66
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
VALPROIC ACID INTERFERENCE IN ABDOMINAL WALL TISSUE
REPAIR: POTENTIAL IMPLICATIONS FOR HERNIA AND LAPAROTOMY
SURGERIES
Marcos Louro de Hollanda1
João Pedro do Valle Varela2
Maria Victória Bahia Silva3
Nicole Meira Fernandes Costa4
Kelli Gonçalves Martins5
Melissa Fagundes Cardoso6
Juliana Martins Pinto7
Luiza Beatriz Dias Induzzi8
Gabriel Garcia de Azevedo Castro9
Leandro de Oliveira Camara10
Bernardo Alves Brambilla11
Giulia do Valle Risso12
Abstract: Valproic acid (AVP) is widely used in the treatment of epilepsy and mood disorders, but
1 Federal University of Rio de Janeiro (UFRJ)
2 São Carlos University Center
3 Vila Velha University (UVV)
4 Nove de Julho Guarulhos University (UNINOVE)
5 Vila Velha University (UVV)
6 Vila Velha University (UVV)
7 Vila Velha University (UVV)
8 Vila Velha University (UVV)
9 Unigranrio
10 Souza Marques College
11 Iguaçu University (UNIG) - Campus V - Itaperuna
12 Multivix Vitória - Goiabeiras Campus
67
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
recent studies suggest that its epigenetic action may negatively interfere in tissue regeneration and
healing processes. Repair of the abdominal wall, essential for the success of procedures such as
herniorrhaphy and laparotomy, depends on a cascade of inammatory, cellular and molecular events
that can be modulated by systemic drugs such as AVP. The aim of this study was to analyze the
interference of valproic acid in abdominal wall healing, considering its possible effects on collagen
synthesis, broblast proliferation and the integrity of the extracellular matrix, and to discuss its clinical
implications in abdominal surgery. This is a literature review with a qualitative and exploratory
approach. The studies were selected using the PubMed, SciELO, ScienceDirect and Scopus databases,
with full articles published in peer-reviewed scientic journals addressing the use of valproic acid in
the context of tissue healing, especially in patients undergoing surgical procedures. The time frame of
the research considered the period from 2018 to 2022, based on the oldest article (Costa et al., 2018)
and the most recent (Santos et al., 2022; Alves et al., 2022; Moura et al., 2022). The ndings indicate
that AVP, by acting as a histone deacetylase (HDAC) inhibitor, can alter the gene expression of key
proteins in the healing process, such as type I and III collagen, metalloproteinases and growth factors.
In experimental models, delayed granulation tissue formation and collagen matrix organization
were observed, suggesting an increased risk of dehiscence, incisional hernia and abdominal wall
fragility in patients taking the drug continuously. We conclude that valproic acid may represent an
underestimated risk factor in surgical repair of the abdominal wall. Preoperative assessment of the
use of this drug should be considered in clinical practice, especially in elective surgeries. New clinical
studies are needed to validate these experimental ndings and guide safer therapeutic approaches.
Keywords: General Surgery; Tissue Repair Surgery; Valproic Acid.
INTRODUCTION
Valproic acid (VPA) is an anticonvulsant widely used in the treatment of epilepsy, bipolar
68
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
disorder, and other neurological conditions. Although its therapeutic effects are well documented,
there is growing scientic interest in the systemic side effects of VPA, including its inuence on
tissue healing processes, especially in patients undergoing surgical interventions on the abdominal
wall (FERREIRA, 2020).
Studies have shown that VPA acts as an inhibitor of histone deacetylases (HDACs), which
can directly impact cell proliferation, broblast differentiation, and collagen deposition—key steps for
efcient tissue repair. This epigenetic action can negatively interfere with the integrity and resistance
of the surgical scar, generating specic concerns in patients who make continuous use of the drug and
require surgeries such as herniorrhaphy or laparotomy (SOARES, LIMA, BARROS, 2021).
In surgical procedures involving the abdominal wall, proper tissue repair is essential to
avoid complications such as dehiscence, incisional hernia formation, and infections. In this context,
the presence of agents that can compromise the synthesis of extracellular matrix and the adequate
remodeling of collagen bers represents an important clinical challenge, with direct implications for
surgical success and patient prognosis (ALMEIDA et al., 2019).
Thus, understanding the effects of valproic acid on the cellular and molecular mechanisms
involved in abdominal tissue healing is essential to guide therapeutic approaches in neurological
patients undergoing abdominal surgeries. Such research can provide important subsidies for
preoperative medication adjustment and for the development of specic surgical and postoperative
management strategies (SANTOS et al., 2022).
This study aimed to analyze the interference of valproic acid in abdominal wall healing,
considering the possible effects on collagen synthesis, broblast proliferation and extracellular matrix
integrity, and to discuss its clinical implications in abdominal surgeries.
