Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.

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Neuronal dysfunction and subsequent apoptosis under high glucose conditions during diabetes contribute majorly to the manifestation of diabetic peripheral neuropathy (DPN). PERK (protein kinase RNA (PKR)-like ER kinase) one among the three canonical arms of unfolded protein response (UPR), is believed to play a crucial role in determining the cell fate during endoplasmic reticulum stress (ERS/ER stress) conditions. We evaluated the role of PERK inhibitor GSK2606414 in high glucose (30 ​mM) treated neuroblastoma (N2A) cells. High glucose resulted in disruption of ER proteostasis by activation of UPR which is evident through increased (p ​< ​0.001) expression of GRP78, p-PERK, p-eIF2α, ATF-4 and CHOP when compared to normal cells. It is accompanied with enhanced GRP78 localization in Endoplasmic Reticulum (ER) lumen evident from ER labeling Immunofluorescence (IF) staining. PERK activation resulted in altered mitochondrial function evident by increased mitochondrial superoxide production and compromised mitochondrial homeostasis with decrease in Mfn-2 levels. Additionally, ER stress induced neuronal apoptosis was attenuated by GSK2606414 treatment via inhibiting the PERK-eIF2α-ATF4-CHOP axis that not only curtailed the levels of apoptotic proteins like Bax and caspase 3 but also elevated the levels of anti-apoptotic Bcl-2. Collectively, our findings revealed the neuroprotective potential of GSK2606414 against high glucose induced neurotoxicity in N2A cells.