Abstract
Exposure to cigarette smoke has been implicated in the progression of cerebrovascular and neurological disorders like stroke through inflammation and blood-brain barrier disruption. In this study, we investigated the signaling cascade activated by cigarette smoke extracts (CSE) and cadmium (Cd) resulting in the COX-2 induction in C6 rat astroglia cells. CSE or Cd induced Notch1 cleavage and activated p38 MAPK and CREB signaling pathways in C6 astroglia cells. Knockdown of nicastrin using siRNA or γ-secretase inhibitors, DAPT and L-685,486, reduced Notch1 cleavage and phosphorylation of p38 MAPK and CREB, while phosphorylation of ERK and JNK remained unaffected. Additionally, the blockage of γ-secretase activity did not show any effect on the phosphorylation of AKT, another upstream activator of CREB, indicating that γ-secretase-mediated CREB activation occurs via p38 MAPK. γ-secretase inhibitor also inhibited the CSE and Cd-mediated increase in the expression of COX-2. Furthermore, recombinant overexpression of Notch1 intracellular domain resulted in an increase in the expression of COX-2. Notch signaling induced by CSE and Cd induced apoptosis in C6 cells. Our results demonstrate that CSE exposure activated the p38 MAPK and CREB-mediated induction in COX-2 expression in astrocytes via γ-secretase-mediated Notch1 signaling. Our data provides novel insights into the potential mechanism of pro-inflammatory response activated by exposure to cigarette smoke.
Highlights
Cigarette smoke is reportedly a major risk factor for stroke and vascular diseases [1]
To determine whether apoptosis is responsible for the vulnerability of astrocyte to Cd or cigarette smoke extract (CSE) induced cell damage, the effect of Cd and CSE on the cellular features of apoptosis was examined with the cleaved caspase-3 (c-caspase-3) and cleaved PARP (c-PARP) (Fig 1G and 1H)
The present study reveals a mechanism of COX-2 upregulation and highlights the role of p38 mitogen-activated protein kinase (MAPK) in mediating the hazards associated with exposure to cigarette smoke or its carcinogen, Cd
Summary
Cigarette smoke is reportedly a major risk factor for stroke and vascular diseases [1]. Several environmental pollutants including heavy metals are associated with neurological disorders, such as ischemic stroke and learning disabilities in children [2,3,4]. Cadmium (Cd), a potent mediator of oxidative stress and inflammation, is an environmental pollutant present in cigarettes and contaminated food. Cd is one of major components of air particulate matters. A few studies report a significant correlation between the increased risk for stroke and Cd or cigarette smoke extract (CSE) exposure [6, 7]. Brain ischemia triggers an inflammatory reaction that contributes to the progression of brain diseases [8]
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