Abstract:
Neuropathic pain is a debilitating chronic pain condition, and its treatment remains a clinical challenge. Cur cumin, a naturally occurring phenolic compound, possesses diverse biological and pharmacological effects but
has not yet been approved as a drug due to its low bioavailability. In order to overcome this limitation, we
synthesized a potential ester prodrug of curcumin, curcumin diethyl diglutarate (CurDDG). In this study, we
evaluated the pharmacological advantages of CurDDG over curcumin in a mouse model of chronic constriction
injury (CCI), and the anti-inflammatory effect of CurDDG in LPS-induced RAW 264.7 macrophage cells was
accessed to clarify the underline mechanism. Mice were treated with various oral doses of curcumin (25, 50, 100
and 200 mg/kg/day, daily for 14 days) or equimolar doses of CurDDG. CurDDG at all doses tested significantly
attenuated CCI-induced thermal hyperalgesia and mechanical allodynia compared with the CCI-control group.
CurDDG at 25, 50 and 100 mg/kg demonstrated significantly greater efficacy on both mechanical and thermal
hypersensitivities compared to that of curcumin. The effect of CurDDG correlated well with the inhibition of
TNF-α and IL-6 levels in both the sciatic nerve and the spinal cord, as compared to its respective control groups.
Similarly, in the in vitro study, CurDDG significantly reduced the LPS-induced expression of TNF-α and IL-6.
Moreover, CurDDG significantly decreased COX-2 and iNOS levels and attenuated p38, JNK, and ERK1/2
phosphorylation as compared to the curcumin-treated cells. Altogether, this study demonstrated the improved
pharmacological effects of curcumin by its diglutarate conjugate, CurDDG.
