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

Abstract

Background

Lead (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.

Methods

Because 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.

Results

Our 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.

Conclusion

Alterations 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.

Keywords:

• synaptic
• oxidative damage
• heavy metal neurotoxicity
• neuropsychiatric
• mitochondrial bioenergetics
• mitochondrial membrane potential

Supplementary material

Figure S1 Supplementation of ascorbic acid alone does not affect the bioenergetics of cortical SM.

Notes: MMP at both basal states (A) and in presence of substrates (B) was not altered in SM fraction isolated from rat pups supplemented with ascorbic acid when compared to aged matched controls. Ascorbic acid supplementation did not affect other mitochondrial functions, including ATP synthesis (C) and activities of complexes I–IV (D–G). Data are represented as mean ± SEM (n=5 pups from 2 litters). Difference between the groups were assessed statistically using unpaired two-tailed Student’s t-test.

Abbreviations: SM, synapse-specific mitochondria; MMP, mitochondrial membrane potential; Ctrl, control; Asc, ascorbic acid; SEM, standard error of the mean.

Acknowledgments

The study was partly funded by Deanship of Scientific Research, Imam Abdulrahman Bin Faisal University, Saudi Arabia (Project No. 2016-087-IRMC). The authors thank Dr Khaldoon Alsamman, Dr Hatem K Herzallah and Dr Sultan T Al-Otaibi for assistance in experiments and in the analysis and review of the results.

Disclosure

The authors report no conflicts of interest in this work.