T-type channel blocking properties and antiabsence activity of two imidazo[1,2-b]pyridazine derivatives structurally related to indomethacin

Effect of Phenylbutazone on Pentylenetetrazole-Induced Seizure in Mice

“…Nevertheless, these secondary glial responses may subsequently contribute to a continuation or progression of epileptic seizures, for example during successful kindling (Bidmon et al, 2009). Rimoli et al (2009) have been shown that two imidazo[1,2-b]pyridazine derivatives, namely DM1 and DM2 are completely devoid of COX-1 and COX-2 inhibitory activity, but are effective in suppressing Spike and Wave Discharges (SWDs) in WAG/Rij rats, a genetic rodent model of absence epilepsy, similar to what was described for their structural congener Indomethacin (IDM), which significantly decreased SWDs in these rats. As T-type channel blockade has been considered as an electrophysiological feature common to antiabsence drugs, they also investigated whether DM1 and DM2 COX-independent antiseizure effect could depend on T-type channel blockade and they found that these compounds are indeed powerful T-type channel blockers and that this property is displayed by IDM as well.…”

“…As T-type channel blockade has been considered as an electrophysiological feature common to antiabsence drugs, they also investigated whether DM1 and DM2 COX-independent antiseizure effect could depend on T-type channel blockade and they found that these compounds are indeed powerful T-type channel blockers and that this property is displayed by IDM as well. The Rimoli et al (2009) study showed that IDM suppresses SWDs in vivo in a rat model of absence epilepsy and blocks CaV3.1 channels in vitro (Rimoli et al, 2009). In addition they report evidence suggesting that both these effects are at least in part independent from COX inhibition as they can be also observed with two indomethacin-like imidazopyridazines DM1 and DM2, which, are ineffective in blocking COXs.…”

“…A large body of experimental data accumulated in the past show that COX inhibitors possess antiseizure activity in different forms of epilepsy, including absence epilepsy. However, doubts still exist on the intimate mechanism responsible for these effects (Rimoli et al, 2009). As the blockade of voltage gated T-type Ca2+ channels has been traditionally considered as a major mechanism of action of antiabsence drugs on the basis of classical electrophysiological evidence and of more work on CaV3.1 knockout mice, in the study of Rimoli et al (2009) investigated whether IDM was effective in blocking these ion channels.…”

“…However, doubts still exist on the intimate mechanism responsible for these effects (Rimoli et al, 2009). As the blockade of voltage gated T-type Ca2+ channels has been traditionally considered as a major mechanism of action of antiabsence drugs on the basis of classical electrophysiological evidence and of more work on CaV3.1 knockout mice, in the study of Rimoli et al (2009) investigated whether IDM was effective in blocking these ion channels. In particular, they investigated IDM effect on CaV3.1 channels, which represent the main T-type isoform responsible for the firing of thalamic relay neurons and whose dysfunction is considered crucial in the genesis of absence epilepsy.…”

“…Their finding that IDM potently blocks CaV3.1 channels suggests that the antiabsence effect of this NSAID could be at least in part related to T-type channel blockade. To the best of their knowledge no previous study has specifically addressed the effect of PGs on T-type channel currents and, thus, the hypothesis that IDM and other NSAIDs could affect the activity of these channels by decreasing PG synthesis remains speculative and could represent an interesting subject of future investigation (Rimoli et al, 2009). A second possible mechanism that could account for IDM-induced decrease in CaV3.1 channel activity could be the accumulation of arachidonic acid that NSAIDs induce by blocking the conversion of this fatty acid in PGs.…”