Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life

Abstract

Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1,000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson’s disease and the development of potential therapeutic treatments.

IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats

“…Neonatal LPS exposure resulted in a sustained increase in microglial activation in the P71 rat brain, as indicated by the number and morphology of the Iba1+ cells (Fan et al, 2011a). In the control rat brain, most of the Iba1+ microglia were in a resting state, as shown by their small rod-shaped soma and ramified processes (indicated by arrows in Fig.…”

“…Intracerebral injection of LPS, or LPS in combination with IL-1ra in 5-day-old male Sprague-Dawley rat pups was performed as previously described (Cai et al, 2003; Fan et al, 2011a; Wang et al, 2011, 2013). Under light anesthesia with isoflurane (1.5–5%), LPS (1 mg/kg from Escherichia coli , serotype 055:B5), IL-1ra (0.1 mg/kg), or LPS (1 mg/kg) plus IL-1ra (0.1 mg/kg) in sterile saline containing 0.1% bovine serum albumin (BSA, total volume 2 ml) was administered into the rat brain (1.0 mm posterior to and 1.0 mm left of bregma, and 2.0 mm deep from the skull surface) by using a stereotaxic apparatus with a neonatal rat adapter.…”

“…The control rats were injected with the same volume of sterile saline containing 0.1% BSA. The dose of LPS used here was based on our previous procedures (Fan et al, 2011a; Wang et al, 2011, 2013). Our previous studies have shown that neonatal LPS (1 mg/kg) exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats (Wang et al, 2013).…”

“…The fifty-six equally spaced thick (40 μm) sections that were to be used in the analysis came from a one-in-six series. Nissl stained sections were scanned by a densitometer (Bio-Rad Hercules, CA, USA) and the areas of the ventricles, white matter, striatum, and hippocampus as well as that of the whole brain section (cerebrum) were outlined and determined using NIH image software in each of the fifty-six sections (Fan et al, 2011a,b,b; Wang et al, 2013). The Cavalieri principle (Gundersen and Jensen, 1987) was used to estimate the reference volumes, est V(ref).…”

Parkinson's disease as a result of aging

“…The exposure of pregnant animals to neuroactive agents can produce permanent effects in the monoaminergic neurons of the offspring (Alonso et al ., 1991a,b; Arevalo et al ., 1991). The pre- or neo-natal exposure of rats to gram(−) bacteriotoxin lipopolysaccharide (LPS) induces a permanent decrease in the number of DA neurons (Ling et al ., 2002; Carvey et al ., 2003; Fan et al ., 2011a,b; Cai et al ., 2012) and an increase in the α-synuclein aggregation in the surviving DAn (Bandiera et al ., 2011). The identification of silent toxics is not easy because subjects are normally exposed to a myriad of chemical mixtures of environmental pollutants during their life and because the effect of these toxics may be modulated by the genetic ‘fingerprint’ of each subject (Paolini et al ., 2004).…”