Neuronal protection correlates with prevention of calcium-calmodulin binding in rats.
We correlated the efficacy of several clinically relevant pharmacotherapies with their ability to prevent calcium influx into neurons and subsequent binding to calmodulin. We studied the administration of CGS 19755, nimodipine, nicardipine, and combinations of these drugs before or immediately after ischemia in globally ischemic rats. Calcium-calmodulin binding was graded by an immunohistochemical assay after 2 and 24 hours of reperfusion (n = 5-6 at each time period), and histologic damage was graded by light microscopy after 72 hours of reperfusion (n = 6). Calcium-calmodulin binding correlated with the severity of delayed histologic damage in various brain regions. In untreated ischemic control rats, marked calcium-calmodulin binding was seen in CA1 and CA3 after 24 hours of reperfusion (p less than or equal to 0.01). Administered before ischemia, CGS 19755 prevented calcium-calmodulin binding across all brain regions after 2 and 24 hours of reperfusion compared with controls (p less than or equal to 0.05). This effect was most prominent in CA3 and CA1, where the drug also reduced delayed neuronal damage (p less than or equal to 0.05). Lower doses or postischemic administration of CGS 19755, nimodipine, nicardipine, and a combination of postischemic CGS 19755 and nicardipine had a more limited effect on calcium-calmodulin binding and did not protect against delayed neuronal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Grotta
J C
JC
Department of Neurology, University of Texas Medical School, Houston 77030.
Picone
C M
CM
Dedman
J R
JR
Rhoades
H M
HM
Strong
R A
RA
Earls
R M
RM
Yao
L P
LP
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D010875:Pipecolic Acids; D010880:Piperidines / Q000494:pharmacology; D051381:Rats
D002147:Calmodulin; D010875:Pipecolic Acids; D010880:Piperidines; C053672:selfotel; D009553:Nimodipine; D009529:Nicardipine; D002118:Calcium