title: Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation.
abstract: Lead is one of the major pollutants of environment and is highly toxic to the functioning of central nervous system (CNS). The chronic exposure of this heavy metal is debilitating to the functional behavior of an organism. Studies have shown that acute exposure to Pb can lead to glial activation and secretion of cyto-chemokines in both in vitro and in vivo models. However, the cellular source of secretion of these cyto-chemokines remains to be identified. Microglia are monocytes of the brain, and are primary source of cytokine secretion in the CNS. We hypothesized that microglia exposed to Pb can secrete cyto-chemokines, thereby resulting in subsequent neuronal death. Our studies show that stimulation of BV-2 mouse microglia with 10μМ dose of Pb resulted in up-regulation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, along with activation of an important transcription factor, nuclear factor-κB (NF-κB). Further, we found that the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) pro-inflammatory enzyme were increased in response to Pb exposure. Furthermore, treatment with conditioned media from Pb treated BV-2 cells lead to neuronal death in neuroblastoma cells, which potentially involved the activation of caspase-3 enzyme. In all, the current study brings forth critical involvement of microglial activation in mediating the neurotoxicity associated with lead exposure.
authors: National Brain Research Centre, Manesar, Haryana 122051, India; Dr. K.N. Modi University, Newai, Rajasthan 304021, India. Electronic address: kanhaiya81@gmail.com.
authors: Kanhaiya Lal
authors: KL
authors: Kumawat
authors: National Brain Research Centre, Manesar, Haryana 122051, India. Electronic address: deepakkaushiik@gmail.com.
authors: Deepak Kumar
authors: DK
authors: Kaushik
authors: Dr. K.N. Modi University, Newai, Rajasthan 304021, India; Poddar International College, Jaipur 302020, India. Electronic address: drpraveen.goswami@gmail.com.
authors: Praveen
authors: P
authors: Goswami
authors: National Brain Research Centre, Manesar, Haryana 122051, India. Electronic address: anirban@nbrc.ac.in.
authors: Anirban
authors: A
authors: Basu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D008970:Molecular Weight; D009474:Neurons / Q000502:physiology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; D048848:MAP Kinase Kinase Kinase 5; D053148:Caspase 3; C008261:lead acetate
keywords: Apoptosis; COX-2; Central nervous system; Lead; Microglia; NF-κB