Format

Send to

Choose Destination
Toxicol Sci. 2017 Sep 1;159(1):137-158. doi: 10.1093/toxsci/kfx124.

From the Cover: Arsenic Induces Hippocampal Neuronal Apoptosis and Cognitive Impairments via an Up-Regulated BMP2/Smad-Dependent Reduced BDNF/TrkB Signaling in Rats.

Author information

1
Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India.
2
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, India.
3
Babu Banarasi Das University, Lucknow 226028, India.
4
Analytical Chemistry Laboratory and Regulatory Toxicology Group, CSIR-IITR, Lucknow, India.

Abstract

Arsenic promotes hippocampal neuronal damage inducing cognitive impairments. However, mechanism arbitrating arsenic-mediated cognitive deficits remains less-known. Here, we identified that chronic exposure to environmentally relevant doses of arsenic increased apoptosis, characterized by caspase-3 activation, poly(ADP-ribose) polymerase cleavage and Terminal deoxynucleotidyl transferase dUTP nick-end labeling of rat hippocampal neurons, marked by NeuN. Investigating apoptotic mechanism through invivo and invitro studies revealed that arsenic promoted bone morphogenetic protein-2 (BMP2) expression, supported by increased BMP-receptor2 (BMPR2) and p-Smad1/5 in hippocampal neurons. BMP2-silencing and treatment with BMP antagonist, noggin, attenuated the arsenic-induced apoptosis and loss in hippocampal neurons. We then investigated whether BMP2/Smad signaling stimulated neuronal apoptosis independently or required other intermediate pathways. We hypothesized participation of brain-derived neurotrophic factor (BDNF) that promotes neuronal survival. We identified an arsenic-mediated attenuation of BDNF-dependent TrkB signaling, and observed that co-treatment with recombinant-BDNF reinstated BDNF/TrkB and reduced neuronal apoptosis. To probe whether BMP2/Smad and BDNF/TrkB pathways could be linked, we co-treated arsenic with noggin or recombinant BDNF. We detected a noggin-mediated restored BDNF/TrkB, while recombinant-BDNF failed to affect BMP2/Smad signaling. In addition, we found that TrkB-inhibitor, K252a, nullified noggin-induced protection, proving the necessity of a downstream reduced BDNF/TrKB signaling for BMP2/Smad-mediated apoptosis in arsenic-treated neurons. We further related our observations with cognitive performances, and detected noggin-mediated restoration of transfer latency time and learning-memory ability for passive avoidance and Y-Maze tests respectively in arsenic-treated rats. Overall, our study proves that arsenic promotes hippocampal neuronal apoptosis through an up-regulated BMP2/Smad-dependent attenuation of BDNF/TrkB pathway, inducing cognitive deficits.

KEYWORDS:

arsenic; attenuated neurotrophin; increased BMP; memory deficits; neuronal loss

PMID:
28903487
DOI:
10.1093/toxsci/kfx124
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center