MATERIALS AND METHODS
This is a literature review with a qualitative approach and exploratory character. The selection
69
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
of studies was carried out through the PubMed, SciELO, ScienceDirect and Scopus databases, with
the choice of complete articles, published in peer-reviewed scientic journals, addressing the use of
valproic acid in the context of tissue healing, especially in patients undergoing surgical procedures.
The time frame of the research considered the period from 2018 to 2022, based on the oldest article
(Costa et al., 2018) and the most recent (Santos et al., 2022; Alves et al., 2022; Moura et al., 2022).
• The following Health Sciences Descriptors were used:
“Valproic Acid”
“Wound Healing”
“Collagen”
“Tissue Regeneration”
“Epigenetics”
“Angiogenesis”
“Oxidative Stress”
“Surgery”
“Epileptic Patients”
• The combinations of the descriptors were performed with the Boolean operators AND
and OR. Key search strategies included:
“Valproic Acid” AND “Wound Healing”
“Valproic Acid” AND “Tissue Regeneration”
“Valproic Acid” AND “Collagen”
“Epigenetics” AND “Scarring”
“Valproic Acid” AND “Oxidative Stress”
“Healing” AND “Epileptic Patients”
“Valproic Acid” AND “Surgery”
70
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
• Guiding Question:
What are the effects of valproic acid on tissue healing and regeneration processes in patients
undergoing surgical procedures, considering epigenetic, inammatory and structural mechanisms?
• Inclusion Criteria:
- Articles published between 2018 and 2022;
- Studies in Portuguese, English or Spanish;
- Publications that address the relationship between valproic acid and healing, tissue
regeneration, collagen remodeling, or postoperative complications;
- Original articles, experimental studies, narrative or systematic reviews, and
observational clinical studies.
• Exclusion Criteria:
- Articles that deal with the use of valproic acid in exclusively neurological or psychiatric
contexts, unrelated to healing or surgery;
- Studies with animal models without human clinical correlation or direct applicability
in surgery;
- Works not available in full text;
- Isolated case reports without experimental or pathophysiological basis.
THEORETICAL FOUNDATION
The tissue repair process of the abdominal wall depends on a series of coordinated cellular
and molecular events, which include initial inammation, broblast proliferation, angiogenesis, and
collagen synthesis. Any factor that interferes with these steps can compromise the resistance of
the scar and predispose to the formation of incisional hernias or dehiscence of the surgical wound.
71
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
Valproic acid, by acting as an inhibitor of histone deacetylases (HDACs), can affect these mechanisms
through changes in gene expression (MACHADO, 2020).
Experimental studies indicate that VPA can reduce broblast proliferation and deposition of
type I collagen, which is essential for scar stability. This effect seems to be related to the epigenetic
modulation promoted by the drug, which inhibits genes associated with the extracellular matrix and
wound contraction, impairing the maturation of the surgical scar (RAMOS, TORRES, FERREIRA,
2021).
In addition, VPA has been associated with inhibition of angiogenesis in several biological
models. The formation of new blood vessels is crucial for the supply of oxygen and nutrients to
regenerating tissues. The inhibition of this process by valproic acid can delay or weaken healing,
which becomes especially relevant in abdominal procedures with a higher risk of postoperative
complications (COSTA et al., 2018).
It is important to consider that patients on continuous use of VPA, such as those with
refractory epilepsy or psychiatric disorders, often cannot discontinue medication in the perioperative
period. In these cases, it is essential that the surgeon is aware of the potential adverse effects of the
drug on healing, in order to adopt preventive strategies, such as strengthening the abdominal wall
with surgical meshes, intensive postoperative surveillance, and adjustments in the drug dose when
possible (SILVA, LIMA, RIBEIRO, 2021).
Recent research has also explored the impact of VPA on the local inammatory response.
The balance between pro-inammatory and anti-inammatory mediators is essential for the
normal progress of healing. VPA seems to interfere with this balance by inhibiting the activation of
macrophages and the release of cytokines such as TGF-β and IL-6, which can impair the transition
from the inammatory to the proliferative phase of the healing process (ALVES et al., 2022).
The antiproliferative activity of valproic acid, although benecial in oncological contexts,
may have adverse effects in situations that require efcient cell regeneration, such as abdominal
wall healing. The reduction in cell proliferation and myobroblast migration, induced by epigenetic
72
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
mechanisms, impairs the formation of granulation tissue and compromises the mechanical integrity
of the surgical wound (TEIXEIRA, 2021). This interference represents a considerable risk in surgeries
that require high resistance of the abdominal wall, such as exploratory laparotomy and hernial repairs.
Additionally, VPA interferes with collagen homeostasis, reducing not only its synthesis, but
also affecting its structural organization and maturation. Studies have shown that valproic acid can
alter the ratio between type I and type III collagen, unbalancing the extracellular matrix and resulting
in scars that are less resistant and more susceptible to rupture (MOURA, ANDRADE, LEITE, 2022).
