RETRACTED ARTICLE: The effect of safranal loaded mucoadhesive nanoemulsion on oxidative stress markers in cerebral ischemia
Authors: Md Aftab Alam
Mohammad Ashafaq
Mastour Safer Al-Ghamdi
Niyaz Ahmad
Atta Abbas Naqvi
Rizwan Ahmad
Farhan Jalees Ahmad
Journal: Artificial Cells Nanomedicine and Biotechnology (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: MCAO; Safranal; cerebral ischemia; mucoadhesive nanoemulsion; oxidative stress.
Affiliations: Department of Pharmaceutics, College of Clinical Pharmacy, Dammam University, Dammam, Kingdom of Saudi Arabia;, Department of Natural Products and Alternative Medicine, College of Clinical Pharmacy, Dammam University, Dammam, Kingdom of Saudi Arabia;, Department of Pharmacy Practice, College of Clinical Pharmacy, University of Dammam, Dammam, Kingdom of Saudi Arabia;, Neuroscience and Toxicology Unit, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia;, Department of Pharmaceutics, School of Medical and Allied Sciences, Galgotias University, Gautam Budh Nagar, Greater, Noida, India;, Nanomedicine Lab, Department of Pharmaceutics, Faculty of Pharmacy, Hamdard Nagar, Jamia Hamdard, New Delhi, India;, Department of Pharmacology, College of Clinical Pharmacy, University of Dammam, Dammam, Kingdom of Saudi Arabia

Abstract:  Antioxidants, with reported neuroprotective activity, encounter free radical induced neural damage leading to reduced risk of cerebral ischemia-reperfusion (IR) injury. Safranal, an antioxidant drug with potential role in the amelioration of cerebral ischemia, endures low solubility and poor absorption property thus resulting a low serum and tissue bioavailability. This research aims to prepare nanoemulsion with the concept; to increase the bioavailability in order to reduce oxidative stress-induced brain injury as well as to evaluate the brain-drug targeting following non-invasive nasal route administration in middle cerebral artery occlusion (MCAO) animal model. Titration method was used to prepare safranal mucoadhesive nanoemulsion (SMNE) followed by further characterization, i.e. entrapment efficiency, particles size, and zeta potential study. Optimized SMNE showed; mean globule size of 89.64 nm (±9.12), zeta potential -11.39 mV (±1.32), drug content 98.47% (±1.01), and viscosity of 124 cp (±14). Rats were subjected to 2 h of MCAO, successively followed by a 22 h reperfusion, after which the grip strength, locomotor activity, and biochemical studies, i.e. glutathione reductase (GR), glutathione peroxidase, lipid peroxidation, catalase, and superoxide dismutase were studied as assessment tool for effective treatment in brain. SMNE administered i.n. (intranasal) in MCAO induced cerebral ischemia rats exhibited significant improvement in neurobehavioral (locomotor and grip strength) and antioxidant activity as well as histopathological studies. The toxicity studies performed at the end revealed safe nature of developed SMNE. 

