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Gene & Protein in Disease NLRP3 in SCI and CHM

NLRP3 in the cytoplasm of host cells increases its activity, 4. Effects of active components targeting
thereby triggering NLRP3 inflammasome activation NOD-like receptor protein 3 (NLRP3) in the
following SCI. 41,65 ROS levels are regulated by voltage- treatment of spinal cord injuries
gated proton channels (Hv1). 27,66 After spinal nerve injury,
Hv1 expression significantly increases in spinal microglial Spinal cord injuries often lead to severe inflammation,
cells. Hence, Hv1 induced-pyroptosis, mediated through with the NLRP3 inflammasome playing an essential
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modulation of the NLRP3 inflammasome, and Hv1 role in inflammation response following SCI. Numerous
induced-neuronal apoptosis are both enhanced after SCI. 67 approaches are currently available for treating SCI,
with surgical interventions and pharmaceutical drugs
Pyroptosis is a complex, programmed form of cell being the most prevalent. However, CHM has recently
death that involves pore formation, cell rupture, and garnered increasing interest among researchers. Studies
swelling following SCI. 68,69 This form of cell death disrupts suggest that active components in CHM can modulate
neuronal cell circuitry and axonal regeneration. 67,70 Unlike the NLRP3 pathway, promoting neuroprotection
apoptosis, pyroptosis is more persistent and is triggered by and suppressing inflammation. Furthermore, these
inflammatory caspases located distal to the lesion site. 34,67,69 components have been shown to reduce oxidative stress
Microglial pyroptosis is mediated by TLR4-induced at the site of injury, thereby minimizing cell death,
activation of the NLRP3 inflammasome. Consistent protecting neural tissues, and creating a more favorable
with previous studies, the upregulation of dead-box environment for spinal cord repair. Consequently, the
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helicase 3 X-linked, which mediates NLRP3 activation, therapeutic potential of these compounds has sparked
is amplified by TLR4 signaling after SCI. At 72 h post- ongoing discussions, with a summary of key components
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SCI, there is an increase in TLR4 expression and DNA- presented in Table 1.
binding activation of toll-like nuclear factor (NF-κB).
1,71
NF-κB initiates inflammatory signaling by promoting 4.1. Curcumin
both transcriptional and post-translational regulation of Curcumin is a phenolic compound with a chemical
the NLRP3 inflammasome, which stimulates IL-1β and structure consisting of two aromatic rings connected by a
IL-18. 1,27,72-74 Notably, although NLRP3 is downstream seven-carbon chain. Its International Union of Pure and
of NF-κB, its exaggerated expression can activate NF-κB Applied Chemistry (IUPAC) name is 1,7-bis(4-hydroxy-
in a positive feedback loop. 27,75 Advanced oxidation 3-methoxyphenyl)-1,6-heptadiene-3,5-dione (1E-6E), and
protein products (AOPPs) are key triggers for reduced its molecular formula is C H O (diferuloylmethane). 83,84
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nicotinamide adenine dinucleotide phosphate (NADPH) Curcumin’s hydrophobic nature results in low solubility
oxidase-mediated ROS production, which in turn induces in water at both acidic and neutral pH levels, although
pyroptosis and activates mitogen-activated protein it readily dissolves in organic solvents such as methanol,
kinases-NF-κB signaling pathways. AOPP levels increase ethanol, and isopropanol, and shows moderate solubility
in plasma and cerebrospinal fluid up to 3 days post-SCI, in hexane, cyclohexane, tetrahydrofuran, and dioxane. 85
after which they gradually decrease. 27
Numerous research findings suggest that curcumin
After SCI, unfolded proteins accumulate in the has the potential to reduce inflammation and apoptosis
endoplasmic reticulum (ER) as part of the cellular response while also acting as an antioxidant. In addition, evidence
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to stressors such as electrolyte imbalance and acidosis. 27,76,77 highlights curcumin’s effect on various inflammasomes,
ER stress induces the expression of thioredoxin-interacting including NLRP3, and its capacity to inhibit their
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protein (TXNIP), which subsequently activates the NLRP3 activity. 87,88 Dysregulation in IL-1β and the NLRP3
inflammasome. Increased TXNIP levels following SCI inflammasome is a notable feature of multiple diseases,
serve as a critical link between the ER stress response and particularly inflammatory conditions such as SCI.
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inflammatory pathways. 27,78,79 Oligodendrocyte progenitor Research indicates that curcumin inhibits the activation of
cells (OPCs) are particularly sensitive to intense ER stress, pro-IL-1β by downregulating the NLRP3 inflammasome
whereas astrocytes can tolerate higher levels of stress. 27,80 and caspase-1, both of which are essential for converting
This tolerance in astrocytes may contribute to their survival pro-IL-1β into its active, secreted form. 89,90 To further
after injury and subsequent glial scar formation. 27,81 Lower support this finding, Ghaffari et al. demonstrated that
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levels of NLRP3 and ASC in astrocytes compared to curcumin effectively inhibits NLRP3 in a rat model of
OPCs in SCI models may be linked to the higher death SCI. Moreover, it has been reported that administering
rate of OPCs. These observations provide a promising doses of 20, 40, and 80 mg/kg of curcumin to male rats
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foundation for therapeutic strategies targeting NLRP3 post-SCI reduces the expression levels of both NLRP3 and
inflammasome in SCI treatment. caspase-1. 90

Volume 4 Issue 3 (2025) 4 doi: 10.36922/gpd.4827