial
infection, most of the 60 mice injected exhibited parkinsonian features
characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and
postural instability. There was a peak of nocardial growth in the brain during
the first 24 h followed by a decrease, so that by 14 days nocardiae could no
longer be cultured. At 24 h after infection, Gram staining showed nocardiae in
neurons in the substantia nigra and occasionally in the brain parenchyma in the
frontal and parietal cortex. At 21 days post-infection, tyrosine hydroxylase
immunolabeling showed a 58% reduction of tyrosine hydroxylase in the substantia
nigra, and a 35% reduction of tyrosine hydroxylase in the ventral tegmental
region. Dopamine levels were reduced from 110 +/- 32.5 to 58 +/- 16.5 ng/mg
protein (47.2% reduction) in brain from infected mice exhibiting impaired
movements, whereas serotonin levels were unchanged (191 +/- 44 protein in
control and 175 +/- 39 ng/mg protein in injected mice). At later times,
intraneuronal inclusion bodies were observed in the substantia nigra. Our
observations emphasize the need for further studies of the potential association
between Parkinson's disease or parkinsonism-like disease and exposure to various
nocardial species.

PMID: 15064817 [PubMed - indexed for MEDLINE]



(It has long been known that living in a rural environment increases the likelihood of PD. Increased endotoxic exposure is an obvious explanation.)

9. LPS and agricultural exposure:
1: Occup Environ Med. 2006 Jan;63(1):59-67.

Agricultural seed dust as a potential cause of organic dust toxic syndrome.

Smit LA, Wouters IM, Hobo MM, Eduard W, Doekes G, Heederik D.

Institute for Risk Assessment Sciences, Division of Environmental and
Occupational Health, Utrecht University, Utrecht, The Netherlands.
L.Smit@iras.uu.nl

AIMS: Episodes of serious work related health problems resembling organic dust
toxic syndrome (ODTS) in workers of a grass seed quality inspection laboratory
prompted the authors to study personal endotoxin exposure levels in this
facility and in the agricultural seed processing industry. In addition,
microbial and inflammatory characteristics of agricultural seeds were studied.
METHODS: The authors assessed inhalable dust and endotoxin levels in 101 samples
from 57 workers in grass, cereal, and vegetable seed plants who were handling
mainly grass seeds as bulk product, and horticulture seeds in smaller
quantities. Additionally, real-time dust exposure was measured using a DataRAM
monitor in 12 grass seed workers to obtain more information on exposure patterns
during specific tasks. Endotoxin concentrations in seed extracts were determined
by LAL assay and seed samples were analysed by scanning electron microscopy.
Release of inflammatory cytokines was measured in supernatants of whole blood
samples stimulated with lipopolysaccharide (LPS) or agricultural seed extracts
in a human whole blood assay (WBA). RESULTS: Endotoxin concentrations in
personal samples were high (geometric mean 1800 EU/m3), particularly in the
grass seed quality inspection lab where endotoxin levels up to 274 000 EU/m3
were measured. The recommended health based endotoxin exposure limit of 50 EU/m3
was amply exceeded in almost all personal samples. Job tasks dumping and mixing
were associated with highest dust and endotoxin exposures, which was confirmed
by real-time measurements. Microbial infestation was found in almost all seed
samples. WBA results showed that most seed extracts were capable of inducing a
pronounced dose dependent cytokine release. CONCLUSIONS: Workers handling grass,
cereal, or vegetable seeds are at risk of exposure to high levels of endotoxin
containing seed dust. Occupational exposure to inhalable agricultural seed dust
can induce inflammatory responses, and is a potential cause of ODTS.

PMID: 16361407 [PubMed - indexed for MEDLINE]


(A greater incidence of PD has been noted among men than among women for reasons unknown.)

10. LPS and gender differences in PD:

1: Curr Pharm Des. 2005;11(8):1017-30.

Estrogen and cytokines production - the possible cause of gender differences in
neurological diseases.

Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I.

