New evidence of an anti-inflammatory mechanism in the brain by which nicotine may be protective against neuronal injury and death was reported in the March 15 online edition of the Journal of Neurochemistry. Preliminary findings suggested “the existence of a brain cholinergic pathway that regulates microglial activation through alpha7 nicotinic receptors,” reported investigators from the University of South Florida College of Medicine in Tampa. “Negative regulation of microglia activation may also represent an additional mechanism underlying nicotine’s reported neuroprotective properties,” they proposed.

THE MICROGLIAL HYPOTHESIS

According to study lead author R. Douglas Shytle, PhD, the prevailing hypothesis among researchers regarding the neuroprotective effects of nicotine documented in cases of patients with Alzheimer’s disease and Parkinson’s disease is that nicotine binds to nicotinic acetylcholine receptors and triggers an increase in the release of neurotransmitters depleted in those and other neurodegenerative diseases. What Dr. Shytle, an Assistant Professor of Neurosurgery, Psychiatry, and Pharmacology at the University of South Florida, and colleagues proposed was an additional, more indirect mechanism of action: microglial regulation.

The investigators based their work on findings in the peripheral nervous system demonstrating that “an endogenous ‘cholinergic anti-inflammatory pathway’ regulates systemic inflammatory responses via alpha7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages.” They hypothesized that a similar cholinergic pathway in the brain might regulate microglial activity and serve as a possible explanation for nicotinic neuroprotection.

Dr. Shytle and colleagues examined the expression of microglial alpha7 nAChR subunits in vitro and in vivo in both N9 microglial cell line murine and primary culture cells isolated from mouse cerebral cortices. The cells were subjected to polymerase chain reaction, Western blot, immunofluorescent, and immunohistochemistry analyses. The results “show that the alpha7 nAChR subunit mRNA was detected in both of these cells,” Dr. Shytle reported.

With this established, the researchers examined the regulatory capacity of the alpha7 nAChR subunit with respect to tumor necrosis factor alpha (TNF-alpha) release. They determined that acetylcholine or nicotine pretreatment resulted in a marked reduction of lipopolysaccharide-induced TNF-alpha release. Co-pretreatment with selective alpha7 nAChR antagonist, a-bungarotoxin, or nonselective nAChR antagonist mecamylamine “significantly blocked acetylcholine- or nicotine-mediated inhibition of TNF-alpha production,” they noted. Additional data showed that nicotine pretreatment significantly attenuated microglial activation as evidenced by decreased TNF-alpha production.

NICOTINIC NEUROPROTECTION

“Our findings demonstrate that physiologically relevant concentrations of acetylcholine and nicotine have the ability to modulate microglial TNF-alpha release evoked by lipopolysaccharide through activation of alpha7 nAChR. This is the first report of functional alpha7 nAChR subunit on microglia involved in a previously unknown cholinergic pathway which regulates microglial activation,” Dr. Shytle and colleagues wrote.

The investigators postulated that in neurodegenerative diseases “the loss of cholinergic communication from damaged neurons and/or astrocytes may be partially responsible for the turning of microglia to a hyperactivated state, which allows them to escape neuronal control and to give rise to persistent inflammation, resulting in exacerbation of neurodegeneration.”

In such cases, nicotine may function as a surrogate for acetylcholine, according to principal investigator Jun Tan, PhD, Director of the Neuroimmunology Laboratory at the University of South Florida Institute for Research in Psychiatry. “In those at risk for Alzheimer’s [disease] and other neurodegenerative diseases, nicotine may act much like the neurotransmitter acetylcholine. It may send signals to help suppress microglial immune response and limit excessive brain inflammation,” he elaborated. “The finding lets us explore a new way of looking at neurodegenerative diseases like Alzheimer’s [disease]. A better understanding of the therapeutic aspects of nicotine may also help us develop drugs that mimic the beneficial action of nicotine without its unwanted side effects,” Dr. Tan concluded.

NR

—C. Justin Romano

Suggested Reading
O’Neill MJ, Murray TK, Lakics V, et al. The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Target CNS Neurol Disord. 2002;1:399-411.
Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther. 1999;289:1545-1552.
Shytle RD, Mori T, Townsend K, et al. Cholinergic modulation of microglial activation by alpha7 nicotinic receptors. J Neurochem. 2004;March 15 [e-pub ahead of print].
Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease–related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821-827.
Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384-388.

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