Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120.
Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIV-associated dementia (HAD). In the healthy state, there are endogenous signals from neurons and astrocytes, which limit excessive central nervous system (CNS) inflammation. However, the signals controlling this process have not been fully elucidated. Studies on the peripheral nervous system suggest that a cholinergic anti-inflammatory pathway regulates systemic inflammatory response by way of acetylcholine acting at the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) found on blood-borne macrophages. Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial anti-inflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.
Giunta
B
B
Neuroimmunology Laboratory, College of Medicine, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA.
Ehrhart
J
J
Townsend
K
K
Sun
N
N
Vendrame
M
M
Shytle
D
D
Tan
J
J
Fernandez
F
F
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005702:Galantamine / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D015699:HIV Envelope Protein gp120; D018722:Nicotinic Agonists; D014409:Tumor Necrosis Factor-alpha; D005702:Galantamine; D009569:Nitric Oxide; D009538:Nicotine; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3