Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol

Abstract

Neuroinflammation is an emerging therapeutic target in chronic degenerative and autoimmune diseases, such as osteoarthritis (OA) and rheumatoid arthritis. Mast cells (MCs) play a key role in the homeostasis of joints and the activation of MCs induces the release of a huge number of mediators, which fuel the fire of neuroinflammation. Particularly, synovial MCs release substances which accelerate the degradation of the extra-cellular matrix causing morphological joint changes and cartilage damage and inducing the proliferation of synovial fibroblasts, angiogenesis, and the sprouting of sensory nerve fibers, which mediate chronic pain. Palmitoylethanolamide (PEA) is a well-known MCs modulator, but in osteoarthritic joints, its levels are significantly reduced. Adelmidrol, a synthetic derivate of azelaic acid belonging to the ALIAmides family, is a PEA enhancer. Preclinical and clinical investigations showed that the intra-articular administration of Adelmidrol significantly reduced MC infiltration, pro-inflammatory cytokine release, and cartilage degeneration. The combination of 1% high molecular weight hyaluronic acid and 2% Adelmidrol has been effectively used for knee osteoarthritis and, a significant improvement in analgesia and functionality has been recorded.

Keywords: adelmidrol; hyaluronic acid; joint degeneration and pain; mast cells; neuroinflammation; osteoarthritis; palmitoylethanolamide; visco-induction.

Figure 1

Schematic representation of the main contribution of MCs to degenerative joint diseases. Hyperactivated synovial MCs trigger the inflammatory process increasing vascular permeability and angiogenesis, recalling circulating PMN cells at the lesion site and activating synovial fibroblasts. Moreover, synovial MCs degranulation releases a massive amount of pro-inflammatory cytokines and chemokines, MMPs, and aggrecanases responsible for ECM protein degradation and, cartilage and bone remodeling.

Figure 2

Visco-supplementation vs. Visco-induction. (A) Visco-supplementation: Exogenous HA is injected in the OA joints where activated MCs release tryptases, hyaluronidases, and β-hexosaminidases which in turn may accelerate HA degradation; (B) Visco-induction: Adelmidrol, by increasing endogenous PEA levels, downregulates MCs activation and shift them towards a physiological condition. Adelmidrol reduces the MCs degranulation, the release of lytic enzymes, and therefore the HA degradation, normalizing the physiological release of heparin, a HA precursor.

Figure 3

Changes in the SF12. Adapted from [73].

Figure 4

Patient Global Impression of Change. Adapted from [69].