Recent studies indicate that perinatal brain infection/inflammation may contribute to not only brain damage and subsequent neurological dysfunction in the neonatal and juvenile stages, but also neurodegenerative diseases that occur in late life. It has been reported in rats that prenatal exposure to lipopolysaccharide (LPS) is linked to loss of dopaminergic (DA) neurons in the offspring brain at adult stages, a hallmark feature of Parkinson's disease (PD) which is a neurodegenerative disease typically seen in aged people. Interestingly, our previously data suggested that perinatal LPS exposure through intraperitoneal (i.p.) injection, an exposure route more likely to be encountered in newborn infants with infections, results in decreased expression of tyrosine hydroxylase in DA neurons, but not the actual death of DA neurons in the substantial nigra (SN). The rationale is that perinatal LPS exposure enhances susceptibility of DA neurons in the SN in the adult brain to an ordinarily non-toxic or sub-toxic dose of rotenone, thus, resulting in actual loss of DA neurons and PD-like symptoms. Based on these observations, we hypothesize that: 1) perinatal systemic LPS exposure may result in chronic brain inflammation and prolonged exposure to such an environment may enhance vulnerability of DA neurons in the SN of adult brain to an ordinarily non-toxic or sub-toxic dose of neurotoxin to develop PD-like symptoms;and 2) the long-term effect of perinatal LPS exposure is mediated, at least partially, by a sustained elevation in IL-1? levels, accumulation of ? -synuclein (?- SYN) aggregation, activation of microglia, and induction of cyclooxygenases-2 (COX-2) in the SN. The following specific aims will be addressed:
Aim 1 : to investigate the effects of environmental toxin, paraquat, at an ordinarily non-toxic or sub-toxic dose, in order to characterize the chronic inflammatory conditions in the SN following perinatal systemic LPS exposure and correlate the enhanced vulnerability of the DA neurons with the chronic inflammatory conditions.
Aim 2 : to determine the role of sustained elevations in IL-1? and accumulation of ?-SYN aggregation following perinatal LPS exposure on the enhanced vulnerability of DA neurons to rotenone at adult stages through i.c. injection of IL-1 ?, or treatments with IL-1ra or ? SYN siRNA in LPS-exposed animals, and then compare the impairment of DA neurons and motor dysfunctions induced by a sub-toxic dose of rotenone in late life.
Aim 3 : to determine the role of sustained activation of microglia an induction of COX-2 following perinatal LPS exposure on enhancement of DA neuron vulnerability to rotenone toxicity, using minocycline, an inhibitor of microglia activation, or celecoxib, a selective COX-2 inhibitor, in both animal and microglia-mesencephalic DA neuron co-cultures. The proposed studies will not only greatly enhance our understanding of mechanisms involved in long-term adverse effects of perinatal brain inflammation on late-onset neurodegenerative diseases, but may also lead to identification of key targets/pathways for developing preventive/therapeutic strategies against these adverse effects.
There is increasing evidence that perinatal infection is not only one of the major contributors to infant mortality and morbidity, but also an important risk factor for development of late-onset neurodegenerative diseases such as Parkinson's disease. This proposed project will explore mechanisms involved in the link between perinatal brain inflammation and the enhanced risk for triggering neurodegenerative diseases in a late life stage, and it is highly relevant to public health.
|Tien, Lu-Tai; Lee, Yih-Jing; Pang, Yi et al. (2017) Neuroprotective Effects of Intranasal IGF-1 against Neonatal Lipopolysaccharide-Induced Neurobehavioral Deficits and Neuronal Inflammation in the Substantia Nigra and Locus Coeruleus of Juvenile Rats. Dev Neurosci 39:443-459|
|Lu, Silu; Shaffery, James P; Pang, Yi et al. (2016) Rapid Eye Movement Sleep Homeostatic Response: A Potential Marker for Early Detection of Parkinson's Disease. J Alzheimers Dis Parkinsonism 6:|
|Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei et al. (2016) Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat. Int J Mol Sci 17:289|
|Pang, Yi; Dai, Xuemei; Roller, Anna et al. (2016) Early Postnatal Lipopolysaccharide Exposure Leads to Enhanced Neurogenesis and Impaired Communicative Functions in Rats. PLoS One 11:e0164403|
|Pang, Y; Lin, S; Wright, C et al. (2016) Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats. Neuroscience 318:157-65|
|Lan, Kuo-Mao; Tien, Lu-Tai; Pang, Yi et al. (2015) IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats. Toxicol Lett 234:30-39|
|Pang, Yi; Tien, Lu-Tai; Zhu, Hobart et al. (2015) Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats. Int J Mol Sci 16:8635-54|
|Fan, Lir-Wan; Bhatt, Abhay; Tien, Lu-Tai et al. (2015) Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro. J Neurochem 133:532-43|
|Wong, C-S; Jow, G-M; Kaizaki, A et al. (2014) Melatonin ameliorates brain injury induced by systemic lipopolysaccharide in neonatal rats. Neuroscience 267:147-56|
|Bhatt, Abhay; Fan, Lir-Wan; Pang, Yi (2014) Strategies for myelin regeneration: lessons learned from development. Neural Regen Res 9:1347-50|