A polyamine-dependent mechanism underlying pharmacoresistance to anticonvulsant drugs in chronic epilepsy

• Applicant: Professor Dr. Heinz Beck
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419278711

Voltage-gated Na+ channels are molecular targets of first-line antiepileptic drugs (AEDs), including several promising new compounds. Use-dependent blocking effects are thought to be particularly important in the efficacy of these drugs to block abnormal excitability, since these effects are most pronounced during high-frequency neuronal activity. In previous work, we have shown a loss of use-dependent block of Na+ channels by carbamazepine (CBZ) in both pharmacoresistant human and experimental epilepsy, establishing this loss as potential mechanism of pharmacoresistance. However, the cellular and molecular mechanisms underlying the emergence of pharmacoresistant Na+ channels have been unclear. In the previous funding period, we have established a polyamine-dependent mechanism that powerfully modulates the responsiveness of Na+ channels not only to CBZ, but also to other anticonvulsant drugs. Specifically, we show that the balance of two intracellular polyamine species (N1-acetylspermine and N1-acetylspermidine) bidirectionally modulate AED responsiveness of Na+ channels. We show that the enzyme spermine synthase, which catalyzes the conversion of spermidine to spermine, and thereby also governs the balance of the acetylated polyamine species N1-acetylspermine and N1-acetylspermidine is essential in controlling pharmacoresponse of Na+ channels in a model system. Moreover, we show that this enzyme is regulated in chronic experimental epilepsy. In the current funding period, we will firstly examine in more detail how polyamine species and anticonvulsant drugs interact using our established model system (Aim 1)- Secondly, we will in more detail look at the expression of SMS in both experimental and human epilepsy (Aim 2). Third, we will perform electrophysiology in human hippocampal dentate granule cells to establish if CBZ efficacy is also modulated by N1-acetylspermine/ spermidine in human native neurons (Aim 3). Fourth, we will perform in-vivo rescue experiments that reinstate SMS expression in experimental epilepsy and examine whether this reinstates in-vivo and in-vitro CBZ responsiveness, and improves cognitive defects (Aims 4-7). Collectively these experiments will establish a mechanism underlying pharmacoresistance, and will provide a proof of principle for a gene therapy-based reinstatement of drug responsivity.

• DFG Programme: Research Grants