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]