In:
Journal of Neurochemistry, Wiley, Vol. 103, No. 2 ( 2007-10), p. 542-556
Abstract:
Cocaine exposure results in aberrant outgrowth and decreased survival for locus coeruleus (LC), a noradrenergic population of neurons that putatively regulates attentional function; however, the underlying mechanisms for these events are not known. We previously showed that cocaine exposure in vitro activates pro‐apoptotic Bax, caspase‐9, and caspase‐3 in LC neurons dissected from embryonic day 14 rats, implicating that apoptosis may be orchestrated via signal transduction events. In the current study in vitro , we examined upstream events to determine the role of the pro‐inflammatory cytokine, tumor necrosis factor alpha (TNF‐α), on LC signal transduction, because cocaine exposure to LC neurons triggered TNF‐α expression at 30 min as measured by ELISA. Exposure of LC neurons to recombinant ‐TNF‐α resulted in decreased metabolic activity, an indicator of reduced neuron viability [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay], and increased apoptosis (terminal deoxynucleotidyl transferase‐mediated DNA nick end labeling assay). Pro‐apoptotic caspase‐3 was induced by cocaine starting at 30 min. Recombinant‐ TNF‐α induced caspase‐3 activity earlier than cocaine (15 and 20 min). The caspase‐3 levels were significantly reduced when cocaine and TNF‐α were combined with neutralizing‐TNF‐α (nTNF‐α), respectively. Further, cocaine alone elevated phospho‐p38‐mitogen‐activated protein kinases that persisted when combined with nTNF‐α. However, both cocaine and TNF‐α independently increased phospho‐c‐Jun NH 2 ‐terminal kinase and Bax levels at concurrent time periods (30 min and 1 h), and this elevation was attenuated in the presence of nTNF‐α. These simultaneous molecular events triggered by cocaine and TNF‐α implicate a potential apoptotic signal transduction pathway via induction of phospho‐c‐Jun NH 2 ‐terminal kinase and Bax that may lead to caspase‐3 activation and apoptosis in cocaine‐exposed fetal LC neurons.
Type of Medium:
Online Resource
ISSN:
0022-3042
,
1471-4159
DOI:
10.1111/jnc.2008.103.issue-2
DOI:
10.1111/j.1471-4159.2007.04750.x
Language:
English
Publisher:
Wiley
Publication Date:
2007
detail.hit.zdb_id:
2020528-4
SSG:
12
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