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Positive allosteric modulation of alpha7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neurons.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2009 Dec; Vol. 158 (8), pp. 1857-64. - Publication Year :
- 2009
-
Abstract
- Background and Purpose: alpha7-Nicotinic acetylcholine receptors (alpha7 nAChRs) play an important role in cognitive function. Positive allosteric modulators (PAMs) amplify effects of alpha7 nAChR agonist and could provide an approach for treatment of cognitive deficits in neuropsychiatric diseases. PAMs can either predominantly affect the apparent peak current response (type I) or increase both the apparent peak current response and duration of channel opening, due to prolonged desensitization (type II). The delay of receptor desensitization by type II PAMs raises the possibility of Ca2+-induced toxicity through prolonged activation of alpha7 nAChRs. The present study addresses whether type I and II PAMs exhibit different cytotoxicity profiles.<br />Experimental Approach: The present studies evaluated cytotoxic effects of type I PAM [N-(4-chlorophenyl)]-alpha-[(4-chlorophenyl)-aminomethylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and type II PAM 1-[5-chloro-2,4-dimethoxy-phenyl]-3-[5-methyl-isoxazol-3-yl]-urea (PNU-120596), or 4-[5-(4chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulphonamide (A-867744). The studies used cultures of PC12 cells and primary cultures of rat cortical neuronal cells.<br />Key Results: Our results showed that neither type I nor type II PAMs had any detrimental effect on cell integrity or cell viability. In particular, type II PAMs did not affect neuron number and neurite outgrowth under conditions when alpha7 nAChR activity was measured by Ca2+ influx and extracellular signal-regulated kinases 1 and 2 phosphorylation, following exposure to alpha7 nAChR agonists.<br />Conclusions and Implications: This study demonstrated that both type I and type II alpha7 nAChR selective PAMs, although exhibiting differential electrophysiological profiles, did not exert cytotoxic effects in cells endogenously expressing alpha7 nAChRs.
- Subjects :
- Allosteric Regulation drug effects
Animals
Calcium metabolism
Cell Survival drug effects
Electrophysiology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Neurites drug effects
Neurites metabolism
Neurons drug effects
Neurons metabolism
Nicotinic Agonists toxicity
PC12 Cells
Phosphorylation drug effects
Rats
Rats, Sprague-Dawley
Receptors, Nicotinic metabolism
alpha7 Nicotinic Acetylcholine Receptor
Isoxazoles toxicity
Phenylurea Compounds toxicity
Pyrroles toxicity
Receptors, Nicotinic drug effects
Sulfonamides toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 158
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20050184
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00474.x