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Curcumin Diethyl γ-Aminobutyrate, a Prodrug of Curcumin, for Enhanced Treatment of Inflammatory Pain.

Curcumin is a naturally occurring polyphenol compound with potential analgesic effects. It has been shown to improve pain-like behaviors in numerous models of pain. Despite its potential, curcumin exhibits poor physicochemical and pharmacokinetic properties, which hinder its oral therapeutic efficacy. Curcumin diethyl γ-aminobutyrate (CUR-2GE), a carbamate prodrug of curcumin, was designed to overcome these limitations and demonstrated greater anti-neuroinflammatory effects compared to curcumin in vitro. Thus, this study evaluated the effect of CUR-2GE and its parent compound on pain-like behaviors in carrageenan- and LPS-induced mouse models. The possible side effects of CUR-2GE were also assessed by exploring its effects on motor coordination and spontaneous locomotor activity after acute and chronic treatments. The results showed that CUR-2GE improved mechanical and thermal hyperalgesia and locomotor activity to a greater extent than curcumin in carrageenan-induced mice. These results are in line with the ability of CUR-2GE to suppress peripheral inflammation in the paw tissue of carrageenan-induced mice, indicated by a significant decrease in TNF-α and IL-6 expression levels. Similarly, in LPS-induced mice, CUR-2GE improved sickness and pain-like behaviors (exploratory behaviors and long-term locomotor activity) to a greater extent than curcumin. Furthermore, CUR-2GE significantly reduced the level of proinflammatory cytokines in both the plasma and spinal cord tissue of LPS-induced mice, exhibiting significantly higher inhibition than curcumin. Moreover, the motor coordination, and locomotive behaviors of mice were not affected by both acute and chronic administration of CUR-2GE, indicating no potential CNS side effects. Thus, CUR-2GE demonstrated enhanced therapeutic efficacy in mouse models of inflammatory pain without any possible CNS side effects, suggesting its potential to be developed as an analgesic agent against inflammatory pain.