We are examining mechanisms of neuronal-glial interactions within the context of how a proinflammatory cytokines and the nicotinic cholinergic neurotransmitter systems interact to determine neuronal susceptibility to excitotoxins in a neuroinflammatory environment, as is often present in neurological disease. The Overall Hypothesis is: Pre-exposure of CNS cells to the cholinergic agonist, nicotine, modifies signaling initiated by TNF alpha and alters neuronal vulnerability to excitotoxins and the CNS response during neuro-inflammatory processes. This hypothesis stems from several key results that include: 1. Cultured cortical neurons are protected against an NMDA-toxic challenge by TNFalpha or nicotine, however, TNF alpha and nicotine induced neuroprotection is abolished when the agents are present together cultures of mixed neurons and glia, 2. These agents are not antagonistic in enriched neuronal cultures suggesting that other non-neuronal cell types are required, 3. The addition of mononuclear phagocytes/microglial cells (MP/MG) to enriched neuronal cultures restores antagonism between nicotine and TNFalpha. 4. MP/MG in culture express nAChRs, and they respond functionally to the presence of nicotine, and 5. Nicotine administration alters the kinetics of TNFalpha-initiated caspase 8 activation, an important intracellular mediator of TNFalpha-signaling. We will determine in Specific Aim 1 if nicotine/TNFalpha antagonism of neuroprotection to NMDA requires specific cell-cell interactions between cells of the CNS including neurons and MP/MG, In Specific Aim 2 if neuronal nicotinic receptors, in addition to nAChRalpha7, and expressed by cell types other than neurons, participate in mechanism(s) related to nicotine/TNFalpha antagonism of neuroprotection and in Specific Aim 3 if nicotine preconditioning of CNS cells alters their response to TNFalpha through modifying caspase/protease activation and/or function. These studies have direct and novel implications toward understanding the consequences of sustained nicotine presence on the normal regulation of neuro-inflammation in the CNS, which may determine susceptibility to many toxins and influence normal and pathological responses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015148-04
Application #
7004567
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Pollock, Jonathan D
Project Start
2003-02-15
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$291,974
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Osborne-Hereford, Amber V; Rogers, Scott W; Gahring, Lorise C (2008) Neuronal nicotinic alpha7 receptors modulate inflammatory cytokine production in the skin following ultraviolet radiation. J Neuroimmunol 193:130-9
Rogers, Scott W; Weis, Janis J; Ma, Ying et al. (2008) Mouse chromosome 11 harbors genetic determinants of hippocampal strain-specific nicotinic receptor expression. Hippocampus 18:750-7
Gahring, Lorise C; Osborne-Hereford, Amber V; Vasquez-Opazo, Gustavo A et al. (2008) Tumor necrosis factor alpha enhances nicotinic receptor up-regulation via a p38MAPK-dependent pathway. J Biol Chem 283:693-9
Gahring, Lorise C; Rogers, Scott W (2005) Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells. AAPS J 7:E885-94
Gahring, Lorise C; Persiyanov, Karina; Rogers, Scott W (2005) Mouse strain-specific changes in nicotinic receptor expression with age. Neurobiol Aging 26:973-80
Gahring, Lorise C; Persiyanov, Karina; Days, Emily L et al. (2005) Age-related loss of neuronal nicotinic receptor expression in the aging mouse hippocampus corresponds with cyclooxygenase-2 and PPAR gamma expression and is altered by long-term NS398 administration. J Neurobiol 62:453-68
Gahring, Lorise C; Days, Emily L; Kaasch, Tuesday et al. (2005) Pro-inflammatory cytokines modify neuronal nicotinic acetylcholine receptor assembly. J Neuroimmunol 166:88-101
Gahring, Lorise C; Persiyanov, Karina; Rogers, Scott W (2004) Neuronal and astrocyte expression of nicotinic receptor subunit beta4 in the adult mouse brain. J Comp Neurol 468:322-33
Gahring, Lorise C; Persiyanov, Karina; Dunn, Diane et al. (2004) Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus. J Comp Neurol 468:334-46
Gahring, Lorise C; Meyer, Erin L; Rogers, Scott W (2003) Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or beta-amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines. J Neurochem 87:1125-36