Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus

Excessive maternal caffeine consumption can lead to fetal and neonatal path ology, but the underlying mechanisms have not been determined. Here, we rep ort that low doses of caffeine generate seizures when applied in conjunctio n with brief anoxic episodes in the hippocampus of neonatal rats in vitro. In control conditions, brief (4-6 minutes) anoxic episodes reversibly depre ssed evoked synaptic responses and blocked the physiological pattern of net work activity. In the presence of caffeine (50 mu M), similar anoxic episod es generated ictal (29%) or interictal (33%) epileptiform activities often followed during reoxygenation by recurrent spontaneous seizure activity tha t persisted for several hours. These effects are likely mediated by a block ade of adenosine receptors by caffeine because (1) in control conditions, c affeine antagonized the inhibitory effect of selective A1 receptor agonist N-6-cyclopentyladenosine on excitatory synaptic responses, and (2) epilepto genic effects of caffeine were reproduced by selective Al receptor antagoni st 8-cyclopentyl-1,3-dipropylxanthine and theophylline. Our findings sugges t that endogenous adenosine released during anoxia acting via Al receptors prevents seizures in the neonatal hippocampus and that the antagonism of th ese receptors by caffeine leads to epileptogenesis. This study suggests con cerns about the safety of caffeine in the fetus and newborn.