TY - JOUR
T1 - Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons
AU - Mansouri, Bobbak
AU - Henne, William M.
AU - Oomman, Sowmini K.
AU - Bliss, Richard
AU - Attridge, Jennifer
AU - Finckbone, VelvetLee
AU - Zeitouni, Tarek
AU - Hoffman, Trent
AU - Bahr, Ben A.
AU - Strahlendorf, Howard K.
AU - Strahlendorf, Jean C.
N1 - Funding Information:
This research was supported in part by a Howard Hughes Medical Institute grant through the Undergraduate Biological Sciences Education Program to Texas Tech University, US Department of Defense Grant #W911SR-04-C-0049, and the TTUHSC Center for Cardiovascular Disease and Stroke.
PY - 2007/2/28
Y1 - 2007/2/28
N2 - AMPA receptor-elicited excitotoxicity is manifested as both a type of programmed cell death termed dark cell degeneration and edematous necrosis, both of which are linked to increased intracellular Ca2+ concentration. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of various destructive enzymes such as calpains, a family of Ca2+-dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and programmed cell death, we sought to determine the role of calpains in mediating both types of AMPA-mediated toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry for cytoskeletal breakdown products of calpain activity coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA-induced dark cell degeneration, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain-derived α-spectrin cleavage products in cerebellar Purkinje neurons that express dark cell degeneration, and the effectiveness of calpain antagonists, PD150606 and MDL28170, to attenuate AMPA-induced dark cell degeneration. Moreover, the AMPA receptor antagonist CNQX, a proven inhibitor of AMPA-elicited dark cell degeneration, also blocked AMPA-induced increases in α-spectrin, further suggesting interplay between abusive AMPA receptor activation, calpain activation and dark cell degeneration. Since AMPA-induced dark cell degeneration possesses morphological changes that resemble those that occur following brain ischemia in vivo, hypoglycemia, or extended seizure episodes, the involvement of calpains as mediators of cell death is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.
AB - AMPA receptor-elicited excitotoxicity is manifested as both a type of programmed cell death termed dark cell degeneration and edematous necrosis, both of which are linked to increased intracellular Ca2+ concentration. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of various destructive enzymes such as calpains, a family of Ca2+-dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and programmed cell death, we sought to determine the role of calpains in mediating both types of AMPA-mediated toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry for cytoskeletal breakdown products of calpain activity coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA-induced dark cell degeneration, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain-derived α-spectrin cleavage products in cerebellar Purkinje neurons that express dark cell degeneration, and the effectiveness of calpain antagonists, PD150606 and MDL28170, to attenuate AMPA-induced dark cell degeneration. Moreover, the AMPA receptor antagonist CNQX, a proven inhibitor of AMPA-elicited dark cell degeneration, also blocked AMPA-induced increases in α-spectrin, further suggesting interplay between abusive AMPA receptor activation, calpain activation and dark cell degeneration. Since AMPA-induced dark cell degeneration possesses morphological changes that resemble those that occur following brain ischemia in vivo, hypoglycemia, or extended seizure episodes, the involvement of calpains as mediators of cell death is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.
KW - AMPA
KW - Calpain
KW - Cerebellum
KW - Neuronal death
KW - α-Spectrin
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U2 - 10.1016/j.ejphar.2006.11.032
DO - 10.1016/j.ejphar.2006.11.032
M3 - Article
C2 - 17188264
AN - SCOPUS:33846575665
SN - 0014-2999
VL - 557
SP - 106
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -