Dysfunction of cortical synapse-specific mitochondria in developing rats exposed to lead and its amelioration by ascorbate supplementation

Abstract

BackgroundLead (Pb) is a widespread environmental neurotoxin and its exposure even in minute quantities can lead to compromised neuronal functions. A developing brain is particularly vulnerable to Pb mediated toxicity and early-life exposure leads to permanent alterations in brain development and neuronal signaling and plasticity, culminating into cognitive and behavioral dysfunctions and elevated risk of neuropsychiatric disorders later in life. Nevertheless, the underlying biochemical mechanisms have not been completely discerned.MethodsBecause of their ability to fulfill high energy needs and to act as calcium buffers in events of high intensity neuronal activity as well as their adaptive regulatory capability to match the requirements of the dynamicity of synaptic signaling, synapse-specific or synaptic mitochondria (SM) are critical for synaptic development, function and plasticity. Our aim for the present study hence was to characterize the effects of early-life Pb exposure on the functions of SM of prepubertal rats. For this purpose, employing a chronic model of Pb neurotoxicity, we exposed rat pups perinatally and postnatally to Pb and used a plethora of colorimetric and fluorometric assays for assessing redox and bioenergetic properties of SM. In addition, taking advantage of its ability as an antioxidant and as a metal chelator, we employed ascorbic acid (vitamin C) supplementation as an ameliorative therapeutic strategy against Pb-induced neurotoxicity and dysfunction of SM.ResultsOur results suggest that early-life exposure to Pb leads to elevated oxidative stress in cortical SM with consequent compromises in its energy metabolism activity. Ascorbate supplementation resulted in significant recovery of Pb-induced oxidative stress and functional compromise of SM.ConclusionAlterations in redox status and bioenergetic properties of SM could potentially contribute to the synaptic dysfunction observed in events of Pb neurotoxicity. Additionally, our study provides evidence for suitability of ascorbate as a significant ameliorative agent in tacking Pb neurotoxicity.

Developmental lead (Pb)-induced deficits in hippocampal protein translation at the synapses are ameliorated by ascorbate supplementation

“…Moreover, in support of previous studies in human subjects,1,6,8,17,32,84,85 our results suggest that blood Pb levels serve as a valuable diagnostic measure of Pb-mediated dysregulation of neurological functions. In addition, while our study implicates alterations in synapse-specific protein translation as a potential mechanism underlying Pb-induced alterations in synapse maintenance, plasticity; and consequently on memory and cognition as well as vulnerability to psychological stress, it also establishes ascorbic acid as an important therapeutic agent against Pb neurotoxicity,44,45,47,48 The mechanism of ascorbate-mediated neuroprotection in Pb toxicity seems to be multifactorial, stemming from both its antioxidant properties and its Pb chelating function. Being a lactone containing an enediol group, ascorbate can form a soluble complex with Pb, enhancing its urinary excretion while also preventing its gastrointestinal absorption, and eventually lowering its blood levels and reducing its bioavailability 70,86,87…”

“…In particular, therapeutic effects of ascorbate in the events of Pb exposure and toxicity have been well-documented by a number of groups 42–47. Of note, our recent study has shown appreciable recovery of early life Pb-induced synapse-specific mitochondrial bioenergetic defects by ascorbate supplementation 48…”

“…All experiments involving animals were carried out in accordance with the institutional guidelines for animal care and use for scientific research and after approval by the institutional review board, Imam Abdulrahman Bin Faisal University, Dammam. The experimental paradigm of pre- and postnatal lead exposure and ascorbate supplementation employed has been previously reported by us 48. In brief, female Wistar rats were housed in cages with sexually mature males (2:1; male to female ratio) under a light/day 12/12 hours regime in rooms with a controlled temperature of 25°C.…”

Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups

“…Pb also disrupts developmental cortical plasticity, causing dysfunction in neurodevelopment [25]. Moreover, prenatal exposure to Pb affects the activity and expression of key synaptic proteins [10], impairs the functioning of synaptic mitochondria [7,42], disrupts the energy metabolism of neurons and astrocytes, and leads to impaired metabolic cooperation between these cells [43].…”

(Ascorb)ing Pb Neurotoxicity in the Developing Brain

“…Our own studies have provided evidence for the amelioration of early-life (perinatal and postnatal—from gestational day (GD) 15 to postnatal day (PND) 21) Pb-mediated effects on the nerve terminals of multiple brain regions, such as cerebral [ 293 ], hippocampal [ 293 ], and cerebellar synapses [ 294 ], by maternal AA supplementation. In particular, we observed a marked reversal of Pb-mediated alterations in synaptic bioenergetics with the rescue of defects in the mitochondrial membrane potential (MMP) and activities of the enzymes of the electron transport chain (ETC) [ 294 , 295 ]. Improvements in endogenous antioxidant pathways (particularly glutathione signaling) concomitantly with reduced oxidative damage to proteins and lipids were also observed in our model of AA supplementation in rats developmentally exposed to Pb [ 294 , 295 ].…”