Mecamylamine prevents neuronal apoptosis induced by glutamate and low potassium via differential anticholinergic-independent mechanisms.
Neuronal loss via apoptosis caused by various stimuli may be the fundamental mechanism underlying chronic and acute neurodegenerative diseases. A drug inhibiting neuronal apoptosis may lead to a practical treatment for these diseases. In this study, treatment with mecamylamine, a classical antagonist of nicotinic acetylcholine receptors (nAChRs), prevented neuronal apoptosis induced by 75 microM glutamate and by low potassium (LK) in cerebellar granule neurons (CGNs) with EC(50)s of 35 and 293 microM, respectively. Two other antagonists of nAChRs, dihydro-beta-erythroidine and tubocurarine, failed to inhibit these two kinds of apoptosis. Mecamylamine inhibited the NMDA (30 microM)-evoked current and competed with [(3)H]MK-801. Furthermore, two inhibiters of the c-Jun N-terminal kinase (JNK) pathway prevented LK-induced apoptosis. Mecamylamine reversed the phosphorylation levels of JNK and c-Jun as well as the expression of c-Jun caused by LK in a Western blot assay. In addition, the JNK/c-Jun pathway was not involved in glutamate-induced cell death of CGNs. Our results suggest that mecamylamine prevents glutamate-induced apoptosis by blocking NMDA receptors at the MK-801 site and LK-induced apoptosis by inhibiting the activation of the JNK/c-Jun pathway.
Fu
Hongjun
H
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
Dou
Juan
J
Li
Wenming
W
Luo
Jialie
J
Li
Kenny C
KC
Lam
Colin S C
CS
Lee
Nelson T K
NT
Li
Mingtao
M
Han
Yifan
Y
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018678:Cholinergic Agents / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D008464:Mecamylamine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D018678:Cholinergic Agents; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D018698:Glutamic Acid; D008464:Mecamylamine; D016291:Dizocilpine Maleate; D011188:Potassium