The effects of valproic acid on skin healing: experimental study in rats

Sixty male Wistar rats were divided into two groups: the experiment treated with VPA (100 mg/kg/day); and the control, with 0.9% sodium chloride by gavage. Skin healing was studied in three moments (the third, the seventh, and the 14th day), evaluating the parameters: inflammatory reaction and its intensity (anti-LCA), angiogenesis (anti-CD34), collagen I and III (anti-collagen I, anti-collagen III and Picrosirius-red F3BA) and myofibroblasts (anti-alpha-AMS).

Results:

The inflammatory reaction was acute or sub-acute in both groups on the third day. On the seventh and the 14th day, chronic predominated in the control (p=0.006), and sub-acute in the experiment (p=0.020). There was a greater number of leukocytes in the group treated only on the third day (p=0.036). The number of vessels was lower in the treated group at the three times (p3=0.002, p7<0.001, and p14=0.027). Myofibroblasts were rare in the third day and moderate quantity in the remaining periods. Collagen I density was higher in the control at the three times (p<0.001) and collagen III in the treated group (p<0.001).

Conclusions:

VPA led to a more intense inflammatory reaction, decreased angiogenesis and collagen deposition, especially type I collagen.

Key words
Valproic Acid; Epigenesis, Genetic; Wound Healing; Cell Proliferation; Collagen

Inflammatory reaction	3 days		7 days		14 days
Inflammatory reaction	Cont.	Exp.	Cont.	Exp.	Cont.	Exp.
Acute/sub-acute	11	10	2	9	3	9
Acute/sub-acute	100%	100%	20%	90%	30%	90%
Cronic	0	0	8	1	7	1
Cronic	0%	0%	80%	10%	70%	10%
Total	11	10	10	10	10	10
p^* * Fisher’s exact test, p<0.05; Cont.: control group; Exp.: experimental group. (Cont. × Exp.)	1		0.006		0.020

Variable	Day	Group	N	Average	Standard deviation	Median	Minimum	Maximum	AIQ	p^* * Fisher’s exact test, p<0.05; Cont.: control group; Exp.: experimental group. (Cont. × Exp.)
LCA	Day 3	Cont.	11	26.27	9.49	25	10	50	8	0.036
	Day 3	Exp.	10	36	15.78	30	25	70	10	0.036
	Day 7	Cont.	10	14.70	6.31	15	5	25	5	0.280
	Day 7	Exp.	10	19	8.10	25	5	25	15	0.280
	Day 14	Cont.	10	5.10	1.52	5	3	8	2	0.529
	Day 14	Exp.	10	5.20	2.49	5	3	12	1	0.529
p^ non-parametric Kruskal-Wallis test (LCA); AIQ: interquantum rage; Cont.: control group; Exp.: experimental group.		Cont.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.142	d3 × d14: p<0.001	d7 × d14: p=0.026
		Exp.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.070	d3 × d14: p<0.001	d7 × d14: p=0.033

Variable	Day	Group	N	Average	Standard deviation	Median	Minimum	Maximum	AIQ	p^* * Student’s test for independent sample; p<0.05; (Cont. × Exp.)
CD34	Day 3	Cont.	11	15.45	2.94	15	11	20	6	0.002
	Day 3	Exp.	10	10.40	3.44	11.50	5	15	6	0.002
	Day 7	Cont.	10	15.50	2.88	15	12	20	5	<0.001
	Day 7	Exp.	10	10.50	2.22	10.50	7	15	3	<0.001
	Day 14	Cont.	10	8.50	2.01	8.50	6	12	3	0.027
	Day 14	Exp.	10	6.10	2.42	6	3	10	4	0.027
p^ one-way analysis of variance (ANOVA) test (CD34); p<0.05; AIQ: interquantum rage; Cont.: control group; Exp.: experimental group.		Cont.		d3 × d7 × d14: p<0.001	d3 × d7: p=1	d3 × d14: p<0.001	d7 × d14: p<0.001
		Exp.		d3 × d7 × d14: p=0.001	d3 × d7: p=1	d3 × d14: p=0.005	d7 × d14: p=0.004

Day	Group	n	Average	Standard deviation	Median	Mínimum	Maximum	AIQ	p^* * Non-parametric Mann-Whitney’s test (day 7 and day 14) or Student’s t-test for independent samples (day 3); p<0.05; (Cont. × Exp.)
Day 3	Cont.	11	15	5	15	10	20	10	<0.001
Day 3	Exp.	10	4.50	3.69	5	0	10	5	<0.001
Day 7	Cont.	10	56	5.16	60	50	60	10	<0.001
Day 7	Exp.	10	17.50	10.07	12.50	5	30	20	<0.001
Day 14	Contr.	10	98.50	2.42	100	95	100	5	<0.001
Day 14	Exp.	10	81.50	7.47	82.50	70	90	15	<0.001
p^ non-parametric Kruskal-Wallis test; p<0.05; AIQ: interquantum rage; Cont.: control group; Exp.: experimental group.	Cont.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.022	d3 × d14: p<0.001	d7 × d14: p=0.038
	Exp.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.100	d3 × d14: p<0.001	d7 × d14: p=0.016

