Ellagic Acid Exerts Dual Action to Curb the Pathophysiological Manifestations of Sickle Cell Disease and Attenuate the Hydroxyurea-Induced Myelosuppression in Berkeley Mice

Abhishek Gour; Dilpreet Kour; Ramajayan Pandian; Mahir Bhardwaj; Sanghapal D Sawant; Ajay Kumar; Utpal Nandi

doi:10.1021/acsptsci.3c00026

Ellagic Acid Exerts Dual Action to Curb the Pathophysiological Manifestations of Sickle Cell Disease and Attenuate the Hydroxyurea-Induced Myelosuppression in Berkeley Mice

ACS Pharmacol Transl Sci. 2023 May 11;6(6):868-877. doi: 10.1021/acsptsci.3c00026. eCollection 2023 Jun 9.

Authors

Abhishek Gour^{1

2}, Dilpreet Kour^{1

2}, Ramajayan Pandian^{1

2}, Mahir Bhardwaj^{1

2}, Sanghapal D Sawant^{2

3}, Ajay Kumar^{1

2}, Utpal Nandi^{1

2}

Affiliations

¹ Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
² Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
³ Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.

Abstract

The use of adjuvant therapy is an attractive approach to manage sickle cell disease (SCD) symptomatically. The present study aimed to investigate the potential of ellagic acid as an adjuvant therapy with hydroxyurea (HU), a key drug for SCD with myelosuppressive toxic effects. A panel of experiments was performed using SCD patient's blood (ex vivo) and transgenic mice model of SCD (in vivo). Ellagic acid exhibited the following beneficial pharmacological actions: (a) potent anti-sickling, polymerization inhibitory, and inherent non-hemolytic activity; (b) pronounced action to abrogate HU-induced neutropenia and to improve key hematological parameters during SCD (RBC, Hb, platelet levels); (c) considerable action to foster vascular tone (L-proline); (d) marked attenuating effect against oxidative stress (nitrotyrosine, hypoxanthine, MDA, GSH); (e) substantial inhibitory role against inflammation (analgesic activity and regulation of hemin, TNF-α, IL-1β, NF-κB/IκBα); (f) remarkable outcome of declining vaso-occlusive crisis (P-selectin, ERK1/2); (g) notable shielding deed against elevated biochemical marker for organ toxicity (creatinine); (h) noticeably prevented histopathological alterations of the spleen. Additionally, the pharmacokinetic study results of HU in the presence and absence of ellagic acid using a mouse model demonstrate that ellagic acid could be safely co-administered with HU. Overall findings suggest that ellagic acid is a promising candidate for adjuvant therapy in SCD based on its own significant ability against SCD and potentiating capability of HU action via targeting improvement at the various stages of pathophysiological complications during SCD and minimizing HU-induced toxicological manifestations.