The cord is lost and the PIC is diminished. In the normal state, the NaPIC and the CaPIC can be modulated by affecting the HIF signaling pathway channels directly or by activating G protein coupled 5 HT2 and NE 1 receptors. Riluzole directly inhibits the NaPIC by blocking inactivated sodium channels. In contrast, the loss of monoaminergic drive decreases the PIC because the 5 HT2 and NE 1 receptors are no longer activated. However, when monoaminergic drive is lost, the PIC amplitude gradually increases because the 5 HT2, and possibly NE 1, receptors become constitutively active and supersensitive. This suggests an interesting speculation, that the loss of monoamines but not direct channel block can result in strong compensatory increases in the PIC amplitude. However, compensatory mechanisms may be impaired or altered during disease and injury and are therefore difficult to compare. Riluzole produces a stronger effect on the SOD1 PIC. It was somewhat unexpected that riluzole TGF-beta treatment would have differential effects on wt versus SOD1 motoneurons. Prolonged riluzole treatment, however, decreased the PIC amplitude in SOD1 but not wt motoneurons.
This result remained even when PDE inhibitors conductance was controlled for and cannot be attributed to changes in the TTX ins current. Although the decrease in PIC amplitude did not change motoneuron firing behavior to injected current, it may have more pronounced effects on synaptic input because of the dendritic location of many PIC channels. The specificity of the result suggests that the sodium channels underlying the PIC in SOD1 motoneurons have an altered response to riluzole that could result in greater channel internalization or stabilization of the channel in an inactive state. Riluzole’s transience: alternative hypotheses. In this study the NaPIC was not upregulated after prolonged riluzole exposure. In ALS patients, however, riluzole treatment is assessed over months, not days. Therefore it is possible that the exposure to riluzole was too short to produce compensatory changes in excitability. In a number of studies, however, compensatory changes in excitability have been reported after 48 h and 3 4 days of exposure to TTX and after 48 h of exposure to prostaglandin E2. An alternative hypothesis is that although prolonged riluzole pimecrolimus exposure does not increase intrinsic excitability, it may increase extrinsic motoneuron excitability through synaptic scaling.
We saw no increase in spontaneous firing when synaptic blockers were absent, but this study did not directly test synaptic scaling, which can occur during periods of hypoexcitability. It has been repeatedly demonstrated that activitydeprived neurons die off because of an increased sensitivity to glutamate mediated postsynaptic responses and/or increased calcium neuron entry through GluR2 lacking AMPA receptors. In these studies, however, synaptic activity was completely blocked through chronic application of TTX. In this study, 2 M riluzole was used, which does not completely block APs. Therefore its capacity to produce synaptic scaling is unknown, however, there was no sign of obvious cellular death between control and cells treated with 2 M riluzole. Finally, riluzole may be unable to permanently slow motoneuron death regardless of its effect on motoneuron excitability.