Widespread neonatal brain damage following calcium channel blockade.
An abundance of evidence exists that shows calcium channel blockade promotes injury in cultured neurons. However, few studies have addressed the in vivo toxicity of such agents. We now show that the L-type calcium channel antagonist nimodipine promotes widespread and robust injury throughout the neonatal rat brain, in an age-dependent manner. Using both isolated neuronal as well as brain slice approaches, we address mechanisms behind such injury. These expanded studies show a consistent pattern of injury using a variety of agents that lower intracellular calcium. Collectively, these observations indicate that postnatal brain development represents a transitional period for still developing neurons, from being highly sensitive to reductions in intracellular calcium to being less vulnerable to such changes. These observations directly relate to current therapeutic strategies targeting neonatal brain injury.
Turner
C P
CP
Department of Neurobiology and Anatomy, Wake Forest University Medical School, Medical Center Boulevard, Winston-Salem, NC 27157-1010, USA. cpturner@wfubmc.edu
Miller
R
R
Smith
C
C
Brown
L
L
Blackstone
K
K
Dunham
S R
SR
Strehlow
R
R
Manfredi
M
M
Slocum
P
P
Iverson
K
K
West
M
M
Ringler
S L
SL
Berry
Z C
ZC
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000254:growth & development* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009553:Nimodipine / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018691:Excitatory Amino Acid Antagonists; D009553:Nimodipine; D016291:Dizocilpine Maleate; D053148:Caspase 3; D002118:Calcium