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Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus
Author(s) -
Dzhala Volodymyr,
Desfreres Luc,
Melyan Zare,
BenAri Yehezkiel,
Khazipov Roustem
Publication year - 1999
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(199907)46:1<95::aid-ana14>3.0.co;2-1
Subject(s) - caffeine , adenosine receptor , adenosine , epileptogenesis , adenosine receptor antagonist , neuroscience , agonist , ictal , adenosine a1 receptor , medicine , excitatory postsynaptic potential , endocrinology , hippocampus , inhibitory postsynaptic potential , pharmacology , chemistry , receptor , epilepsy , psychology
Excessive maternal caffeine consumption can lead to fetal and neonatal pathology, but the underlying mechanisms have not been determined. Here, we report that low doses of caffeine generate seizures when applied in conjunction with brief anoxic episodes in the hippocampus of neonatal rats in vitro. In control conditions, brief (4–6 minutes) anoxic episodes reversibly depressed evoked synaptic responses and blocked the physiological pattern of network activity. In the presence of caffeine (50 μM), similar anoxic episodes generated ictal (29%) or interictal (33%) epileptiform activities often followed during reoxygenation by recurrent spontaneous seizure activity that persisted for several hours. These effects are likely mediated by a blockade of adenosine receptors by caffeine because (1) in control conditions, caffeine antagonized the inhibitory effect of selective A1 receptor agonist N 6 ‐cyclopentyladenosine on excitatory synaptic responses, and (2) epileptogenic effects of caffeine were reproduced by selective A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine and theophylline. Our findings suggest that endogenous adenosine released during anoxia acting via A1 receptors prevents seizures in the neonatal hippocampus and that the antagonism of these receptors by caffeine leads to epileptogenesis. This study suggests concerns about the safety of caffeine in the fetus and newborn. Ann Neurol 1999;46:95–102