Carbamazepine inhibits angiotensin I-converting enzyme, linking it to the pathogenesis of temporal lobe epilepsy

Abstract

We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems.

Figure 1

ACE activity and TLE. (a, b) Distributions of the I/D ACE polymorphism in the control and TLE group (control n=368; TLE n=72). (c, d) Allele frequencies. (e) Percentage of class 1A (best) outcome (Engel's classification) depending on genotype. (f, g) Mean (±s.e.m.) soluble ACE activity according to I/D distribution in the control group (n=127) and in patients with TLE (n=43). (h) Hippocampal tissue ACE activity. ^*P< 0.05, ^**P<0.01, ^***P<0.001.

Figure 2

Inhibition of ACE by carbamazepine. (a) Inhibitory profile of different drugs used in the treatment of epilepsy. Carbamazepine was the only antiepileptic drug able to inhibit plasmatic ACE activity. (b) Enzymatic activity of purified ACE. Mean (±s.e.m.) (^*P<0.05, ^***P<0.001). As a non-specificity control, carbamazepine had no inhibitory effect on either human plasmatic or purified kallikrein (Supplementary Figure 2). (c) HPLC assay demonstrating carbamazepine inhibition of Ang I degradation by ACE (^***P< 0.001). (d) Mean (±s.e.m.) plasmatic ACE activity is decreased 60 min after carbamazepine administration by gavage (150 μg kg⁻¹) in mice (^**P<0.01). (e) Mean (±s.e.m.) plasmatic ACE activity of TLE patients treated with carbamazepine (n=35) resembles that of the control group (n=55), whereas non-carbamazepine-treated TLE patients (n=15) have significantly higher ACE activities (^*P<0.05).