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. 2022 Nov 14;7(47):43290-43305.
doi: 10.1021/acsomega.2c06215. eCollection 2022 Nov 29.

Intranasally Co-administered Berberine and Curcumin Loaded in Transfersomal Vesicles Improved Inhibition of Amyloid Formation and BACE-1

Gaurav Mishra  1 , Rajendra Awasthi  2 , Anurag Kumar Singh  3   4 , Snigdha Singh  5 , Sunil Kumar Mishra  6 , Santosh Kumar Singh  4 , Manmath K Nandi  1
Affiliations

Intranasally Co-administered Berberine and Curcumin Loaded in Transfersomal Vesicles Improved Inhibition of Amyloid Formation and BACE-1

Gaurav Mishra et al. ACS Omega. .

Retraction in

Abstract

Selective permeability of the blood-brain barrier restricts the treatment efficacy of neurologic diseases. Berberine (BBR) and curcumin (CUR)-loaded transferosomes (TRANS) were prepared for the effective management of Alzheimer's disease (AD). The study involved the syntheses of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS by the film hydration method. Vesicles were characterized to ensure the formation of drug-loaded vesicles and their in vivo performance. The particle sizes of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS were 139.2 ± 7, 143.4 ± 8, and 165.3 ± 6.5 nm, respectively. The presence of diffused rings in the SED image indicates the crystalline nature of the payload. Low surface roughness in an AFM image could be associated with the presence of a surface lipid. BBR-CUR-TRANS showed 41.03 ± 1.22 and 47.79 ± 3.67% release of BBR and 19.22 ± 1.47 and 24.67 ± 1.94% release of CUR, respectively, in phosphate buffer saline (pH 7.4) and acetate buffer (pH 4.0). Formulations showed sustained release of both loaded drugs. BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS exhibited a lower percentage of hemolysis than pure BBR and CUR, indicating the safety of the payload from delivery vesicles. Lower percentages of binding were recorded from BBR-CUR-TRANS than BBR-TRANS and CUR-TRANS. Acetylcholinesterase inhibition activity of the prepared transferosomes was greater than that of pure drugs, which are thought to have good cellular penetration. The spatial memory was improved in treated mice models. The level of malondialdehyde decreased in AD animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS, respectively, as compared to the scopolamine-induced AD animals. BBR-CUR-TRANS-treated animals showed the highest decrease in the NO level. The catalase level was significantly restored in scopolamine-intoxicated animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS. The immunohistochemistry result suggested that the BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS have significantly decreased the regulation of expression of BACE-1 through antioxidant activity. In conclusion, the study highlights the utility of formulated transferosomes as promising carriers for the co-delivery of drugs to the brain.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic representation of the hypothetical approach of the present work (created with BioRender.com).
Figure 2
Figure 2
Scanning electron microscopy images of BBR-TRANS (Set A), CUR-TRANS (Set B), and BBR-CUR-TRANS (Set C).
Figure 3
Figure 3
Transmission electron microscopy of BBR-TRANS (a), CUR-TRANS (b), and BBR-CUR-TRANS (c).
Figure 4
Figure 4
Selected area electron diffraction pattern micrographs of BBR-TRANS (A), CUR-TRANS (B), and BBR-CUR-TRANS (C).
Figure 5
Figure 5
Atomic force microscopy images of BBR-CUR-TRANS: 2D image (A) and 3D plane image (B).
Figure 6
Figure 6
Release profile of BBR and CUR from BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS in 100 mL of acid phthalate buffer (pH 4.0) and phosphate buffer saline (pH 7.4) using a dialysis bag method at 37 ± 0.5 °C (mean ± SD, n = 3).
Figure 7
Figure 7
AChE activity (%) with inhibitors (BBR, CUR, BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS) estimated at 412 nm. The data presents mean ± SD, n = 3 (p < 0.001). One-way ANOVA followed by Tukey’s multiple comparison test was used for data analysis.
Figure 8
Figure 8
Percent RBC rupture in comparison to the distilled water n = 3 (p < 0.001).
Figure 9
Figure 9
Plasma protein-binding study of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS.
Figure 10
Figure 10
Result of behavioral analysis in the mouse model. Alteration caused by the BBR, CUR, BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS in the neurobehavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice: Morris water-maze test to reach the hidden platform (A), entries in arms (B), and spontaneous alteration (C). Values are represented as mean ± SEM, n = 8. Data analysis was carried out using one-way ANOVA (***p < 0.001).
Figure 11
Figure 11
Alteration in oxidative stress in different treatment groups: lipid peroxidation test (A) and nitrite test (B) (mean ± SEM, n = 5). Data analysis was carried out using one-way ANOVA (***p < 0.001).
Figure 12
Figure 12
Results of the catalase test (A) and the SOD test (B) showing alteration in antioxidant enzymes in different test groups (mean ± SEM, n = 5). Statistical analysis of data was carried out by using one-way ANOVA (***p < 0.001).
Figure 13
Figure 13
Observations of immunohistochemical analysis to analyze the BACE-1 expression in the brain hippocampus of experimental animals (scale 100 μm). Images present BACE (red signal) and DAPI DNA counterstains (blue signal) (mean ± SEM, n = 5). Statistical calculations were carried out by one-way ANOVA following the Newman–Keuls test (***p < 0.001).
Figure 14
Figure 14
Observations of immunohistochemical analysis to interpret the expression of Aβ in the hippocampus of experimental animal (scale 100 μm). Images present Aβ (red signal) and DAPI DNA counterstain (blue signal) (mean ± SEM, n = 5). Statistical calculations were carried out by one-way ANOVA following the Newman–Keuls test (***p < 0.001).
Figure 15
Figure 15
Results of histopathological examinations of brain, kidney, liver, and spleen (control and treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS).
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