Abstract
Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats’ associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein CaV3.2 and calcitonin gene-related peptide (CGRP) in the surficial spinal dorsal horn of PDN rats. Loganin inhibited oxidative stress and NF-κB activation and decreased the levels of mRNA and protein of proinflammatory factors IL-1β and TNF-α. Moreover, loganin attenuated insulin resistance by modulating the JNK-IRS-1 (insulin receptor substrate-1)-Akt-GSK3β signaling pathway in PDN rats. These results suggested that loganin improved PDN-mediated pain behaviors by inhibiting oxidative stress-provoked inflammation in the spinal cord, resulting in improved neuropathic pain.
Highlights
Introduction iationsDiabetic neuropathy is a common complication of type 2 diabetes mellitus (T2DM), which develops in at least 50% of diabetic patients and usually affects the sensory, motor, and autonomic nervous systems [1,2]
Our results showed that loganin reduced tumor necrosis factor-α (TNF-α) and IL-1β in the serum of Painful diabetic neuropathy (PDN) rats (Figure 3D,E)
SH-SY5Y cells exposed to high glucose were used to confirm the mechanisms of the possible protective effects of loganin against oxidative stress and inflammation induced by hyperglycemia to mimic diabetic neuropathy
Summary
A regular chow diet (maintenance diet 1320; Altromin, Lage, Germany) was provided by the Center for Laboratory Animals of Kaohsiung Medical University. Vazyme (Nanjing, China), rat tumor necrosis factor α (TNF-α, # RTA00) and interleukin-1β (IL-1β, # RLB00) enzyme-linked immunosorbent assay (ELISA) kits from R&D Systems (Minneapolis, MN, USA), rat insulin ELISA kits (10-1250-01) from Mercodia AB (Uppsala, Sweden), catalase (E-BC-K031-M) and reduced glutathione (E-BC-K030-M) activity assay kits from Elabscience Biotech (Wuhan, China), Eagle Minimum Essential Medium (EMEM), Ham’s F12 medium, T-PERTM tissue protein extraction reagent, M-PERTM mammalian protein extraction reagent, and PierceTM BCA protein assay kits from Thermo Fisher Scientific (Waltham, MA, USA), quinazoline (QNZ, S4902) from Selleckchem (Houston, TX, USA), anti-phospho-NF-κB (ser536 , # 3033), anti-NF-κB (# 6956), anti-CGRP (ab47027), antiphospho-JNK (Thr183 /Tyr185 , # 4668), and anti-JNK2 (# 9258) antibodies from Cell Signaling. (Danvers, MA, USA), anti-IL-1β (ab9722), anti-phospho-GSK3β (Ser9 , # 9323), anti-GSK3β (# 12456), anti-phospho-Akt (ser473 , # 4060), and anti-Akt (# 9272) antibodies from Abcam (Cambridge, MA, USA), anti-TNF-α antibody (NBP-19532) from Novus Biologicals (Littleton, CO, USA), anti-insulin receptor substrate-1 (anti-IRS1, AP-0552) from Proteintech (Wuhan, China), anti-phospho-IRS1 (ser307, 17509-1-AP) from ABclonal (Woburn, MA, USA) and anti-CaV 3.2 antibody (ACC-025) from Alomone Labs (Jerusalem, Israel)
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