SSAT - Co-Administration of Valproic Acid (Vpa), a Histone Deacetylase Inhibitor, and a Neurokinin-1 Receptor Antagonist (NK-1RA) Reduces Intraabdominal Adhesion Formation in a Rat Surgical Model and Also Downregulates the Expression of the Early Growth Response (Egr) Genes 1 and 3 Both In Vivo and in Human Mesothelial Cells

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Co-Administration of Valproic Acid (Vpa), a Histone Deacetylase Inhibitor, and a Neurokinin-1 Receptor Antagonist (NK-1RA) Reduces Intraabdominal Adhesion Formation in a Rat Surgical Model and Also Downregulates the Expression of the Early Growth Response (Egr) Genes 1 and 3 Both In Vivo and in Human Mesothelial Cells
Matthew T. Brady^*, Benjamin J. Keenan, Elizabeth G. King, Stanley Heydrick, Michael R. Cassidy, Arthur Stucchi

Surgery, Boston University School of Medicine, Boston, MA

Adhesions occur in ~100% of patients following abdominopelvic surgery. We have shown that both VPA and an NK-1RA administered intraperitoneally (IP) at the time of laparotomy reduce adhesions in a rat model, and further that they have improved efficacy when co-administered. Egr genes, a family of transcription factors that rapidly respond to stressors such as inflammation and ischemia, have been shown to modulate the expression a number of other genes that contribute to adhesion formation. To determine if VPA+NK-1RA may target Egr family members, sixteen rats underwent laparotomy with creation of six adhesive ischemic buttons as previously described and VPA (50mg/kg), NK-1RA (25mg/kg), a combination of both, or saline was administered IP at the time of laparotomy. Adhesive button tissue was collected from each of these animals 30 minutes postoperatively and control peritoneal tissue was taken from 4 nonoperative animal. A parallel study was also conducted in human mesothelial cells subjected to a cytokine cokctail to simulate inflammation to determine if Egr expression could contribute to the adhesiogenic role of the mesothelium, and if that expression could be altered by VPA, NK-1RA, or a combination of the two. In both studies, mRNA levels of Egr family members were measured by RT-PCR. Similar to their efficacy in preventing adhesions, the co-administration of VPA+NK-1RA significantly reduced Egr-1 and Egr-3 mRNA expression in button tissue compared with saline and each drug alone (Table 1). In mesothelial cells, a similar trend was observed for EGR-1, while the two drugs non-additively inhibited Egr-3. These data suggest that Egr-1 and Egr-3 may be novel therapeutic targets for adhesion prevention, with EGR-1 being a potentially more relevant target for specific drug effects we have observed on the mesothelium.

Table 1

Saline VPA NK-1RA VPA+NK-1RA
% Adhesions^a 100 ± 6 49.6 ± 4* 43.3 ± 8* 25.3 ± 5^†*
Egr-1 mRNA 9.0 ± 2.8 4.2 ± 0.8 2.28 ± 0.4* 0.8 ± 0.2^†*
Egr-2 mRNA 2.5 ± 1.3 0.2 ± 0.08 0.3 ± 0.04 0.2 ± 0.1
Egr-3 mRNA 13.6 ± 4.0 8.0 ± 3.9 2.0 ± 0.4* 0.4 ± 0.2^†*
Egr-4 mRNA ND ND ND ND

mRNA data are expressed as fold change of non-operated controls and shown as mean ± SEM; n=4 per group. *p < 0.05 compared with saline. ^† < 0.05 compared with NK1RA and VPA. ^aAdhesion data previously published in abstract form only (J Surg Res 172(2):340; 2012) and presented for correlation with Egr expression. ND, Not detected.

Table 2

Cytokines Cytokines + VPA Cytokines + NK-1RA Cytokines + VPA + NK-1RA
Egr-1 mRNA 12.4 ± 2.0 5.1 ± 1.7 4.3 ± 0.7 2.7 ± 0.2*
Egr-3 mRNA 128.3 ± 17.4 21.4 ± 5.5* 33.7 ± 7.3* 39.6 ± 7.7*

mRNA data are expressed as a fold change of untreated control cells and shown as mean ± SEM; n=3 per group. *p< 0.05 compared with cytokine treatment alone by ANOVA. Data were collected at times of peak expression: 60 minutes for Egr-1 and 90 minutes for Egr-3.

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