Curcumin promotes oligodendrocyte differentiation and their protection against TNF-α through the activation of the nuclear receptor PPAR-γ

Abstract

Curcumin is a compound found in the rhizome of Curcuma longa (turmeric) with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. The current study aims to assess the effects of this natural compound on oligodendrocyte progenitor (OP) differentiation, particularly in inflammatory conditions. We found that curcumin can promote the differentiation of OPs and to counteract the maturation arrest of OPs induced by TNF-α by a mechanism involving PPAR-γ (peroxisome proliferator activated receptor), a ligand-activated transcription factor with neuroprotective and anti-inflammatory capabilities. Furthermore, curcumin induces the phosphorylation of the protein kinase ERK1/2 known to regulate the transition from OPs to immature oligodendrocytes (OLs), by a mechanism only partially dependent on PPAR-γ. Curcumin is also able to raise the levels of the co-factor PGC1-α and of the cytochrome c oxidase core protein COX1, even when OPs are exposed to TNF-α, through a PPAR-γ-mediated mechanism, in line with the known ability of PPAR-γ to promote mitochondrial integrity and functions, which are crucial for OL differentiation to occur. Altogether, this study provides evidence for a further mechanism of action of curcumin besides its well-known anti-inflammatory properties and supports the suggested therapeutic potential of this nutraceutical in demyelinating diseases.

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

“…A small set of molecules has been previously synthesized by combining the functional moieties of curcumin and diallyl sulfide: curcumin is known to activate the NRF2 and PPAR-γ pathways [25,37,38], and diallyl sulfide is known to induce the expression of antioxidant phase II enzymes by activating the NRF2 pathway [24,39] (Figure 1). Among these hybrids, compound 1 was found to be one of the most active in modulating the activation of NRF2 pathway [24,25].…”

“…Curcumin is known to induce both the PPAR-γ and NRF2 pathways. As pio, curcumin induces cell differentiation and protection from TNF-γ damage through activation of the PPAR-γ pathway in OPs [38]. On the other hand, curcumin induces phase II enzymes and protects from oxidative and mitochondrial stress by activating NRF2 in different cell types [57,58].…”

Noise-Induced Cochlear Damage Involves PPAR Down-Regulation through the Interplay between Oxidative Stress and Inflammation

“…Cumulative evidence also indicate an interplay between ROS and inflammation in noise trauma, ototoxicity and age-related hearing loss [ 5 , 10 , 14 , 47 , 48 , 49 , 50 , 51 , 52 ]. Moreover, several studies have demonstrated PPAR ability to inhibit the expression of inflammatory markers and signaling pathways, such as cytokines, metalloproteases and acute phase proteins [ 53 , 54 , 55 , 56 , 57 ]. In order to establish a cause-effect relationship among PPAR down-regulation, increased oxidative stress and increased inflammatory markers in cochlear noise-induced injury, we used both antioxidant (Q-ter) and anti-inflammatory (Anakinra) treatments for investigating the effect of blocking oxidative stress or direct inhibiting inflammation.…”

The Antihypertensive Drug Telmisartan Protects Oligodendrocytes from Cholesterol Accumulation and Promotes Differentiation by a PPAR-γ-Mediated Mechanism

“…This observation could suggest that under stress conditions, cells may become more sensitive to differentiating stimuli. Similarly, other PPAR-γ agonists, such as PIO, DHA or curcumin, were more effective in promoting OP differentiation under inflammatory stress, induced by the inflammatory cytokine TNF-α [21,52,53]. In a general view, the capability to respond to stress by entering a differentiation status might be considered a general feature of cells in the early stages of their development, as OPs are.…”