PUFAs, BDNF and lipoxin A4 inhibit chemical-induced cytotoxicity of RIN5F cells in vitro and streptozotocin-induced type 2 diabetes mellitus in vivo

Siresha Bathina,Undurti N Das

doi:10.1186/s12944-019-1164-7

Abstract

ObjectiveTo study whether minimal doses of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and lipoxin A4 (LXA4) and brain-derived neurotrophic factor (BDNF), when used in combination can protect RIN5F cells from chemical-induced cytotoxicity. As a corollary, to know whether plasma BDNF and LXA4 are altered in STZ-induced type 2 DM animals.Materials and methodsRIN5F cells, alloxan (AL), streptozotocin (STZ), doxorubicin (DB), and benzo(a)pyrene (BP) were used in this study. Chemical-induced apoptosis and changes in antioxidants, lipid peroxides and nitric oxide (NO) and LXA4 and BDNF levels in RIN5F cells were studied. Alterations in plasma concentrations of BDNF and LXA4 in STZ-induced type 2 diabetes animals was estimated.ResultsBDNF, LXA4 and AA, EPA and DHA protected (P < 0.001 and P < 0.01 respectively) against AL/STZ/DB/BP-induced toxicity to RIN5F cells in vitro. AL/ STZ/DB/BP inhibited BDNF and LXA4 production by RIN5F cells and were restored to normal by AA, EPA and DHA. Sub-optimal doses of BDNF, LXA4, AA and EPA when used in combination protected against cytotoxic action of AL/STZ/DB/BP on RIN5F cells in vitro by restoring LXA4/BDNF levels and altered antioxidant/lipid peroxides/NO levels (P < 0.01) to normal. STZ (65 mg/kg)-induced type 2 diabetes mellitus animals showed reduced plasma BDNF and LXA4 levels (P < 0.001).DiscussionAL/STZ/DB/BP-induced cytotoxicity to RIN5F cells in vitro can be prevented by BDNF, LXA4 and AA. AL/STZ/DB/BP are cytotoxic, possibly, by suppressing the production of LXA4 and BDNF in RIN5F cells. STZ-induced type 2 DM animals have decreased plasma levels of LXA4 and BDNF.ConclusionThe results of the present study suggest that BDNF, LXA4, EPA, DHA, AA, GLA and BDNF protect pancreatic β cells from the cytotoxic action of various chemicals and prevent development of diabetes mellitus. LXA4 seems to be the mediator of these cytoprotective actions of BDNF and PUFAs suggesting a close interaction exists among these molecules (BDNF, PUFAs and LXA4). Hence, methods developed to deliver a combination of PUFAs (especially AA), LXA4 and BDNF may prevent development of diabetes mellitus (both type 1 and type 2).

Highlights

Both obesity and type 2 diabetes mellitus are assuming epidemic proportions in several countries that has been attributed to increased consumption of high fat diet or energy dense food and lack of exercise [1, 2]
The results of the present study suggest that brain-derived neurotrophic factor (BDNF), lipoxin A4 (LXA4), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), gamma-linolenic acid (GLA) and BDNF protect pancreatic β cells from the cytotoxic action of various chemicals and prevent development of diabetes mellitus
LXA4 seems to be the mediator of these cytoprotective actions of BDNF and polyunsaturated fatty acids (PUFAs) suggesting a close interaction exists among these molecules (BDNF, PUFAs and LXA4)

Summary

Introduction

Both obesity and type 2 diabetes mellitus (type 2 DM) are assuming epidemic proportions in several countries that has been attributed to increased consumption of high fat diet or energy dense food and lack of exercise [1, 2]. Both passive and active smoking and exposure to environmental pollutants have been linked to increasing incidence of type 2 DM [3,4,5,6,7,8]. BPA, BP and PCBs may directly affect insulin secretion and alter the expression of key proteins involved in the cellular and endoplasmic reticulum stress response and may contribute to the etiology of type 2 DM [17]

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Conclusion