Day	Group	n	Average	Standard deviation	Median	Mínimum	Maximum	AIQ	p* (Cont. × Exp.)
Day 3	Cont.	11	85	5	85	80	90	10	<0.001
Day 3	Exp.	10	95.50	3.69	95	90	100	5	<0.001
Day 7	Cont.	10	44	5.16	40	40	50	10	<0.001
Day 7	Exp.	10	82.50	10.07	87.50	70	95	20	<0.001
Day 14	Cont.	10	1.50	2.42	0	0	5	5	<0.001
Day 14	Exp.	10	18.50	7.47	17.50	10	30	15	<0.001
p**	Cont.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.022	d3 × d14: p<0.001	d7 × d14: p=0.038
p**	Exp.		d3 × d7 × d14: p<0.001	d3 × d7: p=0.100	d3 × d14: p<0.001	d7 × d14: p=0.016

Day	Group	N	Average	Standard deviation	Median	Minimum	Maximum	AIQ	p^* * Student’s t-test for independent sample; p<0.05; (Cont. × Exp.)
Day 3	Cont.	11	15.31	2.58	15.85	11.06	19.73	4.07	0.001
Day 3	Exp.	10	11.15	2.41	10.32	8.05	15.51	3.44	0.001
Day 7	Cont.	10	19.58	3.08	18.68	15.72	25.62	5.16	0.004
Day 7	Exp.	10	15.03	3.07	15.91	9.39	18.72	4.75	0.004
Day 14	Cont.	9	27.47	4.32	27.45	22.84	34.15	6.40	<0.001
Day 14	Exp.	10	19.39	2.58	19.03	15.87	23.22	3.57	<0.001
	Cont.		d3 × d7 × d14 p<0.001	d3 × d7: p=0.021	d3 × d14: p<0.001	d7 × d14: p<0.001
	Exp.		d3 × d7 × d14 p<0.001	d3 × d7: p=0.010	d3 x d14: p<0.001	d7 × d14: p=0.004

Day	Group	N	Average	Standard deviation	Median	Minimum	Maximum	AIQ	p^* * Student’s t-test for independent sample; p<0.05; (Cont. × Exp.)
Day 3	Cont.	11	1.49	0.25	1.42	1.20	1.93	0.49
	Exp.	10	0.83	0.21	0.80	0.62	1.31	0.26	<0.001
Day 7	Cont.	10	6.48	1.17	6.62	4.64	8.67	1.71
	Exp.	10	2.75	0.81	2.77	1.53	4.29	1.12	<0.001
Day 14	Cont.	9	9.91	1.62	10.12	8.01	13.33	1.69
	Exp.	10	6.53	0.83	6.37	5.07	7.91	1.18	<0.001
^ one-way analysis of variance (ANOVA) test and Bonferroni post-hoc test, p<0.05; AIQ: interquantum rage; Cont.: control group; Exp.: experimental group.	Cont.		d3 × d7 × d14 p<0.001	d3 × d7: p<0.001	d3 × d14: p<0.001	d7 × d14: p<0.001
	Exp.		d3 × d7 × d14 p<0.001	d3 × d7: p<0.001	d3 × d14: p<0.001	d7 × d14: p<0.001

Day	Group	N	Average	Standard deviation	Median	Minimum	Maximum	AIQ	p^* * Student’s t-test for independent sample; p<0.05; (Cont. × Exp.)
Day 3	Cont.	11	13.82	2.69	14.65	9.23	18.48	3.67
Day 3	Exp.	10	10.32	2.31	9.65	7.39	14.59	3.63	0.005
Day 7	Cont.	10	13.10	2.50	13.04	9.13	16.95	4.46
Day 7	Exp.	10	12.28	2.69	13.10	7.86	15.91	4.12	0.489
Day 14	Cont.	9	17.55	2.92	17.10	14.15	22.66	3.96
Day 14	Exp.	10	12.87	2.15	12.35	10.37	15.91	3.75	<0.001
^ one-way analysis of variance (ANOVA) test and Bonferroni post-hoc test, p<0.05; AIQ: interquantum rage; Cont.: control group; Exp.: experimental group.	Cont.		d3 × d7 × d14 p=0.003	d3 × d7: p=1	d3 × d14: p=0.014	d7 × d14: p=0.004
	Exp.		d3 × d7 × d14 p=0.061	-

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[1] Conflict of interest: Nothing to declare.