Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-Induced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production

Abstract

Current nonsurgical treatments of discogenic lumbar radiculopathy are neither effective nor safe. Our prior studies have suggested that hydroxylated fullerene (fullerol) nanomaterial could attenuate proinflammatory cytokine tumor necrosis factor alpha (TNF-α)-induced neuroinflammation and oxidative stress in mouse dorsal root ganglia (DRG) and primary neurons. Here, we aim to investigate the analgesic effect of fullerol in a clinically relevant lumbar radiculopathy mouse model and to understand its underlying molecular mechanism in mouse DRGs and neurons. Surprisingly, single and local application of fullerol solution (1 M, 10L) was sufficient to alleviate ipsilateral paw pain sensation in mice up to 2 weeks postsurgery. In addition, microCT data suggested fullerol potentially promoted disc height recovery following injury-induced disc herniation. Alcian blue/picrosirius red staining also suggested that fullerol promoted regeneration of extracellular matrix proteins visualized by the presence of abundant newly formed collagen and proteoglycan in herniated discs. For in vitro DRG culture, fullerol attenuated TNF-α-elicited expression of transient receptor potential cation channel subfamily V member 1 (TRPV-1) and neuropeptides release (substance P and calcitonin gene-related peptide). In addition, fullerol suppressed TNF-α-stimulated increase in intracellular Ca concentrations in primary neurons. Moreover, Western blot analysis in DRG revealed that fullerol's beneficial effects against TNF-α might be mediated through protein kinase B (AKT) and extracellular protein-regulated kinase (ERK) pathways. These TNF-α antagonizing and analgesic effects indicated therapeutic potential of fullerol in treating lumbar radiculopathy, providing solid preclinical evidence toward further translational studies.

Toward Understanding the Antitumor Effects of Water-Soluble Fullerene Derivatives on Lung Cancer Cells: Apoptosis or Autophagy Pathways?

“…This finding was consistent with the literature data showing that fullerene derivatives C 60 (OH) 22 and C 60 (C­(COOH) 2 ) 2 repaired endothelial cells and inhibited actin depolymerization via attenuating the intracellular ROS . Recent publications demonstrate that the hydroxylated fullerenes affected the protein kinase B (AKT) and extracellular protein regulated kinases (ERK) pathways in mouse dorsal root ganglia neurons . The AKT pathway is one of the important pathways in endothelial cell biology, such as endothelial cell proliferation, differentiation, and migration .…”

“…61 Recent publications demonstrate that the hydroxylated fullerenes affected the protein kinase B (AKT) and extracellular protein regulated kinases (ERK) pathways in mouse dorsal root ganglia neurons. 62 The AKT pathway is one of the important pathways in endothelial cell biology, such as endothelial cell proliferation, differentiation, and migration. 63 Besides, a previous report indicated that the fullerene derivatives C 60 (OH) 22 and C 60 (C(COOH) 2 ) 2 protected primary rat brain cerebral microvessel endothelial cells against nitrogen oxide (NO)-induced damage.…”

Interactions of nanomaterials with ion channels and related mechanisms

“…ER, endoplasmic reticulum; IP 3 R, inositol 1,4,5-trisphosphate receptor; MCU, mitochondrial calcium uniporter; NCX, Na + /Ca 2+ exchanger; PEG, polyethylene glycol; PMCA, plasma membrane Ca 2+ ATPase; RyR, ryanodine receptor; STIM1, stromal interaction molecule 1; TRPC, transient receptor potential canonical; TRPM, transient receptor potential mucolipin; TRPV, transient receptor potential vanilloid channel, and Si NPs inhibited the activation of TRPV4 channels but enhanced the activation of TRPV1 channels in cultured airway epithelial cells (Sanchez et al, 2017). In addition, fullerol reversed the TNF-αinduced change in TRPV1 expression and attenuated the [Ca 2+ ] i increase in dorsal root ganglion neurons (Xiao et al, 2018). Other studies have found that some types of TRPV channels (TRPV1, Dubes et al, 2017;Veronesi, de Haar, Roy, & Oortgiesen, 2002;TRPV4, Dubes et al, 2017;Gilardino et al, 2015;and TRPM2, P. Yu et al, 2015) participate in NMs-induced Ca 2+ influx and increasing [Ca 2+ ] i .…”

Fullerenol protects cornea from ultraviolet B exposure

“…In bone injury models, fullerenol was found to enhance the osteogenic differentiation of stem cells through activation of the FoxO 1/SOD2 pathway and expression of osteoclastogenesis genes, which promoted bone healing [ 33 ]. Through antagonizing TNF-α-induced ion channel activation and neuropeptide production, fullerenol was reported to relieve lumbar radiculopathy [ 34 ]. As oxidative stress is a key pathophysiological event of cornea injury induced by UVB exposure, it has not been clarified whether fullerenol will reconstruct the injured cornea through similar mechanisms.…”