The neuronal apoptotic death in global cerebral ischemia in gerbil: important role for sodium channel modulator.
Global ischemia was induced in gerbil by bilateral occlusion of the common carotid arteries for 5 min. Sodium ionophore monensin or sodium channel blocker tetrodotoxin (TTX) was administered at doses of 10 micorg/kg, i.p., 30 min before ischemia induction; the dose was repeated after 22 hr. Subsequently, brain infarct occurred, determined at 24 hr after occlusion. Large, well-demarcated infarcts were observed in both hemispheres, an important observation because it critically influences the interpretation of the data. Because nitric oxide (NO) production is thought to be related to ischemic neuronal damage, we examined increases in Ca(2+) influx, which lead to the activation of nitric oxide synthase (NOS). Then we evaluated the contributions of neuronal NOS, endothelial NOS, and inducible NOS to NO production in brain cryosections. The cytosolic release of apoptogenic molecules like cytochrome c and p53 were confirmed after 24 hr of reflow. TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) labeling detected the apoptotic cells, which were confirmed in neuron-rich cell populations. After 24 hr, all the ischemic changes were amplified by monensin and significantly attenuated by TTX treatment. Additionally, the nesting behavior and histological outcomes were examined after 7 day of reflow. The neuronal damage in the hippocampal area and significant decrease in nesting scores were observed with monensin treatment and reduced by TTX pretreatment after day 7 of reflow. To our knowledge, this report is the first to highlight the involvement of the voltage-sensitive Na(+) channel in possibly regulating in part NO system and apoptosis in a cytochrome c-dependent manner in global ischemia in the gerbil, and thus warrants further investigation.
Brahma
Manoja Kumar
MK
Division of Pharmacology, Central Drug Research Institute, Lucknow, India.
Dohare
Preeti
P
Varma
Saurabh
S
Rath
Srikanta Kumar
SK
Garg
Puja
P
Biswal
Prasanta Kumar
PK
Chowdhury
Piyali Dhar
PD
Ray
Madhur
M
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D042783:Endothelial Cells / Q000502:physiology; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008985:Monensin / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007476:Ionophores; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016159:Tumor Suppressor Protein p53; D013779:Tetrodotoxin; D045304:Cytochromes c; D008985:Monensin; D019001:Nitric Oxide Synthase; D002118:Calcium