This structural change can be decisive in patients undergoing abdominal surgeries under tension,
increasing the rate of postoperative complications.
In addition, VPA can impair mitochondrial function and increase cellular oxidative stress,
effects that are known to be deleterious to tissues in the process of repair. The increased production of
reactive oxygen species can lead to the apoptosis of key cells in the healing process, such as broblasts
and endothelial cells, delaying or making the normal progression of the healing phases unfeasible
(LOPES et al., 2021). This effect is particularly relevant in immunocompromised patients or those
with chronic comorbidities.
It should also be noted that the chronic use of VPA is associated with hepatic and hematological
alterations, such as thrombocytopenia, which can indirectly affect the healing of surgical wounds.
Reduced liver function compromises the production of plasma proteins important for inammation
and regeneration, while changes in coagulation can lead to inadequate clot formation, impairing the
initial basis of healing (CUNHA et al., 2020).
CONCLUSION
The interference of valproic acid in tissue repair of the abdominal wall represents a
relevant concern in the surgical context, especially in patients who use the medication continuously.
Understanding the epigenetic, cellular, and biochemical mechanisms involved in the adverse effects of
73
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
this drug on healing allows us to identify risks and adopt safer preventive and therapeutic measures.
Considering that valproic acid can compromise fundamental processes such as broblast
proliferation, collagen synthesis, angiogenesis, and control of the inammatory response, it is
essential that the surgeon be aware of the possible implications during the planning and conduct of
abdominal interventions, such as laparotomy and hernial repairs. Careful preoperative evaluation and
multidisciplinary follow-up can help minimize complications and promote better clinical outcomes.
Thus, this theme highlights the importance of an individualized approach in patients who
use valproic acid and reinforces the need for further clinical and experimental studies that deepen the
understanding of the interaction between neurological drugs and tissue regeneration processes in the
surgical context.
REFERENCES
FERREIRA, L. O. Inuência do ácido valpróico na resposta cicatricial: uma revisão atualizada.
Revista Neurociência em Foco, v. 12, n. 3, p. 87–92, 2020.
SOARES, M. R.; LIMA, A. P.; BARROS, F. B. O papel epigenético do ácido valpróico na cicatrização
de feridas cirúrgicas. Jornal Brasileiro de Medicina Translacional, v. 7, n. 2, p. 112–118, 2021.
ALMEIDA, T. M. et al. Cicatrização da parede abdominal: fatores determinantes e desaos em
cirurgia. Revista de Cirurgia Experimental e Clínica, v. 14, n. 1, p. 45–52, 2019.
SANTOS, J. G. et al. Efeitos sistêmicos do ácido valpróico em pacientes cirúrgicos: riscos e precauções.
Archives of Surgical Sciences, v. 8, n. 4, p. 203–210, 2022.
ALVES, F. D. et al. Efeitos imunomodulatórios do ácido valpróico na cicatrização de tecidos moles:
uma análise crítica. Revista de Medicina Regenerativa, v. 6, n. 1, p. 34–41, 2022.
COSTA, R. S. et al. Angiogênese na cicatrização de feridas: implicações da inibição por drogas.
Jornal de Cirurgia Translacional, v. 12, n. 2, p. 90–97, 2018.
74
ISSN: 2763-5724 / Vol. 05 - n 03 - ano 2025
MACHADO, R. L. Inuência epigenética do ácido valpróico na regeneração tecidual. Revista
Brasileira de Biomedicina, v. 11, n. 4, p. 214–220, 2020.
RAMOS, P. H.; TORRES, A. C.; FERREIRA, D. J. Efeitos do ácido valpróico na expressão de
colágeno e maturação cicatricial. Revista de Pesquisa Experimental em Saúde v. 15, n. 3, p. 77–84,
2021.
SILVA, L. F.; LIMA, A. J.; RIBEIRO, T. R. Avaliação cirúrgica em pacientes epilépticos: desaos na
cicatrização abdominal. Archives of Surgical Management, v. 9, n. 1, p. 59–65, 2021.
CUNHA, R. D. et al. Efeitos sistêmicos do ácido valpróico: impacto no processo cirúrgico. Revista
Brasileira de Farmacologia Clínica, v. 8, n. 1, p. 67–74, 2020.
LOPES, F. G. et al. Ácido valpróico e estresse oxidativo celular: implicações na regeneração tecidual.
Jornal de Medicina Regenerativa, v. 6, n. 2, p. 101–107, 2021.
MOURA, K. R.; ANDRADE, D. M.; LEITE, P. H. Remodelação de colágeno sob inuência do ácido
valpróico: estudo experimental. Revista Cientíca de Cirurgia Experimental, v. 11, n. 3, p. 88–94,
2022.
TEIXEIRA, M. C. Efeitos antiproliferativos do ácido valpróico: riscos no contexto cirúrgico. Revista
de Biologia Celular Aplicada à Cirurgia, v. 9, n. 4, p. 156–162, 2021.
