Adelmidrol

Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol

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.

Adelmidrol protects against non-alcoholic steatohepatitis in mice

Non-alcoholic steatohepatitis (NASH) is a more serious condition of non-alcoholic fatty liver disease (NAFLD), a widely spread type of chronic liver disease. Oxidative stress and inflammation induced by lipotoxicity are involved in hepatic injury of NASH. This work aimed to investigate the possible protective effect of adelmidrol (PPAR α and γ agonist) against NASH in mice.Thirty-six mice were divided into six equal groups: sham-operated, NASH, vehicle, adelmidrol 5 mg/kg, adelmidrol 10 mg/kg, and adelmidrol 20 mg /kg. Adelmidrol was injected intraperitoneally once daily for 7 weeks along with high-fat diet (HFD). Mice were euthanized, and livers were removed for light microscopic examination and detection of reduced glutathione (GSH) content while blood samples were collected for assessment of transaminases (ALT& AST), tumor necrosis factor (TNF-α), matrix metalloproteinase-1 (MMP-1), adiponectin, cholesterol, high-density lipoprotein (HDL), and triglyceride. NASH mice had increments in MMP-1, TNF-α, AST, ALT, triglyceride, and cholesterol levels while HDL, adiponectin levels, and GSH content were decreased with vesicular steatosis, lobular inflammation, hepatocyte ballooning, and degeneration. Administration of adelmidrol decreased MMP-1, TNF-α, AST, ALT, triglyceride, and cholesterol levels while increased HDL, adiponectin levels, and GSH content as well as ameliorated the histopathological changes. Adelmidrol protected mice from NASH; an effect could be attributed to its anti-inflammatory and antioxidant actions.

Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-γ Independent Action

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called "entourage" effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expression/transcription of PEA metabolic enzymes following Adelmidrol administration. The "entourage effect" with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities.

Adelmidrol: A New Promising Antioxidant and Anti-Inflammatory Therapeutic Tool in Pulmonary Fibrosis

Background: Chronic pulmonary diseases are characterized by airway remodeling due to complex multicellular responses and the production of free oxygen radicals. They lead to a progressive decline of pulmonary functions. Adelmidrol is an analogue of palmitoylethanolamide (PEA), which is a well-known anti-inflammatory and anti-oxidant compound. In this study, we investigated the efficacy of adelmidrol (10 mg/Kg) for bleomycin-induced pulmonary fibrosis in mice.
Methods: Bleomycin intratracheal administration was performed on the first day and for the following twenty-one days, mice were treated with adelmidrol (10 mg/Kg).
Results: The survival rate and body weight gain were recorded daily. At the end of the experiment, adelmidrol-administered animals showed reduced airway infiltration by inflammatory cells, Myeloperoxidase (MPO) activity, and pro-inflammatory cytokine overexpression (IL,6 IL-1β, TNF-α, and TGF-1β). Moreover, adelmidrol treatment was able to manage the significant incapacity of antioxidants and elevation of the oxidant burden, as shown by the MDA, SOD, and GSH levels and decreased nitric oxide production. It was also able to significantly modulate the JAK2/STAT3 and IκBα/NF-kB pathway. Histologic examination of the lung tissues showed reduced sample injury, mast cell degranulation, chymase activity, and collagen deposition.
Conclusions: In sum, our results propose adelmidrol as a therapeutic approach in the treatment of pulmonary fibrosis.

Aerosol-Administered Adelmidrol Attenuates Lung Inflammation in a Murine Model of Acute Lung Injury

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress to acute respiratory distress syndrome (ARDS). Adelmidrol (ADM), an analogue of palmitoylethanolamide (PEA), is known for its anti-inflammatory and antioxidant functions, which are mainly due to down-modulating mast cells (MCs) and promoting endogenous antioxidant defense. The aim of this study is to evaluate the protective effects of ADM in a mice model of ALI, induced by intratracheal administration of lipopolysaccharide (LPS) at the dose of 5 mg/kg. ADM 2% was administered by aerosol 1 and 6 h after LPS instillation. In this study, we clearly demonstrated that ADM reduced lung damage and airway infiltration induced by LPS instillation. At the same time, ADM counteracted the increase in MC number and the expression of specific markers of MC activation, i.e., chymase and tryptase. Moreover, ADM reduced oxidative stress by upregulating antioxidant enzymes as well as modulating the Nf-kB pathway and the resulting pro-inflammatory cytokine release. These results suggest that ADM could be a potential candidate in the management of ALI.