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It is presently unclear whether the antiseizure effects exerted by NSAIDs are totally dependent on COX inhibition or not. To clarify this point we investigated whether 7-methyl-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM2), two imidazo[1,2-b]pyridazines structurally related to indomethacin (IDM) but ineffective in blocking COXs, retain IDM antiabsence activity. When administered by intraperitoneal injection in WAG/Rij rats, a rat strain which spontaneously develops SWDs, both DM1 and DM2 dose-dependently suppressed the occurrence of these seizures. Importantly, these compounds were both more potent in suppressing SWD occurrence than IDM. As T-type channel blockade is considered a mechanism of action common to many antiabsence drugs we explored by whole cell patch clamp electrophysiology in stably transfected HEK-293 the effect of DM1 and DM2 on Ca(V)3.1 channels, the T-type channel subtype preferentially expressed in ventrobasal thalamic nuclei. Both these compounds dose-dependently suppressed the currents elicited by membrane depolarization in these cells. A similar T-type blocking effect was also observed when the cells were exposed to IDM. In conclusion, DM1 and DM2 whilst inactive on COXs, are potent antiabsence drugs. This suggests that compounds with structural features typical of NSAIDs may exert antiepileptic activity independently from COX inhibition and possibly by a direct interaction with T-type voltage-dependent Ca(2+) channels.

Abstract: The 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid, DM2, exerts anti-absence activity and blocks Cav3.1 channel, a T-type voltage-dependent Ca2+ channel subtype, in vitro. The current study investigated the effect of intra-ventrolateral periaqueductal grey (VLPAG) administration of DM2 on formalin-induced nocifensive responses in rats. In addition, the effect of intra-VLPAG microinjection of DM2 on the ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) cell population was also investigated. Formalin was injected subcutaneously into the dorsal surface of the hind paws of awake rats. We found that DM2 reduced nocifensive responses in the late phase of the formalin test. Moreover, in the RVM, the intra-VLPAG microinjection of DM2 reduced the ongoing and tail flick-related activity of the nociceptive ON cells, whereas it increased the ongoing activity and reduced the tail flick-induced pause of the antinociceptive OFF cells, consistent with antinociception. Behavioural and electrophysiological effects were reproduced by intra-VLPAG microinjection of ethosuximide, a conventional T-type Ca2+ channel blocker. Finally, DM2 administration did not produce any adverse cardiovascular effects as blood pressure and heart rate remained unchanged. In conclusion, DM2 plays an analgesic role in vivo and changes RVM cell activity, consistent with antinociception. These effects were even more potent than those elicited by ethosuximide treatments. [Copyright &y& Elsevier]