Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway

Mol Neurobiol. 2016 Oct;53(8):5310-23. doi: 10.1007/s12035-015-9451-4. Epub 2015 Oct 3.

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.

Keywords: Astrocytes; Memory impairment; Neuroinflammation; Nrf2; Okadaic acid; Sulforaphane.

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Apoptosis / drug effects
  • Biomarkers / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Heme Oxygenase-1 / metabolism*
  • Inflammation / pathology
  • Isothiocyanates / pharmacology
  • Isothiocyanates / therapeutic use*
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / chemically induced*
  • Memory Disorders / drug therapy*
  • Memory Disorders / physiopathology
  • Motor Activity / drug effects
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neuroprotective Agents / pharmacology
  • Okadaic Acid
  • Oxidative Stress / drug effects
  • Protoporphyrins / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Signal Transduction* / drug effects

Substances

  • Antioxidants
  • Biomarkers
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Protoporphyrins
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • zinc protoporphyrin
  • Okadaic Acid
  • Heme Oxygenase-1
  • Glutamate-Cysteine Ligase
  • GCLC protein, rat
  • sulforafan
  • Glutathione