Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models

Buendía, Izaskun; Gómez‐Rangel, Vanessa; González‐Lafuente, Laura; Parada, Esther; León, Rafael; Gameiro, Isabel; Michalska, Patrycja; Laudon, Moshe; Egea, Javier; López, Manuela G.

doi:10.1016/j.neuropharm.2015.07.014

Cited by 38 publications

(31 citation statements)

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“…Another NRF2 inducer in phase I clinical study for the treatment of acute kidney disease is CXA-10, a nitro fatty acid with anti-inflammatory properties through the activation of NRF2 (Batthyany and Lopez, 2015). Many other NRF2 inducers with the same mechanism of action have been described in the last years (Buendia et al, 2015a(Buendia et al, ,b, 2016, and some are in preclinical studies, such as the compound VEDA-1209, a chalcone derivative with a good anti-inflammatory profile for the treatment of ulcerative colitis.…”

Section: A Electrophilic Nuclear Factor (Erythroid-derived 2)-like 2mentioning

confidence: 95%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Section: A Electrophilic Nuclear Factor (Erythroid-derived 2)-like 2mentioning

confidence: 95%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

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“…Similarly, novel melatonin derivatives, such a Neu-P11 (a MT1/MT2 receptor agonist), have also been found to be neuroprotective in brain ischemia related models [158]. The neuroprotection obtained by the combination of melatonin with therapeutic hypothermia after transient hypoxia–ischemia in a piglet model of perinatal asphyxia has already been shown [27].…”

Section: New Approaches To Antioxidant Therapymentioning

confidence: 99%

Role of Antioxidants in Neonatal Hypoxic–Ischemic Brain Injury: New Therapeutic Approaches

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Álvarez

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et al. 2017

IJMS

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Hypoxic–ischemic brain damage is an alarming health and economic problem in spite of the advances in neonatal care. It can cause mortality or detrimental neurological disorders such as cerebral palsy, motor impairment and cognitive deficits in neonates. When hypoxia–ischemia occurs, a multi-faceted cascade of events starts out, which can eventually cause cell death. Lower levels of oxygen due to reduced blood supply increase the production of reactive oxygen species, which leads to oxidative stress, a higher concentration of free cytosolic calcium and impaired mitochondrial function, triggering the activation of apoptotic pathways, DNA fragmentation and cell death. The high incidence of this type of lesion in newborns can be partly attributed to the fact that the developing brain is particularly vulnerable to oxidative stress. Since antioxidants can safely interact with free radicals and terminate that chain reaction before vital molecules are damaged, exogenous antioxidant therapy may have the potential to diminish cellular damage caused by hypoxia–ischemia. In this review, we focus on the neuroprotective effects of antioxidant treatments against perinatal hypoxic–ischemic brain injury, in the light of the most recent advances.

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“…5A in presence of IG20 or IG20 combined with the Jak2/STAT3 inhibitor AG490, the MEK/ERK1/2 inhibitor PD98059 and the PI3K/Akt antagonist LY294002, at 10 M each. Previously, we demonstrated that these inhibitors had no effect on cell death induced by OGD/reox (Buendia et al, 2015a;Buendia et al, 2015b). As shown in Fig.…”

Section: 4-the Neuroprotective Effects Of Ig20 Partially Depend Onmentioning

confidence: 67%

“…The Nrf2/ARE pathway might be activated by different mechanisms such as electrophilic modification of Keap1 cysteine residues, by the phosphorylation of different kinases related with neuroprotective pathways or by receptor activation (Buendia et al, 2015b;Chen et al, 2010). IG20 increased ERK1/2 and Akt phosphorylation ( Fig.…”

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confidence: 99%

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

et al. 2017

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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...

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Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models

Cited by 38 publications

References 56 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Role of Antioxidants in Neonatal Hypoxic–Ischemic Brain Injury: New Therapeutic Approaches

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

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