Curcumin and its Multi-target Function Against Pain and Inflammation: An Update of Pre-clinical Data

Abstract

: Pain is an unpleasant sensation that have complex and various causative etiology. Modern drug discovery focuses on identifying potential molecules that target multiple pathways with safer profile compared to those with a single target. Current treatment of pain and inflammation with the available therapeutics has a number of major side effects. Pain is one of the major clinical problems that needs functional therapeutics which act on multiple targets and with low toxicity. Curcumin, a naturally occurring polyphenolic compound from Curcuma longa, has been used for years in Ayurvedic, Chinese, and in many other systems of traditional medicine. Pre-clinical data published thus far, demonstrated that curcumin possesses multi-target biological functions, suggesting its potential use to cure different diseases. However, there is no or little systematic review on its potential use in pain and inflammation with underlying mechanisms for such activities. Accordingly, the aim of the current review was to update the pre-clinical data of curcumin and its multiple targeting pathways for analgesic and anti-inflammatory action, and to further propose a molecular mechanism. Literature study was conducted using different known databases including Pubmed, Sci-finder, Google scholar, and Science Direct. Available pre-clinical data suggest the ameliorating effect of curcumin in pain and inflammation is rendered through the modulation of a of pain pathways including inhibition of a number of pro-inflammatory mediators, inhibition of oxidative stress and Cox-2, down-regulation of Ca2+/calmodulin-depend protein kinase II (CaMKIIα) and calcium channels like transient receptor potential (TRP), modulation of metabotropic glutamate receptor-2 (mGlu2), modulation of monoamine system, inhibition of JAK2/STAT3 signaling pathway, remodeling of extracellular matrix proteins, inhibition of apoptosis, inhibition of JNK/MAPK and ERK/CREB signaling pathway, and activation of opioid system. Taken all together, it is evident that curcumin is one of the promising safe natural polyphenolic molecules that target multiple molecular pathways in pain, and can be beneficial in the treatment and management of pain and inflammation.

The efficacy and safety of Curcuma longa extract and curcumin supplements on osteoarthritis: a systematic review and meta-analysis

“…Curcuma longa contains more phenolic pigments (including curcumin, demethoxycurcumin, bisdemethoxycurcumin) and essential oils (including cineole, linalool, α-terpinene, caryophyllene, ar-curcumene, zingiberen, curcumol, dl -turmerone, arturmerone, dehydrocurdione); it also contains campesterol, stigmasterol, β-sitosterol, cholesterol, fatty acids and metal elements potassium, sodium, magnesium, calcium, manganese, iron, copper, zinc and other multicomponent botanicals [ 52–55 ]. Compared with curcumin monomer, because Curcuma longa extract contains more components, it may play a multitarget and multisignal pathway transduction role in the treatment of OA pain and inflammation in the molecular pathology mechanism [ 56 , 57 ]. Meanwhile, Curcuma longa is a multicomponent botanical drug, and the synergy between its components may bring potential clinical effects in the treatment of OA [ 58 , 59 ].…”

“…Compared with curcumin monomer, because Curcuma longa extract contains more components, it may play a multi-target and multi-signal pathway transduction role in the treatment of OA pain and inflammation in the molecular pathology mechanism [56][57]. Meanwhile, Curcuma longa is a multicomponent botanical drug, and the synergy between its components may bring potential clinical effects in the treatment of OA [58][59].…”

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

“…These previous findings, along with our study findings, indicate the potential of curcumin to exert synergistic multimodal analgesia with other drugs, which could be due to the diverse and complementary mechanisms of action of curcumin. The analgesic effect of curcumin was explained by its ability to attenuate neurotransmitters related to pain (substance P), suppress the immune response, and prostaglandin E2 production by suppressing cyclooxygenase-2 (COX-2), modulating purinergic and chemokine receptors, and activate the opioid system 49 . The pharmacodynamic interaction between curcumin and metformin is plausible as metformin shows a distinct mechanism of analgesia to curcumin: activation of AMPK, opioidergic mechanisms, and suppressing peripheral and central inflammation 6 , 13 , 14 , 50 .…”

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

“…Curcumin modulates several transcription factors, such as Nrf2, β-catenin, NF-κB, inflammatory mediators, and MAPK kinase. Accordingly, it is able to inhibit the JNK-MAPK and ERK-CREB signaling pathways [ 463 ]. The mechanism in which curcumin exerts its varied effects is also related to the epigenetic regulation [ 464 ].…”