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Anti-Angiogenic Activity of Chloride and Potassium Channel Modulators

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Anti-Angiogenic Activity of Chloride and Potassium Channel Modulators Kamili et al. Future Journal of Pharmaceutical Sciences (2020) 6:24 Future Journal of https://doi.org/10.1186/s43094-020-00041-1 Pharmaceutical Sciences RESEARCH Open Access Anti-angiogenic activity of chloride and potassium channel modulators: repurposing ion channel modulators Chandana Kamili1* , Hima Sowmya Kandoti1, Sharadha Radhakrishnan1, Abbulu Konde1 and Uma Maheshwara Rao Vattikutti2 Abstract Background: Excessive angiogenesis can be the root cause of many pathological conditions. Various types of ion channels are found on the endothelial cells. These ion channels play a vital role in the multi-stepped process of angiogenesis. The study aims to investigate the anti-angiogenic effects of specific ion channel modulators mefloquine (volume-regulated chloride channel blocker), lubiprostone (ClC-2 channel agonist), and 4-aminopyridine (voltage-gated potassium channel blocker). Results: The anti-angiogenic activity of ion channel modulators was screened by measuring its effects on the area of neovascularization and histopathological studies by in vivo (corneal neovascularization) method and by in vitro assays, endothelial cell proliferation assay, cell migration assay, and matrigel cord-like morphogenesis assay. The test and standard drug (bevacizumab) groups were compared with the control group using one-way ANOVA, followed by post hoc test, and Dunnett’s test to compare the mean of all the groups with the control mean. The results revealed that mefloquine at the dose of 0.6% w/v and 1.0% w/v, lubiprostone at the dose of 0.5% w/v and 1.0% w/ v, and 4-aminopyridine at the dose of 2% w/v and 4% w/v showed significant anti-angiogenic property. In the studies on human umbilical vein endothelial cells, the test drugs (100 nM) showed significant inhibition of proliferation, migration, and decrease in network length of cord-like tubes. Conclusion: The scientific findings indicate that the test drugs have potent anti-angiogenic activity by inhibiting the cell proliferation, inhibiting the cell volume increase, arresting the cell cycle progression and by causing membrane hyperpolarization. The potent anti-angiogenic drugs obtained by repurposing these ion channel modulators, in the further studies, will be able to treat the diseases due to excess angiogenesis from the root cause. Keywords: Anti-angiogenesis, Ion channel modulators, Corneal neovascularization, Mefloquine, Lubiprostone, 4- Aminopyridine Background excess or reduced proliferation of vascular endothelial Tumor angiogenesis was extensively studied by Judah cells (ECs), leading to various disease conditions [1]. Folkman, the pioneer in the area of angiogenesis at the Neurovascularization, which is the primary cause of beginning of the 1970s. Angiogenic switch refers to the blindness in diabetic retinopathy, is the main feature of equilibrium between the levels of angiogenic and angio- various eye disorders [2, 3]. Proliferative diabetic retin- static factors. Alterations in this equilibrium cause either opathy (PDR) is primarily characterized by the excessive generation of leaky blood vessels that spread unevenly * Correspondence: [email protected] on the retinal surface, leading to hemorrhage, fibrosis, 1 Department of Pharmacology, CMR College of Pharmacy, Hyderabad, and tractional retinal detachment. Compared to other Telangana 501401, India Full list of author information is available at the end of the article conditions, macular degeneration is said to be the key © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Kamili et al. Future Journal of Pharmaceutical Sciences (2020) 6:24 Page 2 of 8 cause responsible for the formation of new choroidal the Institutional Animal Ethics Committee (IAEC) with vessels. This, when left untreated, leads to diabetic retin- project license numbers (CPCSEA/1657/IAEC/CMRCP/ opathy (DR) and vision loss. DR refers to a clinical con- PhD-15/42). dition characterized by abnormal retinal vessels. Vascular endothelial growth factor (VEGF) plays a vital Selection of drugs role in the promotion of angiogenesis in both retinal and Endothelium expresses a huge variety of ion channels, and choroidal blood vessels. High levels of VEGF in eyes these ion channels regulate the crucial steps which result were found in diabetic