Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or beta-amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines.
Nicotine, the causative agent of addiction to tobacco, can also be a neuroprotectant. Nicotine-induced neuroprotection against different toxins is imparted through pharmacologically distinct neuronal nicotinic acetylcholine receptors (nAChR) where protection against chronic N-methyl-d-aspartic acid (NMDA) exposure is through nAChRalpha7 but protection against the toxic peptide of amyloid precursor protein, Abeta25-35, is through nAChRalpha4beta2. The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is also neuroprotective, however, in the presence of nicotine, neuroprotection against NMDA is abolished. The specificity of nicotine-TNFalpha antagonism was further refined using a mouse transgenic dominant negative of nAChRalpha7 in which nicotine failed to induce neuroprotection against NMDA and antagonism of TNFalpha was absent. However, nicotine-mediated neuroprotection against Abeta25-35 was unaffected and, therefore, did not require the expression of functional nAChRalpha7s. The mechanism of TNFalpha-mediated neuroprotection and antagonism by nicotine was independent of caspase 8 activation or nuclear factor kappa B translocation in neurons but C6-ceramide addition to neuronal cultures subsequently exposed to NMDA mimicked the neuroprotective effect of TNFalpha and, like TNFalpha, it was antagonized by cotreatment with nicotine. Therefore, the neuroprotective effects of nicotine against differing toxic assaults requires distinct nAChR subtypes and proceeds through intracellular pathways that overlap with similarly different mechanisms initiated by pro-inflammatory cytokines. These results provide insight into how nicotine imparts neuroprotection and modulates inflammatory responses.
Gahring
Lorise C
LC
Geriatric Research, Education and Clinical Center, Salt Lake City VA, Salt Lake City, UT 84132, USA. Lorise.Gahring@hsc.utah.edu
Meyer
Erin L
EL
Rogers
Scott W
SW
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D019610:Cytoprotection / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016202:N-Methylaspartate / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019076:Transgenes; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D002518:Ceramides; C579166:Chrna7 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C074636:amyloid beta-protein (25-35); C403531:nicotinic receptor alpha4beta2; C101954:N-caproylsphingosine; D016202:N-Methylaspartate; D009538:Nicotine