The Effect of the Anticonvulsant Topiramate on Acetylcholine-Induced Calcium Signals is Linked to Sirt-1 Activity

Abstract

Although some forms of epilepsy directly result from mutations in nicotinic acetylcholine receptors, none of the currently avail able antiepileptic drugs (AEDs) is specifically designed to target the cholinergic system. However, there is growing evidence that some established AEDs, which were primarily designed to modulate excitatory glutamatergic and/or inhibitory GABAergic currents, may also influence cholinergic signalling. This study therefore investigated whether topiramate (TPM), a second- generation AED, directly affects calcium signals and whether the deacetylase sirtuin- 1 (Sirt- 1) contributes to this effect. Calcium imaging in the human neuroblastoma cell line SH- SY5Y was used to quantify acetylcholine- and nicotine- induced calcium signals following TPM treatment. To evaluate the role of protein deacetylases, TPM effects were further analysed in the pres ence of the deacetylase inhibitors trichostatin A (TSA) and inauhzin. TPM treatment significantly enhanced acetylcholine- and nicotine- induced calcium signals. This effect of TPM was completely abolished in the presence of TSA. However, the presence of inauhzin resulted in an inhibitory effect of TPM on acetylcholine- induced calcium signals. These findings reveal a previ ously uninvestigated modulatory effect of TPM on cholinergic calcium signalling that is directly dependent on the activity of deacetylases, like Sirt- 1. The results may contribute to a better understanding of TPM's anticonvulsive mechanisms of action.