Physicochemical investigation of a novel curcumin diethyl γ-aminobutyrate, a carbamate ester prodrug of curcumin with enhanced anti-neuroinflammatory activity

Abstract

Curcumin is a polyphenol compound that alleviates several neuroinflammation-related diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy and cerebral injury. However, the therapeutic efficacy of curcumin is limited by its poor physicochemical properties. The present study aimed to develop a new carrier-linked curcumin prodrug, curcumin diethyl γ-aminobutyrate (CUR-2GE), with improved physicochemical and anti-neuroinflammatory properties. CUR-2GE was designed and synthesized by conjugating curcumin with gamma-aminobutyric acid ethyl ester (GE) via a carbamate linkage. The carbamate linkage was selected to increase stability at acidic pH while GE served as a promoiety for lipophilic enhancement. The synthesized CUR-2GE was investigated for solubility, partition coefficient, stability, and bioconversion. The solubility of CUR-2GE was less than 0.05 μg/mL similar to that of curcumin, while the lipophilicity with log P of 3.57 was significantly increased. CUR-2GE was resistant to chemical hydrolysis at acidic pH (pH 1.2 and 4.5) as anticipated but rapidly hydrolyzed at pH 6.8 and 7.4. The incomplete hydrolysis of CUR-2GE was observed in simulated gastrointestinal fluids which liberated the intermediate curcumin monoethyl γ-aminobutyric acid (CUR-1GE) and the parent curcumin. In plasma, CUR-2GE was sequentially converted to CUR-1GE and curcumin within 1 h. In lipopolysaccharide (LPS)-stimulated BV-2 microglial cells, CUR-2GE effectively attenuated the pro-inflammatory mediators by decreasing the secretion of nitric oxide and cytokines (TNF-α and IL-6) to a greater extent than curcumin due to an increase in cellular uptake. Altogether, the newly developed acid-stable CUR-2GE prodrug is a potential pre-clinical and clinical candidate for further evaluation on neuroprotective and anti-neuroinflammatory effects.

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

“…The GABA promoiety could facilitate the transport of CUR-2GE through the blood–brain barrier via amino acid transporters, inhibiting pain neurotransmission . The central immune cells, including microglia and astrocytes, also highly express the amino acid transporters, which could facilitate increased cellular uptake of CUR-2GE, inhibiting central immune response. , In line with this, our previous findings indicate higher uptake of CUR-2GE in BV-2 cells compared to curcumin . Hence, amino acid transporters may substantially contribute to the improved pharmacological activity of CUR-2GE.…”

“…A carbamate prodrug of gabapentin, XP13512, showed better stability and transcellular absorption than its parent drug, leading to increased bioavailability and more prolonged drug exposure. , With the same expectation, the main objective of synthesizing CUR-2GE was to improve therapeutic efficacy by transporting and releasing the parent compound into the systemic circulation. Although CUR-2GE was found to have aqueous solubility no better than curcumin, CUR-2GE exhibited better stability under an acidic condition, anti-neuroinflammatory activity, and cellular uptake than curcumin in vitro . The presence of GABA ethyl ester also potentially provides additional effects of curcumin since GABA was found to exert anti-inflammatory effects and modulate GABAergic systems. , These factors may have contributed to the better efficacy of CUR-2GE in carrageenan and LPS-induced inflammatory pain models compared to curcumin.…”

“…37,38 In line with this, our previous findings indicate higher uptake of CUR-2GE in BV-2 cells compared to curcumin. 39 Hence, amino acid transporters may substantially contribute to the improved pharmacological activity of CUR-2GE.…”

“…Although CUR-2GE was found to have aqueous solubility no better than curcumin, CUR-2GE exhibited better stability under an acidic condition, anti-neuroinflammatory activity, and cellular uptake than curcumin in vitro. 39 The presence of GABA ethyl ester also potentially provides additional effects of curcumin since GABA was found to exert anti-inflammatory effects and modulate GABAergic systems. 50,51 These factors may have contributed to the better efficacy of CUR-2GE in carrageenan and LPSinduced inflammatory pain models compared to curcumin.…”

“…Our previous findings demonstrated that CUR-2GE had similar water solubility to curcumin but possessed better stability, anti-neuroinflammatory activity, and cellular uptake. 21 Thus, the objective of the present study was to assess whether CUR-2GE improves painlike behaviors to a greater extent than curcumin in the mouse models of inflammatory pain and its possible CNS side effects.…”