EF is defined as the excessive formation of a scar tissue in the epidural space following a lumbar laminectomy; it is a major cause of persistent pain after spinal surgery, and it often causes hospital re-admissions. Due to fibrosis, the adhesions in the epidural region prevent the movement of a nerve in a nerve root canal . Following reoperations due to epidural fibrosis, adhezions may develop again. New and varied treatment options that prevent the development of epidural fibrosis have become necessary as the current treatments are not sufficiently effective with prolonged medical treatments and re-surgical interventions.
The formation of an epidural scar tissue is an indication of wound healing. EF results from the migration of fibroblasts induced by the chemotactic agents released as a result of the degradation of erythrocytes and thrombocytes after hemorrhage. Fibrosis formation begins in the early stages of inflammation and consists of four phases, namely, fibroblast migration and proliferation, extracellular matrix deposition, angiogenesis, and finally reorganization of the scar tissue . The resulting fibrotic tissue causes distension or compression of a root nerve, ultimately leading to a radicular pain after a spinal surgery .
Fibroblast and vascular endothelial cells begin to proliferate within 24 h after tissue damage and also after a surgery, leading to granulation tissue formation, which is an indication of wound healing. Given that the volume of fluid and protein leakage from new vessels induced by angiogenesis is relatively high, the granulation tissue formed in this stage displays an edematous appearance . Fibroblast migration is induced by growth factors, including platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and transforming growth factor, as well as by macrophages and lymphocyte-derived cytokines. Some cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), stimulate collagen synthesis. In advanced stages of fibrosis, the cellular components of a granulation tissue diminish, leading to the formation of a rigid tissue that is denser than collagen and elastic fibers and that involves a small number of vessels . In our study, intense fibrosis was observed in the entire control laminectomy group, and the fibrosis caused adhesions to the duramater (Fig. 1a).
Although medical agents such as analgesics, myorelaxants, steroids, and/or local anesthetic injections are commonly used in the treatment of EF to eliminate the symptoms associated with fibrosis, a standard treatment for the underlying cause of EF remains unavailable. The abovementioned medical therapies are supported by symptomatic treatment methods, such as physical therapy, bed rest, and exercise . However, given that these treatments do not eliminate a scar tissue, patients’ complaints are only reduced and not completely gone.
For the prevention of EF progression, the most commonly used and recommended technique that causes less tissue damage is microsurgery . Given that microsurgery leads to less dead space in the paraspinal region and epidural area, it is likely to result in less scar tissue. Moreover, given that the blood elements remaining in the epidural area may aggravate a scar tissue, a rapid hemostasis is needed. Another technique used to prevent EF is the preservation of the ligamentum flavum along with the epidural adipose tissue, although this technique demonstrates limited effectiveness .
Literature reviews have shown that although numerous clinical and experimental studies on EF prevention have been conducted, no definitive outcomes have been obtained. Additionally, some experimental studies have used various synthetic and organic substances in combination with drugs to prevent scar tissue formation and adhesion in laminectomy defects [3, 4, 10, 11]
Methylprednisolone is a type of synthetic glucocorticoid (steroid) drug. Steroids are known to exhibit anti-inflammatory, anti-allergic, and immunosuppressive activity, and they also affect the hematopoietic system. Steroids prevent the migration of cells to areas of inflammation, and they inhibit the synthesis of acute-phase reactants as well as the synthesis and release of cytokines . Moreover, they inhibit further recruitment of neutrophils and monocytes/macrophages in an inflammation site and reduces the number, the effect, and the proliferation of fibroblasts in a connective tissue.
A previous study reporting on the effect of long-acting steroids on EF prevention has revealed that the intraoperative irrigation of long-acting dexamethasone in the laminectomy site significantly reduced hospitalization and narcotics usage as a result of the inhibition of anti-inflammatory effects and pain mediators . Consistent with these findings, our results showed that compared with the control and DMSO treatments, the administration of epidural methylprednisolone prevented EF formation. Also, the incidence rates of fibrosis grades were significantly low under this treatment.
Curcumin is the main bioactive component derived from the rhizome (Rhizoma Curcumae) of turmeric (Curcuma longa), which belongs to the ginger family Zingiberaceae. Curcumin is used in wound healing and in the treatment of arthritis owing to its antibacterial and anti-inflammatory properties; it is also used in the treatment of cancer patients, particularly in preventing the development of lymph node metastasis and the progression of tumors [7, 14]. Additionally, curcumin has been shown to inhibit hydrogen peroxide-induced damage in human keratinocytes and fibroblasts [14, 15]. This effect indicates that curcumin exhibits antioxidant activity in wound healing. Studies have evaluated the effect of curcumin on wound healing in rats, and they found that the administration of curcumin enhanced wound healing, improved cell proliferation, and demonstrated an efficient free radical scavenging activity compared with the control and collagen treatments [16, 17]. Furthermore, curcumin significantly suppresses TNF-α-induced neuroinflammation and the expression levels of IL-6, PGE2, and COX-2. Our results showed that the rate of grade 2 EF was higher in the curcumin group than in the control group. Conversely, the rate of grade 3 EF was higher in the control group than in the curcumin group. This finding may have been caused by the various effects of curcumin. Moreover, curcumin has been found to decrease post-traumatic inflammation owing to its anti-inflammatory properties in experimental spinal cord trauma studies [17, 18].
In a study, curcumin was considered to provide therapeutic benefits by suppressing lung fibroblasts through the inhibition of the protein kinase C epsilon, leading to the absence of apoptosis in normal fibroblasts . The abovementioned studies strengthen the theory that fibroblasts may be inhibited by curcumin and thus may play a role in preventing EF. Our study also showed that curcumin exerted a significant effect in the prevention of EF formation by inhibiting further recruitment of fibroblasts to the laminectomy site compared with the control and methylprednisolone treatments (Fig. 1b).