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Enhanced antichemobrain activity of amino acid assisted ferulic acid solid dispersion in adult zebrafish (Danio rerio)

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Abstract

Chemotherapy-induced cognitive impairment (CICI), also known as “chemobrain,” is a common side effect of breast cancer therapy which causes oxidative stress and generation of reactive oxygen species (ROS). Ferulic acid (FA), a natural polyphenol, belongs to BCS class II is confirmed to have nootropic, neuroprotective and antioxidant effects. Here, we have developed FA solid dispersion (SD) in order to enhance its therapeutic potential against chemobrain. An amorphous ferulic acid loaded leucin solid dispersion (FA-Leu SD) was prepared by utilizing amino acid through spray-drying technique. The solid-state characterization was carried out via Fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM). Additionally, in-vitro release studies and antioxidant assay were also performed along with in-vivo locomotor, biochemical and histopathological analysis. The physical properties showed that FA-Leu SD so formed exhibited spherical, irregular surface hollow cavity of along with broad melting endotherm as observed from FE-SEM and DSC results. The XRD spectra demonstrated absence of sharp and intense peaks in FA-Leu SD which evidenced for complete encapsulation of drug into carrier. Moreover, in-vitro drug release studies over a period of 5 h in PBS (pH 7.4) displayed a significant enhanced release in the first hr (68. 49 ± 5.39%) and in-vitro DPPH assay displayed greater antioxidant potential of FA in FA-Leu SD. Furthermore, the in-vivo behavioral findings of FA-Leu SD (equivalent to 150 mg/kg of free FA) exhibited positive results accompanied by in-vivo biochemical and molecular TNF-α showed a significant difference (p < 0.001) vis-à-vis DOX treated group upon DOX + FA-Leu SD. Additionally, histopathological analysis revealed neuroprotective effects of FA-Leu SD together with declined oxidative stress due to antioxidant potential of FA which was induced by anticancer drug doxorubicin (DOX). Overall, the above findings concluded that spray-dried FA-Leu SD could be useful for the treatment of chemotherapy induced cognitive impairment.

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Abbreviations

FA:

Ferulic Acid

Leu:

Leucine

PM:

Physical mixture

FA-Leu SD:

Ferulic acid loaded solid dispersion

UV:

Ultraviolet spectrophotometer

FTIR:

Fourier transform infrared spectrophotometer

DSC:

Differential scanning colorimeter

PXRD:

Powder X-ray diffraction

FESEM:

Field emission scanning electron microscope

DPPH:

1,1-Diphenyl-2-picrylhydrazyl

SD:

Solid dispersion

CICI:

Chemotherapy-induced cognitive impairment

DOX:

Doxorubicin

ATChI:

Acetylthiocholine iodide

ROS:

Reactive oxygen species

FZ:

Favorable zone

UFZ:

Unfavourable zone

LZ:

Light zone

DZ:

Dark zone

LDT:

Light and Dark test

TSLZ:

Time spent in light zone

TSDZ:

Time spent in dark zone

OF:

Open field

OFT:

Open field test

TSFZ:

Time spent in favorable zone

TSUZ:

Time spent in unfavourable zone

LPO:

Lipid peroxidation

AChEs:

Acetylcholinesterase

GSH:

Glutathione

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor α

Eq.:

Equivalent

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Acknowledgements

DS duly acknowledges Sanchit Arora, Pharmaceutics Department, DPSRU, New Delhi for rendering help to finalize the revised manuscript. CS is thankful to the Dr. Rajendra Kumar, School of Medicine, Johns Hopkins University, Baltimore, MD, United States for hel** to address the comments. The authors acknowledge generous support of ISF College of Pharmacy and IK Gujral Punjab Technical University, Kapurthala for providing appropriate facilities and instrumentation during the study. The authors would like to thank Punjab University, Chandigarh for providing the PXRD and FE-SEM instrumentation facilities; ISF College of Pharmacy, Moga for providing the instrumentation facilities for UV, FTIR and DSC studies and for performing in-vivo studies on zebrafish. CS duly acknowledges the Science and Engineering Research Board (SERB, GoI) for providing the necessary equipment (spray dryer) to develop the novel formulation under the project EEQ/2020/000616.

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Authors and Affiliations

  1. Department of Pharmaceutics, ISF College of Pharmacy, Moga, Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 142001, India

    Deeksha Shukla, Raj Kumar Narang & Charan Singh

  2. Department of Pharmacology, ISF College of Pharmacy, Moga, Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 142001, India

    Simranjit Kaur & Arti Singh

  3. Department of Pharmaceutical Sciences, School of Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Srinagar Garhwal, Uttarakhand, 246174, India

    Charan Singh

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  1. Deeksha Shukla
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Contributions

DS: Performed experiments and written the manuscript. SK: Performed in vivo studies. AS: Planned and supervised in vivo studies. RKN and CS: Designed the project and Supervision.

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Correspondence to Arti Singh, Raj Kumar Narang or Charan Singh.

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Ethics approval and consent to participate: The experimental design and protocol was approved by the Institutional Biosafety Committee (Approval No. ISFCP/IBSC/M1/2021/16) and conducted according to the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPSCEA) guidelines for the rational use and care of experimental animals. No human subjects were involved in this work.

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Shukla, D., Kaur, S., Singh, A. et al. Enhanced antichemobrain activity of amino acid assisted ferulic acid solid dispersion in adult zebrafish (Danio rerio). Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01546-5

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