patients. The above discovery be- in angiogenesis. Thus, in the present research work, spe- came the main foundation for conducting research to cific ion channel agonists and antagonists like mefloquine find the potential effect of VEGF in the pathophysiology (volume-regulated chloride channel blocker), lubiprostone of PDR [4, 5]. Blockade of the development of new blood (ClC-2 channel agonist), and 4-aminopyridine (voltage- vessels may be a good approach in the treatment of dis- gated potassium channel blocker) have been selected to eases that are caused due to excess angiogenesis [6, 7]. evaluate their anti-angiogenic effect. Corneal endothelium plays a vital role in the propaga- tion of signals, resulting in multicellular functioning. It Corneal neovascularization method regulates various vascular processes like blood flow con- Corneal neovascularization (stromal neovascularization) trol, blood pressure, clotting of blood, blood vessel perme- is the ingrowths of blood vessels from the limbus in the ability, wound healing, and angiogenesis. Interestingly, corneal stroma. Because the normal stroma is avascular, various types of ion channels are expressed in the ECs. stromal neovascularization is always considered a patho- Ion channels can be defined as the pore-forming cell logic response. The response of the antiangiogenic drugs membrane proteins, which play a significant role in many is evaluated based on the above principal. This technique physiological processes like cell volume, muscle constric- was carried out by cauterizing the right cornea of every tion, neural depolarization, hormonal release, etc. Various rat with 75% silver nitrate and 25% potassium nitrate, ion channels like sodium (Na+), calcium (Ca2+), potassium and the left eye served as the control for all animals in (K+), and volume-regulated anion channels (VRAC), are all the groups. The rats were cauterized by pressing an recognized on the surface of ECs. Recently, the occurrence applicator stick with a diameter of 1.5 mm, on the center and functional role of vascular ion channels in angiogen- of the cornea for 5 s while the animal is deeply anesthe- esis has been investigated [8–11]. Corneal endothelial tized with cocktail of ketamine (80 mg/kg) and xylazine angiogenesis model is a valuable means to study neovas- (5 mg/kg). After the animals recovered from the cularization mechanism and evaluate the treatment. Anti- anesthesia, the degree of burn was checked by a scoring angiogenic agents selectively target branching blood ves- method. To increase the reproducibility of the injuries, sels and, hence, find use in the treatment of various dis- the same investigator cauterized all the animals. Follow- eases that occur due to excess angiogenesis. This study ing the procedure for determining the burn score, the aims at pinpointing the exact function of these specific ion rats were randomized to eliminate potential bias in the channel modulators in anti-angiogenesis which can be the degree of injury within the different groups; six animals basis for further studies to repurpose the role of channel were used in each group. Test and standard drugs were modulators in anti-angiogenic therapy. given as eye drops from day 1 to day 13 as 20 μl drop three times a day (Table 1). To make the solution vis- Methods cous to about 25–50 cps, which is the ideal viscosity Chemicals range for eye drops, 1% methylcellulose was added. On Bevacizumab, mefloquine, lubiprostone, and 4- the 14th day, percentage inhibition of neovascularization aminopyridine were purchased from Sigma-Aldrich Pvt. Ltd. was seen after enucleating the animals. Rats were anes- All the other chemicals (AgNO3,KNO3,ethanol,10%for- thetized and sacrificed; the eyes were removed to check malin, hematoxylin, eosin, methylcellulose, sodium pentobar- for inhibitory effect [12]. bitone) used in the research are of AR grade. Procedure for determining burn score Experimental animals The applicator stick was dipped in a solution of 75% Experimental animals and maintenance AgNO3 and 25% KNO3, and the tip of the stick was Wistar rats weighing in between 150 and 200 g were superficially touched over the cornea for about 8–10 s purchased from Teena Labs Pvt. Ltd., Hyderabad, India. and the burn score was estimated. The animals were maintained at a controlled Burn score: temperature (22–25 °C, 45% humidity) on a 12:12-h dark-light cycle. All the procedures were performed ac- 0. No blister on the cornea
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