Anti-Inflammatory Activities of an Anti-Histamine Drug, Loratadine, by Suppressing TAK1 in AP-1 Pathway

Abstract

Loratadine is an anti-histamine routinely used for treating allergies. However, recent findings have shown that Loratadine may also have anti-inflammatory functions, while their exact mechanisms have not yet been fully uncovered. In this paper, we investigated whether Loratadine can be utilized as an anti-inflammatory drug through a series of in vitro and in vivo experiments using a murine macrophage cell line and an acute gastritis mouse model. Loratadine was found to dramatically reduce the expression of pro-inflammatory genes, including MMP1, MMP3, and MMP9, and inhibit AP-1 transcriptional activation, as demonstrated by the luciferase assay. Therefore, we decided to further explore its role in the AP-1 signaling pathway. The expression of c-Jun and c-Fos, AP-1 subunits, was repressed by Loratadine and, correspondingly, the expression of p-JNK, p-MKK7, and p-TAK1 was also inhibited. In addition, Loratadine was able to reduce gastric bleeding in acute gastritis-induced mice; Western blotting using the stomach samples showed reduced p-c-Fos protein levels. Loratadine was shown to effectively suppress inflammation by specifically targeting TAK1 and suppressing consequent AP-1 signaling pathway activation and inflammatory cytokine production.

Evaluation of the Effect of Loratadine versus Diosmin/Hesperidin Combination on Vinca Alkaloids-Induced Neuropathy: A Randomized Controlled Clinical Trial

“…Hesperidin also alleviated neuroinflammation through the reduction of IL1-β and TNF-α in patients with type 2 diabetes [54]. Loratadine also diminished inflammatory mediators such as IL1-β and TNF-α through the inhibition of NF-κB in a mouse model [23]. Additionally, loratadine, when combined with montelukast, resulted in a reduction in IL-4 and TNF-α without increasing adverse effects in children with asthma [55].…”

“…Loratadine also showed promising results in the mitigation of neuropathic pain and inflammation [22]. Loratadine substantially decreased the production of genes associated with inflammation, inhibited NF-κB, and blocked activating protein-1 (AP-1) stimulation via MAPK [23]. Loratadine binds to H1-receptors in different cells and decreases the activation of peripheral nociceptive receptors [24].…”

The Combination Sorafenib-raloxifene-loratadine as a Novel Potential Therapeutic Approach Against Human Liver Cancer

“…The anti-inflammatory activity of loratadine by suppressing NF-kB has also been shown (28) and involves the reduction in proinflammatory component levels like IL-6 and TNF-α. In addition, loratadine, by inhibiting TAK1 suppresses the activator protein 1 (AP-1) signaling pathway, which enables the transcription of inflammation-related enzymes including MMPs (29), and has an important role in cell proliferation, survival, differentiation, apoptosis, and migration (30). Very recently, it was described that desloratadine possesses potential antineoplastic activity through the blockade of Nmyristoyl transferase 1 (NMT1) activity, an enzyme that contributes to HCC progression (31).…”

Role of Marine Bacterial Contaminants in Histamine Formation in Seafood Products: A Review

“…According to El-Banna et al [89], the improved effectiveness of such antibiotics to control histamine producing bacteria in the presence of histamine could be due to anti-histamines being inhibitory to the bacterial efflux pumps. Another possibility of this phenomenon may be due to the main structural feature of anti-histamines, which is likely to be similar to surfactants [90]. With this structure, it might cause alterations in the biological membrane permeability of the histamine producers [86].…”