Novel sulfoglycolipid IG20 causes neuroprotection by activating the phase II antioxidant response in rat hippocampal slices

Abstract

Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Neuropharmacology 116 (2017) SummaryCompound IG20 is a newly synthesised sulphated glycolipid that promotes neuritic outgrowth and myelinisation, at the time it causes the inhibition of glial proliferation and facilitates exocytosis in chromaffin cells. Here we have shown that IG20 at 0.3-10 M afforded neuroprotection in rat hippocampal slices stressed with veratridine, glutamate or with oxygen plus glucose deprivation followed by reoxygenation (OGD/reox). Excess production of reactive oxygen species (ROS) elicited by glutamate or ODG/reox was prevented by IG20 that also restored the depressed tissue levels of GSH and ATP in hippocampal slices subjected to OGD/reox.Furthermore, the augmented iNOS expression produced upon OGD/reox exposure was also counteracted by IG20. Additionally, the IG20 elicited neuroprotection was prevented by the presence of inhibitors of the signalling pathways Jak2/STAT3, MEK/ERK1/2, and PI3K/Akt, consistent with the ability of the compound to increase the phosphorylation of Jak2, ERK1/2, and Akt. Thus, the activation of phase II response and the Nrf2/ARE pathway could explain the antioxidant and anti-inflammatory effects and the ensuing neuroprotective actions of IG20.Keywords: Sulfoglycolipid IG20, neurotoxicity, neuroprotection, oxidative stress, neuronal excitability, hippocampal slices, hippocampal neurons 3 1.-IntroductionSulfoglycolipid IG20 was designed and synthesised at our laboratory in the context of a programme to obtain new compounds aimed at promoting neuritogenesis and myelinisation, with a special focus to inhibit glial proliferation. This last property mainly focused the treatment of cerebral gliomas (Doncel-Perez et al., 2013; FernandezMayoralas et al., 2003;Garcia-Alvarez et al., 2007). The synthetic strategy was inspired in the fact that in mammalian brain there are natural inhibitors of astroblasts and astrocytes division (Nieto-Sampedro, 1988;Nieto-Sampedro and Broderick, 1989); one such inhibitor is neurostatin, first found in the rat brain (Valle-Argos et al., 2010).Although neurostatin happened to be a very potent blocker of glial proliferation, its molecular complexity makes difficult its purification from brain tissue or its laboratory synthesis. Thus, the simple compound IG20 was synthesised and although with lesser potency, it shared with neurostatin its ability to inhibit gliomas growth (Garcia-Alvarez et al., 2007). Recently, IG20 was shown to inhibit astrocyte and microglia proliferation, the main cellular components of the glial scar, and promote axonal outgrowth and myelin production in vitro (Garcia-Alvarez et al., 2015). This compound has a structure very similar to sulfatides, a class of sulfated galactosylceramides that are synthesised mainly in brain oligodendrocytes and belong to the great family of sphingosine derived sphingolipids (Honke, 2013) ( Fig.1).From a drug therapy point of view, compounds like IG20 could have various pote...