Curcumin usage for inflammation and spinal cord injury

Introduction

Traumatic spinal cord injury (SCI) causes necrosis of the central nervous system and subsequent permanent neurological deficit. The mechanism of SCI broadly comprises two stages. First, a primary injury, attributable to the mechanical insult itself and structural damage. A secondary injury is a series of systemic and local neurochemical and physiological changes following the primary injury. The secondary injury occurs via subsequent edema, ischemia, inflammation, cytokine production, free radical damage, glial scar formation, apoptosis, and necrosis ( ). Primary injury is immediate and irreversible; in contrast, a secondary injury worsens with time and necessitates therapeutic intervention ( ; ; ). The secondary injury develops within hours or days after SCI, causing neurochemical alterations that lead to neurologic functional impairments. Therapeutic modalities that promote recovery could be better understood with detailed knowledge of SCI pathophysiology ( ). Neurochemical alterations in SCI include increases in the excitatory amino acids, elevation in the calcium influx, stimulation of the calcium-dependent enzymes, generation of reactive oxygen species (ROS), and release of cytokines leading to neuroinflammation ( ). These neurochemical alterations affect the neuron and astrocyte activity, induce demyelination, modulate leukocyte infiltration, and activate macrophages ( ; ). In addition, secreted inflammatory cytokines and growth factors generally up-regulate the pro-survival molecules, such as nuclear factor kappa B (NF-κB) ( ). Thus, the key obstacle in the treatment and recovery process from catastrophic SCI is gliosis caused by the up-regulation of inflammation. Moreover, several studies have demonstrated the potential therapeutic role of curcumin in alleviating the second injury process.

Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3, 5-dione] is a yellow extract obtained from Curcuma longa and is commonly used in India as a seasoning and food-coloring agent ( Fig. 1 ). It is a polyphenol compound that possesses non-steroidal anti-inflammatory properties. Recent studies indicate that it may have anti-oxidant ( ), anti-inflammatory ( ; ; ), neuroprotective ( ) and anti-apoptotic effects ( ) for SCI. Curcumin has emerged as a promising therapeutic drug in SCI treatment with a tendency to reduce the formation of glial scar and suppress the expression of glial fibrillary acidic protein (GFAP), thus contributing to a more favorable recovery environment ( ). In a recent study, curcumin inhibited the hypoxia-induced up-regulation of GFAP and neurofilament-H (NF-H) following hypoxia and down-regulated the expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 (IL-1) ( ).

Structure, pharmacology, and biological targets

Curcumin is a polyphenol substance that has been widely used for medicinal purposes, religious rituals, and local cuisines in the Indian subcontinent. The molecule is symmetric in structure. The keto-enol tautomer in the center, the flexible α,β-unsaturated β-diketo linker, and the terminal o-methoxyphenolic groups comprise the three main components of curcumin molecule ( Fig. 2 ).

Curcumin has a complex pharmacophore that could act as an anti-oxidant, chelate metals, and Michael reaction ( ). Further, curcumin is a hydrophobic molecule comprising two ferulic acid residues linked by a methylene bridge and has high affinity for cellular membranes ( ). Curcumin can participate in hydrogen bonding interactions with its β-diketone moiety and the substituents on the aromatic rings. The aromatic rings can also form π-π Van der Waals interactions ( ). Structure-activity relationships demonstrate that the β-diketone (keto-enol) moiety serves as a chelator for cationic metals present in the protein-binding sites and as a Michael reaction acceptor for nucleophilic groups, such as reduced selenocysteine and sulfhydryl, that form covalent bonds with curcumin ( ). The phenolic hydroxyl group is essential for the anti-oxidant action of curcumin ( ; ). This group and the methylene hydrogen are crucial for free radical scavenging activity, wherein ROS and nitrogen species are subjected to electron transfer or H-atom abstraction ( ). The diversity of the interactions that curcumin offers may explain its binding to multiple proteins ( Fig. 3 ).

Molecular docking studies suggest that curcumin adopts different conformations for the maximization of these interactions, primarily via the α,β-unsaturated β-diketone moiety, and generally favors hydrophilic pockets near the cysteine residues ( ; ). Curcumin shares two important characteristics with the phorbol ester pharmacophore owing to the presence of the hydroxyl and carbonyl groups ( ). Removing the methylene group and carbonyl group and cutting off the pharmacophore produces a more potent molecule 1,5-bis (4-hydroxy-3-methoxiphenyl)-1,4-pentadiene-3-1 that maintains all curcumin activity ( ; ).

Curcumin regulates about 100 biological targets ( ) via various mechanisms, including changing of the activity of cellular proteins via changes in the phosphorylation status ( ). Generally, curcumin demonstrates its effects at concentrations above the micromolar range. This weak binding affinity has facilitated several attempts to optimize the activity of curcumin using a structural-based drug design.

Anti-inflammatory effects

After primary SCI, therapeutic strategies and outcomes depend on how we achieve reduction of inflammation and glial scar. Curcumin is a well-known anti-inflammatory molecule that evokes global inhibition of the inflammation network by suppressing transcription factors, such as NF-κB and signal transducer, as well as the activator of transcriptions (STAT) in the upstream signaling pathways of inflammatory mediators, such as prostaglandins, cytokines, and chemokines ( ). Curcumin may also bind directly to inflammatory mediators and enzymes in downstream inflammation pathways, such as interleukin 1β converting enzyme (ICE), TNF-α, TNF-α converting enzyme (TACE), p38 mitogen-activated protein kinase (MAPK), myeloid differentiation protein 2 (MD-2), α1-acid glycoprotein (AGP), and glycogen synthase kinase 3 beta (GSK-3β) ( ; ). Curcumin inhibited the expression of pro-inflammatory cytokines and suppressed reactive gliosis. Moreover, curcumin inhibited the generation of transforming growth factor beta (TGF-β)1, TGF-β2, and sex-determining region Y-box transcription factor 9 (SOX-9); decreased the deposition of chondroitin sulfate proteoglycan by inhibiting the transforming growth factors and transcription factor; and improved the microenvironment that enabled nerve growth ( ). Occurring concurrently with acute inflammation and preceding fibrosis, spinal cord edema plays a crucial role in neurologic damage and patient symptoms; this is a primary reason behind the clinical usefulness of corticosteroids in SCI patients ( ). An experimental rat model that was administered 40 mg/kg curcumin intraperitoneally (IP) showed reduced hemorrhage, edema, and neutrophil infiltration of the traumatic spinal cord. Curcumin also inhibited the SCI-associated aquaporin 4 (AQP4) overexpression and GFAP as well as repressed the unusual activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway ( ). Studies on the effect of curcumin on inflammation, fibrosis, and edema after SCI have been summarized in Table 1 .