title: Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway.
abstract: Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA-induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-κB, TNF-α, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA-induced memory impairment in rats. Graphical Abstract ᅟ.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Dwivedi
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: N
authors.initials: N
authors.lastname: Rajasekar
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
authors.affiliation: Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India.
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. rakeshshuklacdri@gmail.com.|Academy of Scientific and Innovative Research (AcSIR), Chennai, India. rakeshshuklacdri@gmail.com.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D017879:Isothiocyanates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019319:Okadaic Acid; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013454:Sulfoxides; C017803:zinc protoporphyrin; D019319:Okadaic Acid; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; C016766:sulforaphane; D005978:Glutathione
keywords: Astrocytes; Memory impairment; Neuroinflammation; Nrf2; Okadaic acid; Sulforaphane