Gender difference in epileptogenic effects of 2-BFI and BU224 in mice

Imidazoline I₂ receptors are involved in pain modulation and psychiatric disorders and its ligands may represent a new therapeutic strategy against pain and depression. In particular, 2-BFI and BU224 are the two most widely studied I₂ receptor ligands and have antinociceptive and antidepressant-like activities in rodents. However, little is known of the toxicological effects and potential gender differences of these I₂ receptor ligands. This study examined the epileptogenic activities of 2-BFI and BU224 in male and female mice and also examined their underlying receptor mechanisms. 2-BFI (10-40 mg/kg, i.p.) and BU224 (10-40 mg/kg) produced epileptic seizures in a dose-related manner, as did the epileptogenic agent, pentylenetetrazole (PTZ, 15-60 mg/kg). However, female mice were significantly more sensitive than male mice in all the measures. The commonly used I ₂ receptor antagonist, idazoxan (10 mg/kg), did not block the onset and magnitude of the epileptic seizures or lethality induced by 2-BFI and BU224. When studied in combination, PTZ potentiated the epileptogenic effect of 2-BFI and BU224. The lack of antagonism by idazoxan of the epileptogenic activities of 2-BFI and BU224 suggests that the epileptogenic effects of 2-BFI and BU224 are mediated by non-imidazoline I₂ receptors and that I₂ receptors remain a viable therapeutic target for neurological disorders such as pain.