Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated whether in utero exposure to the Gram(-) bacteriotoxin lipopolysaccharide (LPS) induces dopamine (DA) neuron loss in rats. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) kills DA neurons and is elevated in the brains of patients with Parkinson's disease (PD). LPS is a potent inducer of TNF-alpha, and both are increased in the chorioamniotic environment of women who have bacterial vaginosis (BV) during pregnancy, suggesting that BV might interfere with the normal development of fetal DA neurons. Gravid female rats were injected intraperitoneally with either LPS or normal saline at embryonic day 10.5 and their pups were killed at postnatal day 21. The brains of the pups were assessed for DA and TNF-alpha levels and DA cell counts in the mesencephalon using tyrosine hydroxylase immunoreactive (THir) cells as a DA neuron marker. Prenatal LPS exposure significantly reduced striatal DA (29%) and increased DA activity (72%) as well as TNF-alpha (101%). Stereological cell counts in the mesencephalon were also significantly reduced (27%) by prenatal LPS exposure. Prenatal exposure to LPS, as might occur in humans with BV, produces a significant loss of THir cells in rats that is still present 33 days following a single injection of LPS. Since this cell loss is well past the normal phase of DA neuron apoptosis that occurs in early postnatal life, rats so exposed may have a permanent loss of DA neurons, suggesting that prenatal infections may represent risk factors for PD.
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PMID:In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. 1183 48

The cause of Parkinson's disease (PD) is currently unknown. Although a genetic cause has been implicated in familial PD, the vast majority of cases are considered idiopathic. Environmental toxins have been implicated as a cause for PD by many investigators. Unfortunately, the magnitude of this exposure would likely need to be very high and as a result, would likely have been identified by the many epidemiological studies performed to date. Recently, we inadvertently realized that exposure to neurotoxins while still in utero may also represent a risk factor. Thus, exposure to the bacteriotoxin, lipopolysaccharide (LPS) during a critical developmental window in rats, leads to the birth of animals with fewer than normal dopamine (DA) neurons. This DA neuron loss is apparently permanent as it is still present in 16 months old animals (the longest period studied to date). Moreover, the loss of DA neurons seen in these animals increases with age thereby mimicking the progressive pattern of cell loss seen in human PD. The DA neuron loss is accompanied by reductions in striatal DA, increases in DA activity, and increased production of the pro-inflammatory cytokine Tumor Necrosis Factor alpha (TNF-alpha). These are also characteristics of the PD brain. This model therefore shares many of the same characteristics with PD, and most importantly exhibits a slow, protracted loss of DA neurons - a characteristics of this animal model not found in other models. Interestingly, a common complication of pregnancy is a condition known as bacterial vaginosis (BV), which is known to produce increased levels of LPS and pro-inflammatory cytokines in the chorioamniotic environment of the fetus. This raises the interesting possibility that BV may be a risk factor for PD. The possibility that prenatal toxin exposure may contribute to the development of a neurodegenerative disease of the aged raises interesting new pathogenic questions and draws attention to the possibility that in utero exposure to neurotoxins may represent a here to fore unrecognized cause of PD.
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PMID:Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease. 1295 70

We previously reported that injection of the Gram (-) bacteriotoxin, lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the birth of animals with fewer than normal dopamine (DA) neurons when assessed at postnatal days (P) 10 and 21. To determine if these changes continued into adulthood, we have now assessed animals at P120. As part of the previous studies, we also observed that the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) was elevated in the striatum, suggesting that these animals would be more susceptible to subsequent DA neurotoxin exposure. In order to test this hypothesis, we injected (at P99) 6-hydroxydopamine (6OHDA) or saline into animals exposed to LPS or saline prenatally. The results showed that animals exposed to prenatal LPS or postnatal 6OHDA alone had 33% and 46%, respectively, fewer DA neurons than controls, while the two toxins combined produced a less than additive 62% loss. Alterations in striatal DA were similar to, and significantly correlated with (r(2)=0.833) the DA cell losses. Prenatal LPS produced a 31% increase in striatal TNFalpha, and combined exposure with 6OHDA led to an 82% increase. We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson's disease.
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PMID:Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain. 1498 Jul 32

Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Inflammation may be associated with the neuropathology of PD due to the following accumulating evidence: excessive microglial activation and increased levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin-1beta in the SNpc of patients with PD; the emergence of PD-like symptoms following influenza infection; the increased susceptibility to PD associated with bacterial vaginosis; the presence of inflammatory mediators and activators in animal models of PD; the ability of anti-inflammatory drugs to decrease susceptibility to PD; and the emerging possibility of the use of microglial activation inhibitors as a therapy in PD. In this review, we will discuss the role of inflammation in PD. We will focus on the influence of microglia in the pathogenesis of PD and discuss potential therapeutic interventions for PD, that target microglia.
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PMID:The influence of microglia on the pathogenesis of Parkinson's disease. 1968 99