Resolvin D1 Decreases Severity of Streptozotocin-Induced Type 1 Diabetes Mellitus by Enhancing BDNF Levels, Reducing Oxidative Stress, and Suppressing Inflammation

• Main Authors: Siresha Bathina, Undurti N. Das
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: International Journal of Molecular Sciences
• Subjects: type 1 diabetes mellitus; streptozotocin; resolving D1; antioxidants
• Online Access: https://www.mdpi.com/1422-0067/22/4/1516
• ISSN: 1661-6596; 1422-0067

Type 1 diabetes mellitus is an autoimmune disease characterized by increased production of pro-inflammatory cytokines secreted by infiltrating macrophages and T cells that destroy pancreatic β cells in a free radical-dependent manner that causes decrease or absence of insulin secretion and consequent hyperglycemia. Hence, suppression of pro-inflammatory cytokines and oxidative stress may ameliorate or decrease the severity of diabetes mellitus. To investigate the effect and mechanism(s) of action of RVD1, an anti-inflammatory metabolite derived from docosahexaenoic acid (DHA), on STZ-induced type 1 DM in male Wistar rats, type 1 diabetes was induced by single intraperitoneal (i.p) streptozotocin (STZ-65 mg/kg) injection. RVD1 (60 ng/mL, given intraperitoneally) was administered from day 1 along with STZ for five consecutive days. Plasma glucose, IL-6, TNF-α, BDNF (brain-derived neurotrophic factor that has anti-diabetic actions), LXA4 (lipoxin A4), and RVD1 levels and BDNF concentrations in the pancreas, liver, and brain tissues were measured. Apoptotic (<i>Bcl2/</i><i>Bax</i>), inflammatory (<i>COX-1/COX-2/</i><i>Nf-κb</i><i>/</i><i>iNOS</i><i>/PPAR-γ</i>) genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) were measured in the pancreatic tissue along with concentrations of various antioxidants and lipid peroxides. RVD1 decreased severity of STZ-induced type 1 DM by restoring altered plasma levels of TNF-α, IL-6, and BDNF (<i>p</i> < 0.001); expression of pancreatic <i>COX-1/COX-2</i><i>/</i><i>PPAR-γ</i> genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) and the concentrations of antioxidants and lipid peroxides to near normal. RVD1 treatment restored expression of <i>Bcl2/Pdx</i> genes, plasma LXA4 (<i>p</i> < 0.001) and RVD1 levels and increased brain, pancreatic, intestine, and liver BDNF levels to near normal. The results of the present study suggest that RVD1 can prevent STZ-induced type 1 diabetes by its anti-apoptotic, anti-inflammatory, and antioxidant actions and by activating the <i>Pdx</i> gene that is needed for pancreatic β cell proliferation.