title: Choline blocks AMPA-induced dark cell degeneration of Purkinje neurons: potential role of the alpha7 nicotinic receptor.
abstract: The objective of the present study was to assess the contribution of sodium influx to development of dark cell degeneration (DCD) in Purkinje neurons (PNs) following AMPA (DL-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) receptor activation. During the course of these experiments, we observed inconsistent protection against DCD by Na(+) ion substitutes leading us to consider other potential mechanisms. A 30 min application of AMPA (30 microM, induction or trigger phase) followed by a 90-120 min AMPA-free expression period produced DCD in the majority of PNs. Substitution of NaCl with choline chloride (120 mM) produced a marked suppression of AMPA-induced toxicity. Suppression of DCD by choline was concentration dependent. Concentrations of choline as low as 10 mM effectively attenuated DCD when substituted on an equimolar basis for NaCl in the artificial cerebrospinal fluid (ACSF). Unlike choline, substitution of NMDG for NaCl failed to suppress AMPA-induced DCD. Lidocaine and TTX (tetrodotoxin), two agents that inhibit Na(+) influx failed to significantly alter DCD. Because choline is a prototypical alpha7 nicotinic receptor selective agonist, methyllycaconitine (MLA), an alpha7 receptor antagonist was tested and significantly attenuated the protective effects of choline in a concentration-dependent manner. Nicotine (100 microM) added to normal ACSF was effective in attenuating AMPA-induced toxicity. These findings suggest that DCD is not heavily dependent on Na(+)-mediated phenomena and that nicotinic alpha7 receptor activation may be neuroprotective against some types of excitotoxicity that are mediated by active cellular programs.
authors.affiliation: Departments of Physiology and Pharmacology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA. phyjcs@ttuhsc.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Strahlendorf
authors.forename: S
authors.initials: S
authors.lastname: Acosta
authors.forename: R
authors.initials: R
authors.lastname: Miles
authors.forename: H K
authors.initials: HK
authors.lastname: Strahlendorf
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives*; D000818:Animals; D002794:Choline / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005942:Gluconates / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D018690:Excitatory Amino Acid Agonists; D005942:Gluconates; D007306:Insecticides; D009498:Neurotoxins; D018697:Nootropic Agents; D018091:Receptors, AMPA; D011978:Receptors, Nicotinic; D015222:Sodium Channels; D064569:alpha7 Nicotinic Acetylcholine Receptor; C051643:N-methylglucamine gluconate; C054634:methyllycaconitine; D013779:Tetrodotoxin; D012965:Sodium Chloride; D008536:Meglumine; D009538:Nicotine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008012:Lidocaine; D012964:Sodium; D002794:Choline; D000157:Aconitine