Long-term treatment with nicotine suppresses neurotoxicity of, and microglial activation by, thrombin in cortico-striatal slice cultures.
The mechanisms of tissue injury associated with intracerebral hemorrhage involve multiple actions of thrombin, a blood-derived coagulation factor, on cells within the brain parenchyma, including activation of microglia as well as direct cytotoxicity on neurons. Based on emerging evidence that stimulation of nicotinic acetylcholine receptors provides neuroprotective effects and also suppresses cytotoxic properties of activated microglia, we investigated the effect of nicotine on thrombin-induced pathological changes in cortico-striatal slice cultures. Long-term (15 days), but not short-term (up to 144 h), treatment with nicotine (3-30 microM) partially prevented thrombin-induced neuron loss in the cortical region and tissue shrinkage in the striatal region. In addition, long-term treatment with nicotine suppressed thrombin-induced increase in microglia in a concentration-dependent manner, which was accompanied by suppression of morphological changes of microglia into their activated form. Methyllycaconitine (an alpha7-selective antagonist) and dihydro-beta-erythroidine (an antagonist specific for beta2-containing receptors), as well as mecamylamine (a non subtype-selective nicotinic receptor antagonist), abrogated the protective effect of nicotine against thrombin-induced striatal shrinkage and the inhibitory effect of nicotine against thrombin-induced increase in activated microglia. Besides adding further evidence that nicotinic receptor stimulation exerts neuroprotective functions, these results reveal a novel mode of action of nicotine on neural tissues that appears after long-term treatment.
Ohnishi
Masatoshi
M
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Katsuki
Hiroshi
H
Takagi
Mikako
M
Kume
Toshiaki
T
Akaike
Akinori
A
D000818:Animals; D066298:In Vitro Techniques; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010296:Parietal Lobe / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
D018696:Neuroprotective Agents; D009498:Neurotoxins; D009538:Nicotine; D011978:Receptors, Nicotinic; D013917:Thrombin; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579165:Chrna7 protein, rat