Retracted: Yes

PubPeer comments:
 At left, Figure 9.  Representative photomicrographs showing the TS of ratsu2019 brain (A, B, and C) ... for SHAM (normal control), MNE (placebo), SMNE treated groups, respectively after 14 days. A and C are more similar than one would expect. There are also repeated regions of neural tissue in C, which is not biologically plausible. Shown at right with enhanced contrast. ![] So I color-reversed C and superimposed it on A with 50% transparency, and they cancel out (i.e. they re identical) except in those repeated regions within C. ![file] Other versions of the same tissue slice (differently coloured, with different areas of repeating wallpaper) appear in 10(f) of [Ahmad et al (2019)] and Fig 10B from [Ahmad et al (2014)] . ![] , 
 Figure 7.  Effect of safranal mucoadhesive nanoemulsion (SMNE at 10u2009mg kg) administration on haematoxylin and eosin staining in the brain sections of the SHAM, MCAO, Safranal Solution (Saf. Sol.), and safranal mucoadhesive nanoemulsion (SMNE). **A, Cortical area of SHAM-group animal showed uniform distribution of neurons. Normal neurons with the characteristic conical outlines with no abnormal features are seen.** B, Tissues around infarcted area in the MCAO group show a focal area of vacuolation and neuronal loss. C, The MCAOu2009+u2009SMNE group rats show partial neuronal loss. Below, Figure 12 from [Ahmad et al (2017)] :  Synergistic effect of curcuminoids-CS-NPs administration on hematoxylin and eosin staining in the brain sections of the sham, MCAO, and MCAO u00fecurcuminoids-CS-NPs groups. **(a) Cortical area of sham group animal showed uniform distribution of neurons. Normal neurons with the characteristic conical outlines with no abnormal features are seen.** (b) Tissues around infarcted area in the MCAO group show a focal area of vacuolation and neuronal loss. (c) The MCAO u00fecurcuminoids-CS-NPs group rats show partial neuronal loss. ![file] 7(A) and 12(a) overlap, though not entirely, differing outside the marked zone. How does this happen? , 
 Figure 8.  Effect of Safranal pretreatment for 21 days on brain infarct size by TTC stain after middle cerebral artery occlusion for 2u2009h and reperfusion of 22u2009h. A. Representative photographs of brain sections stained with 0.1% TTC, and measurement of infarct volumes of MCAO, MCAOu2009+u2009safranal mucoadhesive manoemulsion (SMNE) group, and MCAOu2009+u2009Mucoadhesive Nanoemulsion-Placebo group are presented . Below, Fig. 9(C) from [Ahmad et al (2016)] :  Effect of Rutin pretreatment for 21 days on brain infarct size by TTC stain after middle cerebral artery occlusion for 2 h and reperfusion of 22 h. (C.) Representative photographs of brain sections stained with 0.1% TTC, and measurement of infarct volumes of MCAO, MCAO + RUT solution group, and MCAO + RUT-CS-NPs group are presented (C). ![] I can see a rationale for re-using the same MCAO images in both papers. But  Sham from Fig 8 becomes  MCAO + RUT in Fig 9;  MCAO + SMNE from Fig 8 becomes  Sham in Fig 9 (after horizontal compression);  Sham+Placebo from Fig 8 becomes  MCAO + RUT-CS-NPs in Fig 9, apart from the white areas representing infarcts. , 
 Figure 1.  CLSM images of non-mucoadhesive safranal nanoemulsion (SNE) (A) and safranal mucoadhesive nanoemulsion (SMNE) (B). ![] Figure 2 from [Ahmed et al (2018)] .  CLSM images of quercetin non-mucoadhesive nanoemulsion (QNE) and quercetin mucoadhesive nanoemulsion (QMNE). ![] No other comment. , 
 Figure 9.  Representative photomicrographs showing the TS of ratsu2019 ... nasal mucosa (D, E, and F) for SHAM (normal control), MNE (placebo), SMNE treated groups, respectively after 14 days. At right, contrast-enhanced for clarity. ![file] (E) (MNE treatment) seems to be the same as  (B) CS-coated-PCL-NPs (Placebo Group) from Fig 3 of [Ahmad et al (2018a)] - red boxes. (F) (SMNE treatment) matches  (C) CS-coated-GRA-loaded-PCL-NPs from Fig 9 of [Ahmad et al (2018b)] - green boxes. ![file] , 
 Retracted [11 January 2021] . ------------------------------------------------- We, the Editors and Publishers of Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Niyaz Ahmad, Rizwan Ahmad, Atta Abbas Naqvi, Mohammad Ashafaq, Md Aftab Alam, Farhan Jalees Ahmad Mastour Safer Al-Ghamdi. (2017). The effect of safranal loaded mucoadhesive nanoemulsion on oxidative stress markers in cerebral ischaemia. Artificial Cells, Nanomedicine, and Biotechnology, 45:4, 775u2013787. DOI: 10.1080 21691401.2016.1228659 This article is retracted due to reuse of images from other articles by the same authors, representing results of different experiments. This includes Figure 1, which can also be found in: Ahmad et al. (2018). Intranasal delivery of quercetin-loaded mucoadhesive nanoemulsion for treatment of cerebral ischaemia. Artificial Cells, Nanomedicine, and Biotechnology. https: doi.org 10.1080 21691401.2017.1337024 In addition, concerns were raised regarding the integrity of other Figures in the article, including Figures 3, 7(a), 8 and 9. When asked for an explanation, the authors were unable to provide raw data that would support the integrity of their research. As the authors were unable to provide the original images, the Editors agreed the findings of the study are no longer valid and advised for the article to be retracted. The authors do not agree with the retraction. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. ,