PMC

Chemical structures of valproic acid (VPA) and sec-butylpropylacetamide (SPD). Asterisks denote chiral carbons.

Effect of SPD and VPA on heat hyperalgesia in the carrageenan model. Each point represents the mean withdrawal latency ± s.e.m. of the injected paw in all groups tested. (* p<0.05, *** p<0.001 Tukey multiple comparison test vs. Carr/MC group, n=14 in the 10, 30 mg/kg, n=23 in the 50, 70 mg/kg and VPA groups, n=30 and 40 in the Sal/MC and Carr/MC groups respectively).

The effect of 10, 30, 50 and 70 mg/kg SPD administered i.p. in the writhing test; (A) and 10, 50 and 100 mg/kg VPA (B) on the mean number of writhes in the writhing test compared to control. Each bar represents the number of writhes ± s.e.m. (n=11 in each group, ** p<0.01 *** p<0.001 Tukey multiple comparison test).

Plasma concentration vs. time curve following i.p. administration of 80 mg/kg SPD in mice (a) and rats (b). Each point represents mean ± s.e.m. of four animals per time point (n=4). Table represents PK parameters derived from plasma concentration vs. time plot of SPD following i.p. administration of 80 mg/kg to both mice and rats compared to VPA. The units for each PK parameter are shown in brackets.
^a Taken from [] parameters derived following administration of 50 mg/kg VPA orally (p.o.) to mice.
^b Taken from [] following administration of 300 mg/kg VPA i.p. to rats.

The effect of SPD and VPA on the licking time in the formalin test following i.p. administration of 35 and 70 mg/kg SPD (A), 70, 100 and 300 mg/kg VPA (B). The graph shows two phases: acute (0–10 min) and inflammatory (10–40 min). Each point represents mean ± s.e.m. (* p<0.01 Tukey test for multiple comparisons, n=8). C. Table indicating the mean AUC values ± s.e.m. and % reduction vs. control vehicle in the acute and inflammatory phases of both SPD and VPA.

A. Paw thickness as measured in the injected and uninjected hind paws in the carrageenan test for all groups tested. Bars represent mean ± s.e.m. for all animals tested in the study. Ipsi= injected paw, Contra= uninjected paw. (*** p<0.001, Tukey multiple comparison test, n=14 in the 10, 30 mg/kg for SPD, n=23 in the 50, 70 mg/kg SPD and 100 mg/kg VPA groups, n=30 and 40 in the Sal/MC and Carr/MC groups respectively). B. Effect of 70 mg/kg SPD (Carr/SPD) vs. 100 mg/kg Ibuprofen (Carr/Ibu) on carrageenan induced paw thickness as measured for 24h following plantar injection of carrageenan. Each point represents mean ± s.e.m. (* p<0.05, Tukey multiple comparison test, n=5 per group).

Representative compound action potential (CAP) recorded following tonic (A) and phasic (B) stimulation of the rat sciatic nerve in vitro. A. The left and right CAPs correspond to the A and C fibers respectively; recorded after 0.2 Hz stimulation frequency (tonic). Bold traces represent CAPs following perfusion with 3 mM SPD (upper panel) or 1 mM lidocaine (lower panel). Each trace represents an average of 10 consecutive traces. B. Upper panels represent individual CAPs in the phasic protocol following control (light gray), 3mM SPD and 1mM lidocaine (dark gray). Lower panels represent CAP recorded in 40 Hz stimulation frequency (phasic) following control, 3mM SPD, washout and 1mM lidocaine.

A. Tonic stimulation. Percent normalized peak to peak area ratio measured from A fibers (right white bar) and C fibers (left gray bar) before treatment (baseline) and following 1 and 3 mM SPD or 1 mM lidocaine. Each bar represents mean area ± s.d. (** p<0.01 Dunnet’s test, n=5). Bars represent 92%, 96%, 97%, 95% reduction for the A and C fibers following 1 and 3 mM SPD respectively, and 51% and 39% reduction of CAP from base line for the A and C fibers respectively following 1mM lidocaine. B. Phasic stimulation. left: Data presented as percent decrease in amplitude of the last CAP compared to the first CAP (Δf) at baseline and following perfusion with 3 mM SPD and 1mM lidocaine. Right: Percent peak area ratio normalized to baseline following the first and last CAP measured in the stimulus train. Bars represent mean ± s.e.m. (n=5). (*** p<0.001 one way ANOVA).

The effect of i.p. administration of SPD and MTMCD (as a positive control) on tactile allodynia in rats with SNL neuropathy. A. Data shows withdrawal threshold for the ipsilateral paw before (0) and 30, 60, 120, 180, and 240 min after treatment. The protective criterion (15g) is indicated by the dashed gray horizontal line. Each time point represents the mean pain threshold ± s.e.m. for the entire group of rats evaluated. B. box whisker plots representing the area under the curve (AUC) for each treatment in A. Both 60 and 80 mg/kg SPD had a significant higher AUC compared to control vehicle. MTMCD as a positive control was significantly different than MC and 40 mg/kg SPD but not 60 or 80 mg/kg SPD. (*p<0.05, **p<0.01, ***p<0.001, Tukey multiple comparison test (n=8 for MC and 40 mg/kg, n=9 for 60 and 80 mg/kg, n=7 for MTMCD). Table. The table indicates the ratio of protected rats (not responding to the 15g VFF denoted by the left number) to the total number of rats tested. The 60 minute time point (highlighted) corresponding to SPD’s time to peak antiallodynic effect. .