Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

Abstract

BACKGROUND AND PURPOSENeuroinflammation is initiated by a variety of stimuli including infections, sepsis, neurodegenerative diseases or traumatic brain injury and, if not adequately controlled, can lead to various degrees of neuronal damage and behavioural impairment. A critical event in the initial steps of inflammation is neutrophil extravasation. Semicarbazide-sensitive amine oxidase (SSAO, also known as vascular adhesion protein 1 or VAP-1) regulates neutrophil adhesion and extravasation. Here, we elucidate the role of SSAO/VAP-1 in the early stage inflammatory response after LPS insult in the brain. EXPERIMENTAL APPROACHPXS-4681A, a selective and irreversible SSAO/VAP-1 inhibitor, was tested in two rat models of neuroinflammation, following systemic or i.c.v. LPS. Immunohistochemical and immunofluorescence techniques were used to measure neutrophils and microglia. VAP-1 was quantitated by Western blotting. KEY RESULTSBoth systemic and i.c.v. administration of LPS induced an increase in neutrophil recruitment and microglial response in various brain areas including the substantia nigra and striatum. PXS-4681A produced a significant inhibition of neutrophil recruitment and extravasation after i.c.v. LPS injection and also reversed microglial cell recruitment and morphological changes to the level of the sham controls in both LPS models. CONCLUSIONS AND IMPLICATIONSPXS-4681A acted as an effective anti-inflammatory agent after both systemic and i.c.v. LPS injections suggesting that SSAO/VAP-1 inhibition could be beneficial in the treatment of brain inflammation. AbbreviationsBBB, blood-brain barrier; BCA, bicinchoninic acid; DAB, 3,3 0 -diaminobenzidine; Iba-1, ionized calcium-binding adapter molecule 1; MPO, myeloperoxidase; PFA, paraformaldehyde; RECA-1, rat endothelial cell antibody 1; SSAO, semicarbazidesensitive amine oxidase; VAP-1, vascular adhesion protein 1

BAP31 regulates IRAK1-dependent neuroinflammation in microglia

“…Our present results are consistent with our previous reports that BAP31 plays an essential role in Alzheimer’s disease by inhibiting the formation of amyloid-β [17]. As expected, Iba1-positive cells significantly increased in the CA1 and DG regions of the hippocampus after challenge with LPS [70, 71], and BAP31 deficiency significantly increased the number of Iba1-positive microglia in mice. Moreover, we demonstrated that intracerebroventricular injection of LPS induced increased IL-1β, TNFα, iNOS, and COX2 levels in the mouse brain 6 h after the injection, consistent with the results from the BV2 cells that BAP31 deficiency exacerbated the expression of these cytokines.…”

Attenuation of Weight Gain and Prevention of Associated Pathologies by Inhibiting SSAO

“…SSAO is highly sensitive to semicarbazide [30,41], which significantly suppresses the body weight gain in Wistar Hannover GALAS rats of both sexes [42], however, severe health outcomes followed due to the chronic toxicity and carcinogenicity of this inhibitor [43]. PXS-4681A has shown a noteworthy irreversible inhibition property on mice [35] and rats [34]. The mentioned compound represents a very suitable candidate for clinical progression, which is a mechanism-based inhibitor with lasting and lower dosing at 2 mg/kg once daily efficacy [35].…”

Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

“…VAP-1 activity and protein levels increase during inflammation [10]. VAP-1 inhibition curtails leukocyte recruitment to sites of inflammation in vivo [15] as well as the transendothelial migration of leukocytes in vitro [15,16]. Since VAP-1 has both enzymatic activity and inflammatory properties, it has become a promising therapeutic target.…”

“…Increases in VAP-1 activity and/or protein levels have been observed in many inflammation-associated diseases [10], such as primary sclerosing cholangitis [11], chronic obstructive pulmonary disease [12], atherosclerosis [13], and chronic liver disease [14]. Inhibition of the amine oxidase activity of VAP-1 has been shown to abrogate the recruitment of leukocytes, especially neutrophils, to sites of inflammation in vivo and the transendothelial migration of leukocytes in vitro [15,16]. These findings have led to medicinal chemistry efforts to inhibit VAP-1 deamination activity as an approach to anti-inflammation therapies [17][18][19].…”