**Background**
Histamine H1 receptors play a critical role in mediating allergic reactions and inflammatory responses. Beyond its traditional role in treating allergies, the modulation of H1 receptors has gained attention in the context of oncology and organ protection. For instance, the PI3K/Akt/mTOR pathway is frequently dysregulated in various malignancies, including pancreatic cancer, making the discovery of agents that can modulate these signaling cascades essential for therapeutic development. Furthermore, chemotherapy-induced organ toxicity, such as cisplatin-induced nephrotoxicity, remains a significant clinical challenge that necessitates the development of preventive pharmacological interventions. In this context, we will introduce a first-generation histamine H1-receptor antagonist – Diphenhydramine.
**Definition**
Diphenhydramine is a first-generation H1-receptor antagonist with anti-cholinergic effects. According to the Diphenhydramine technical information, this compound targets the H1 receptor and is characterized by the molecular formula C17H22ClNO.
**In Vitro and In Vivo Studies**
The Diphenhydramine biological activity has been extensively studied across various models. In vitro, Diphenhydramine hydrochloride inhibits cisplatin-induced cell death in kidney proximal tubular cells, specifically HK-2 and LLC-PK1 cells. In cancer research, Diphenhydramine (0.2-1 mM, 24 h) inhibits cell viability and induces apoptosis in CCRF-CEM and Jurkat cells. Furthermore, in PANC-1 cells, treatment with Diphenhydramine (0-10 μg/mL, 24 or 48 h) increases the expression of Bad and Bax while decreasing BCL-2 levels. Western blot analysis reveals that it decreases the expression of p-AKT (Thr308), p-AKT (Ser 473), p-mTOR (Ser 2448), p-FoxO1 (Ser 256), p-MDM2 (Ser 166), p-NF-ĸB p65 (Ser 536), and p-GSK-3 (Ser 9), demonstrating its potential in Diphenhydramine Cancer research.
Regarding Diphenhydramine in vivo studies, administration of Diphenhydramine (20 mg/kg) hydrochloride inhibits cisplatin-induced kidney toxicity in mice. Additionally, in rats exposed to acute, severe dichlorvos, Diphenhydramine (3-30 mg/kg, i.m., administered 5 minutes prior to s.c. 25 mg/kg Dichlorvos) significantly reduces mortality. It is also noted that the compound can cross the ovine blood-brain barrier. In conclusion, Diphenhydramine is a versatile H1-receptor antagonist with significant potential in protecting against chemotherapy-induced toxicity and inhibiting the growth of certain cancer cell lines.
Keywords
Diphenhydramine, 147-24-0, Histamine Receptor, Endogenous Metabolite, Bacterial, Apoptosis, anti-cholinergic, Cisplatin, kidney toxicity, Inhibitor, inhibitor, inhibit
References
[1] Simons FE. H1-receptor antagonists. Comparative tolerability and safety. Drug Saf. 1994;10(5):350-380.
[2] Sadiq MW, et al. Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. J Pharm Sci. 2011;100(9):3912-3923.
[3] Hamano H, et al. Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity. Kidney Int. 2021 Apr;99(4):885-899.
[4] Jangi SM, et al. Apoptosis of human T-cell acute lymphoblastic leukemia cells by diphenhydramine, an H1 histamine receptor antagonist. Oncol Res. 2004;14(7-8):363-72.
[5] Zhang R, Chen M, Yu L, et al. Anticancer activity of diphenhydramine against pancreatic cancer by stimulating cell cycle arrest, apoptosis, and modulation of PI3K/Akt/mTOR pathway[J]. Cell proliferation, 2021, 69: 5.