Second Department of Neurology, Institute of Psychiatry and Neurology,
Sobieskiego 9, 02-957 Warsaw, Poland. czlonkow@ipin.edu.pl

Naturally occurring sexual dimorphism has been implicated in the risk,
progression and recovery from numerous neurological disorders. These include
head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases
(Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral
sclerosis (ALS). Accumulating evidence suggests that observed differences
between men and women could result from estrogen's wide range of effects within
the mammalian central nervous system (CNS), with it's neuroprotective effect
being one of the most important. It seems possible that neuroprotective activity
of estrogen could be partially a result of it's anti-inflammatory action. It has
been well established that inflammation plays an important role in the
etiopathogenesis and manifestation of brain pathological changes. In this
regard, an important role has been suggested for pro-inflammatory cytokines
produced by activated glial cells, neurons and immune cells that invade brain
tissue. Within the CNS, cytokines stimulate inflammatory processes that may
impair blood-brain barrier permeability as well as promote apoptosis of neurons,
oligodendrocytes and induce myelin damage. Given that estrogen may modulate
cytokine expression, coupled with the fact that gender differences of cytokine
production are apparent in animal models of PD and MS, suggests an important
connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS
patients and mice subjected to experimental autoimmune encephalomyelitis (EAE)
display gender specific alterations of IFN-gamma and IL-12, variations of TNF
and IL-6 were associated with PD. Also in case of more acute neurodegenerative
conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was
different in males and females. Given that our understanding of the role of
estrogen on cytokine production and accompanying CNS pathological conditions is
limited, the present reviews aims to present some of our recent findings in this
area and further evaluate the evidence that may be relevant to the design of new
hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.

Publication Types:
Review

PMID: 15777251 [PubMed - indexed for MEDLINE]

(Sleep disturbances are common in PD for reasons unknown. Also, dopamine is produced and stored during REM sleep. Non-REM sleep may shorten the time available to complete this process each night.)

11. LPS inflammation and sleep:

1: Bull Exp Biol Med. 2003 Aug;136(2):110-3.

Activity of the hypothalamic-pituitary-adrenocortical system and sleep-wake
cycle in rats with acute systemic inflammation.

Eliava MI, Grinevich VV, Oganesyan GA.

I. M. Sechenov Institute of Evolutional Physiology and Biochemistry, Russian
Academy of Sciences, St. Petersburg. m_eliava@hotmail.com

Activity of the hypothalamic-pituitary-adrenocortical system and EEG
characteristics of the sleep-wake cycle were studied on adult male Wistar rats
with acute inflammation produced by bacterial lipopolysaccharide in a dose of
250 microg/100 g body weight. Blood concentrations of adrenocorticotropic
hormone and corticosterone increased by 6 and 10 times, respectively, 30 min
after lipopolysaccharide administration and peaked 2 hours after challenge. In
this period the sleep-wake cycle underwent the most pronounced changes that
could be attributed to the stupor-like state observed in clinical practice. It
was manifested in dissociation between locomotor activity of animals and EEG
characteristics, suppression of EEG components in slow-wave sleep, increase in
the number of beta-waves, and decrease in the number of delta-waves in EEG. In
the present work we consider possible mechanisms of temporal relationships
between activity of the hypothalamic-pituitary-adrenocortical system and
disorganization of the sleep-wake cycle during acute systemic inflammation.

PMID: 14631484 [PubMed - indexed for MEDLINE]



1: Am J Physiol Regul Integr Comp Physiol. 2000 Apr;278(4):R947-55.

Dose-dependent effects of endotoxin on human sleep.

Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmacher T.

Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
mullingt@caregroup.harvard.edu

The role of the central nervous system in the host response to infection and
inflammation and modulation of these responses by the
hypothalamic-pituitary-adrenal system are well established. In animals,
activation of host defense mechanisms increases non-rapid eye movement (NREM)
sleep amount and intensity, which, in turn, are thought to support host defense,
or the body's ability to defend itself against challenges to its immune system.
In humans, the evidence is conflicting. Therefore, we investigated the effects
of three placebo-controlled doses of endotoxin on host response, including
nocturnal sleep in healthy volunteers. Administered before nocturnal sleep
onset, endotoxin dose dependently increased rectal temperature, heart rate, and
the plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors,
interleukin (IL)-1 receptor antagonist, IL-6, and cortisol. The lowest dose
reliably increased circulating levels of cytokines and soluble cytokine
receptors, but it did not affect rectal temperature, heart rate, or cortisol.
This subtle host defense activation increased deep NREM sleep amount, often
referred to as slow-wave sleep (stages 3 and 4), and intensity (delta power).
Conversely, the highest dose of endotoxin disrupted sleep. Whereas it is well
established that the endocrine and thermoregulatory systems are very sensitive
to endotoxin, this study shows that human sleep-wake behavior is even more
sensitive to activation of host defense mechanisms.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 10749783 [PubMed - indexed for MEDLINE]

Bacterial toxins - Part 5
 

(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]

OK, it is a weighty tome...