Abstract
In addition to being the universal cellular energy source, ATP is the primary reservoir for the neuromodulator adenosine. Consequently, adenosine is produced during ATP‐depleting conditions, such as epileptic seizures, during which adenosine acts as an anticonvulsant to terminate seizure activity and raise the threshold for subsequent seizures. These actions protect neurones from excessive ionic fluxes and hence preserve the remaining cellular content of ATP. We have investigated the consequences of manipulation of intracellular ATP levels on adenosine release and epileptiform activity in hippocampal slices by pre‐incubating slices (3 h) with creatine (1 mM) and the combination of ribose (1 mM) and adenine (50 μM; RibAde). Creatine buffers and protects the concentration of cellular ATP, whereas RibAde restores the reduced cellular ATP in brain slices to near physiological levels. Using electrophysiological recordings and microelectrode biosensors for adenosine, we find that, while having no effect on basal synaptic transmission or paired‐pulse facilitation, pre‐incubation with creatine reduced adenosine release during Mg2+−free/4‐aminopyridine‐induced electrographic seizure activity, whereas RibAde increased adenosine release. This increased release of adenosine was associated with an attenuation of both the intensity and frequency of seizure activity. Given the depletion of ATP after injury to the brain, the propensity for seizures after trauma and the risk of epileptogenesis, therapeutic strategies elevating the cellular reservoir of adenosine may have value in the traumatized brain. Ribose and adenine are both in use in man and thus their combination merits consideration as a potential therapeutic for the acutely injured central nervous system.
Highlights
In addition to being the universal cellular energy source, adenosine triphosphate (ATP) is the primary reservoir for the neuromodulator adenosine
We explored the release of adenosine during in vitro seizure activity when the availability of intracellular ATP is experimentally influenced by both creatine, which buffers ATP decline, and ribose and adenine (RibAde), which elevates cellular ATP levels
Influence of creatine and RibAde on basal synaptic transmission Hippocampal slices were pre-incubated for at least 3 h in standard artificial cerebrospinal fluid (aCSF), or aCSF supplemented with either creatine
Summary
In addition to being the universal cellular energy source, ATP is the primary reservoir for the neuromodulator adenosine. Adenosine is produced during ATP-depleting conditions, such as epileptic seizures, during which adenosine acts as an anticonvulsant to terminate seizure activity and raise the threshold for subsequent seizures These actions protect neurones from excessive ionic fluxes and preserve the remaining cellular content of ATP. Using electrophysiological recordings and microelectrode biosensors for adenosine, we find that, while having no effect on basal synaptic transmission or paired-pulse facilitation, pre-incubation with creatine reduced adenosine release during Mg2+Àfree/4-aminopyridine-induced electrographic seizure activity, whereas RibAde increased adenosine release. This increased release of adenosine was associated with an attenuation of both the intensity and frequency of seizure activity. Cellular ATP & adenosine release in seizures 179 associated with neuronal activity must be minimized until as such time as ATP production resumed and/or ATP levels restored
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