Our previous study revealed that cordycepin features important neuroprotective effects against hypoxic insult by improvement of neuronal electrophysiological function. across the neuronal membrane, OSI-420 inhibitor database activation of VGSC takes on a critical part in mediating sustained Na+ access during ischemia and hypoxia, which then induce membrane depolarization [3, 18]. Thus, obstructing these channels may exert neuroprotection during hypoxia [4, 5]. Although our earlier study discovered that cordycepin selectively regulates activities of whole-cell Na+ current (represents conductance at each control voltage, represents the current amplitude measured from each control voltage, 0.05 level of confidence was considered statistically significant. 3. Results 3.1. Cordycepin Inhibited = 10; 0.01). After cordycepin (80? 0.05, ?? 0.01 as compared with the control group. 3.2. Effects of Cordycepin on = 10) and cordycepin (= 10) treatment groups SOCS-3 did not show a significant shift, as shown in Figure 2(c) ( 0.05). 3.3. Effect of Cordycepin on = 10; cordycepin: ?54.8??4.1, = 10; 0.05). Application of cordycepin produced a 7.4?mV negative shift in the inactivation curve. Open in a separate window Figure 3 Effects of cordycepin on 0.05, ?? 0.01 as compared with the control group. 3.4. OSI-420 inhibitor database Effect of Cordycepin on = 10) and cordycepin (= 10) ( 0.05) groups, respectively. Cordycepin significantly reduced the rate of 0.05, ?? 0.01 as compared with the control group. 3.5. Preapplication of Cordycepin-Induced Mild Inhibition on = 12; Figures 5(a) and 5(b), Table 1; 0.01). Steady-state inactivation was shifted by ?9.2??0.8?mV, and recovery time from inactivation also increased (recovery time constant in control: 1.51??0.06?ms, = 12; hypoxia: 2.21??0.12?ms, = 12; 0.05). Interestingly, response of = 12; Figures 5(a) and 5(b), Table 1) compared with hypoxia only (50.6%??5.12% of initial = 12; Figures 5(a) and 5(b), Table 1; 0.05). In the cordycepin pretreatment group, the descending slope (4.6??0.32?mV/min, = 12; Figure 5(b), Table 1) between 0 and 3?min after hypoxia treatment was obviously decreased when compared with hypoxia only (15??0.11?mV/min, = 12; Figure 5(b), Table 1). And most notably, the onset time of hypoxia-induced rapid dramatic inhibition on peak 0.05 as compared with the cordycepin pretreatment group. Table 1 Preapplication of cordycepin-induced mild inhibition on = 10)96.8??3.8?47.4??3.71.48??0.06Cordycepin (= 10)77.6??4.58##?54.8??4.1#2.10??0.14#Hypoxia (= 12)50.6??5.12##15??0.11?55.9??3.9#2.21??0.12#Cordycepin?+?hypoxia (= 12)66.3??5.53?,##4.6??0.32???54.3??3.8#2.26??0.14# Open in a separate window Descending slope means the inhibition rate induced by hypoxia from 0 to 3?min; ? 0.05 and ?? 0.01 compared to the hypoxia group; # 0.05 and ## 0.01 compared to the control group. 4. Discussion In the present study, we observed that cordycepin decreased the amplitude of em I /em Na in a concentration-dependent manner (Figure 1). Steady-state inactivation curves of em I /em Na shifted to more negative potentials (Figure 3), and time of em I /em Na recovery from inactivation was prolonged significantly by cordycepin (Figure 4). A negative shift on inactivation curve indicates low membrane potential threshold required for closing these channels. Slower recovery from inactivation implies prolonged transition of VGSC in cordycepin from inactivated to closed state and reduced fraction of available VGSC during spike trains . These results imply that suppression of em I /em Na by cordycepin may inhibit intrinsic bursting and thus lead to a reduction in neuronal activity in CA1 neurons. This speculation was also confirmed by our previous study, which indicated that cordycepin can inhibit neuronal activity with low-frequency action potential bursting . Furthermore, cordycepin pretreatment can significantly attenuate and delay hypoxia-induced rapid dramatic inhibition on em I /em Na (Figure 5, Table 1) with no additional effects on shifts in steady-state inactivation and recovery time course from inactivation (Table 1). This result indicates that suppression effect of cordycepin on em I /em Na and em I /em Na kinetics may contribute to its neuroprotection from hypoxic insult. em I /em Na is OSI-420 inhibitor database responsible for both action potential generation and propagation and therefore plays a crucial role in neuronal excitability [1, 2, 25]. Thus, em I /em Na modulation may possess biological significance. Previous studies suggested that influx of Na+ contributes to brain damage during ischemia insult, as through activation of VGSC, Na+ influx across neuronal membrane mediates sustained Na+ entry, which in turn induces excessive membrane depolarization [2C4, 18,.