Cholinergic Modulation of Inflammatory CNS Cytokines

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DESCRIPTION (provided by applicant): 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.