Na channel modulators

Voltage-gated Na channels The DDT group, pyrethroids, Sabadilla Indoxacarb Delayed Na inactivation (Na channel modulators) Na channel blocker... 

Lysko, P.G., Webb, C.L., Yue, T.L., Gu, J.L., and Feuerstein, G. 1994. Neuroprotective effects of tetrodotoxin as a Na channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia. Stroke 25, 2476-2482. 

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

Can have fewer adverse effects and be better tolerated than carbamaze-pine Oxcarbazepine and its monohydroxy metabolite increase K+ conductance modulates the activity of high-voltage activated Ca+ channels and blocks Na+ channels. 

Safinamide is in Phase 111 clinical trials for Parkinson disease. The molecule possesses multiple mechanisms of action it combines inhibition of dopamine uptake and potent, selective, and reversible inhibition of MAO-B, sodium (Na" ") channel blockage, and calcium channel modulation, while being devoid of a MAO-A inhibitory effect (Figure 8.37). 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

The excitatory amino acid glutamate plays a key role in the modulation of nociceptive processing by acting through two distinct types of receptors excitatory ionotropic (tetrameric Ca /Na -channels NMDA, a-amino-3-hydroxyl-5-methyl-... 

The compound combines frequency and use-dependent blockade of Na channels, Ca " channel modulation, inhibition of glutamate release, and monoamine oxidase B inhibition. A study in human volunteers was successfully completed. The findings of MAOB inhibition at the dosages tested indicate the possibility of the potential use in Parkinson s disease. 

Theme number two is a very rich biology. Different channels may subserve different roles in different cell types, and possibly under different conditions. We are beginning to understand the complex network of factors and molecules that control or modulate channel expression and function. We are also beginning to understand dynamic aspects of channel expression. Recent work suggests that plasticity of Na channel expression can play an adaptive role in the normal nervous system, but there are also dynamic aspects of channel expression in diseased neurons, and in some cases changes are maladaptive. 

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