Rationale:
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels play an essential role in the control of excitability in neurons and cardiomyocytes. These channels have been implicated in the pathophysiology of epilepsy, as reduced HCN channel currents were found in human and experimental epilepsy. However, their contribution to inherited generalized tonic-clonic seizure susceptibility remains unclear. Here, we investigate the effects of Ivabradine hydrochloride (IVA), a HCN channel blocker and FDA-approved drug for heart failure, on acoustically evoked seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s).Methods:
For the acute treatment experiment, male (n=10) and female (n=10) GEPR-3s were used; each GEPR-3 was used as its respective control (vehicle-treated). Initially, the vehicle for IVA was administered, and then the GEPR-3s were tested for seizures at 0.5, 1, 2, 4, and 24 h posttreatment time points. IVA was intraperitoneally administered at doses of 5, 10, and 20 mg/kg of body weight 0.5 h before acoustically evoked seizure testing. For the five-day treatment experiment, GEPR-3s were randomly divided into male (n = 6) and female (n = 6) groups, each group serving as its respective control. The vehicle for IVA was administered, and then the GEPR-3s were tested for seizures at 0.5, 1, 2, 4, and 24 h posttreatment time points. IVA was then administered intraperitoneally daily at 10 mg /kg body weight for five consecutive days, with seizure testing carried out on the fifth day. Seizure testing involved placing the GEPR-3s in an acoustic chamber, and pure tones (100–105 decibels) were delivered until either a seizure was elicited or a maximum of 60 seconds. For the brainstem-triggered limbic seizures experiment, we tested the effects of 10 mg/kg (i.p.) IVA on fully kindled seizures in male (n=4) and female (n=5) GEPR-3s at 1 and 24 hours posttreatment time points.
Results:
The results showed that IVA significantly decreased the occurrence of generalized tonic-clonic seizures (90% at 2nd hour, P< 0.001 posttreatment) and seizure severity (2nd hour, z= 2.70, P= 0.006 posttreatment) in both male and female GEPR-3s. These anticonvulsant effects were associated with delayed seizure onset (P< 0.001) and reduced seizure duration (P< 0.001). Interestingly, female GEPR-3s were more responsive to the antiseizure effects of IVA than males (P= 0.006). IVA 10 mg/kg suppresses the seizure in females between 1- 24 hrs. posttreatment. A five-day treatment completely suppressed seizures in both male and female GEPR-3s. Additionally, IVA acute treatment suppressed limbic seizures in both male (P= 0.01) and female (P= 0.006) GEPR-3s.