title: Molecular Mechanism of Switching of TrkA/p75(NTR) Signaling in Monocrotophos Induced Neurotoxicity.
abstract: We demonstrate the role of molecular switching of TrkA/p75(NTR) signaling cascade in organophosphate pesticide-Monocrotophos (MCP) induced neurotoxicity in stem cell derived cholinergic neurons and in rat brain. Our in-silico studies reveal that MCP followed the similar pattern of binding as staurosporine and AG-879 (known inhibitors of TrkA) with TrkA protein (PDB ID: 4AOJ) at the ATP binding sites. This binding of MCP to TrkA led to the conformational change in this protein and triggers the cell death cascades. The in-silico findings are validated by observing the down regulated levels of phosphorylated TrkA and its downstream molecules viz., pERK1/2, pAkt and pCREB in MCP-exposed cells. We observe that these MCP induced alterations in pTrkA and downstream signaling molecules are found to be associated with apoptosis and injury to neurons. The down-regulation of TrkA could be linked to increased p75(NTR). The in-vitro studies could be correlated in the rat model. The switching of TrkA/p75(NTR) signaling plays a central role in MCP-induced neural injury in rBNSCs and behavioral changes in exposed rats. Our studies significantly advance the understanding of the switching of TrkA/p75(NTR) that may pave the way for the application of TrkA inducer/p75(NTR) inhibitor for potential therapeutic intervention in various neurodegenerative disorders.
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: CSIR-Central Drug Research Institute, Lucknow-226001, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Gupta
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Rajendra Kumar
authors.initials: RK
authors.lastname: Shukla
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Tripathi
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Jahan
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Pandey
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Akriti
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Megha
authors.initials: M
authors.lastname: Agrawal
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Yadav
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Khanna
authors.affiliation: CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Aditya Bhushan
authors.initials: AB
authors.lastname: Pant
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D008999:Monocrotophos / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009419:Nerve Tissue Proteins; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D008999:Monocrotophos; D020917:Receptor, trkA