In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain

Abstract

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.

α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

“…Intrauterine exposure to LPS has been shown to cause reduced TH immunoreactivity and loss of dopamine neurons in the SN (Ling et al, 2002). Our previous results also showed LPS administration in the forebrain may cause injury to dopamine neurons as indicated by the reduction in the number of TH positive neurons in the rat brain 16 days after LPS injection; however, it is not known whether this is due to neuronal loss or to a functional abnormality (Fan et al, 2005b).…”

“…Our previous studies and data reported by other investigators indicate that perinatal LPS exposure reduces the number of TH positive neurons in these areas (Fan et al, 2005b;Ling et al, 2002), but it is unknown whether the reduction in the number of TH positive cells is a consequence of phenotypic suppression of TH expression or actual neuronal cell death. To answer this question, double labeling with TH and NeuN antibodies was performed and all TH positive and NeuN positive cells in the three midbrain sections for each animal (at a level 1/3 rostral from the lambda to the bregma) were counted bilaterally.…”

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

“…In fact, we demonstrated recently that chronic intranigral infusion of LPS results in a delayed and progressive degeneration of nigral dopaminergic neurons (Gao et al, 2002b). In addition, Ling et al (2002) has also demonstrated that in utero exposure of developing fetuses to LPS results in a loss of nigral dopaminergic neurons in neonates.…”

Paraquat and Parkinson's disease

“…Gravid female rats were injected intraperitoneally with LPS at embryonic day 10.5. 58 Pups showed reduced numbers of tyrosine hydroxylase positive neurons, an effect that was still present at 33 days after a single injection of LPS.…”