Quinolinyl Nitrone RP19 Induces Neuroprotection after Transient Brain Ischemia

Abstract

There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model. RP19 (50 μM) induced long-term neuroprotection at 5 days of recovery after OGD in primary neuronal cultures, evaluated by cell viability assay, and decreased both ROS formation and lipid peroxidation upon recovery after OGD. Furthermore, treatment of animals with RP19 at the onset of reperfusion after either global or focal ischemia, at the dose range that was demonstrated to be neuroprotective in neuronal cultures, decreased neuronal death and apoptosis induction, reduced the size of infarct, and improved the neurological deficit scores after 48 h or 5 days of reperfusion after ischemia. The molecule proposed, quinolyl nitrone RP19, induced substantial neuroprotection on experimental ischemia in neuronal cells, and against ischemic injury following transient brain ischemia in treated animals. This molecule may have potential therapeutic interest in ischemic stroke and to reduce the reoxygenation-induced injury after induced reperfusion.

Neuroprotective Effects of Diets Containing Olive Oil and DHA/EPA in a Mouse Model of Cerebral Ischemia

“…Transient occlusion of a distal branch of the middle cerebral artery (tMCAo) was induced in male C57BL/6J mice (10-week-old), as described previously [26,27]. Briefly, mice were anesthetized with 4% isoflurane for induction and 1.5–2% isoflurane for maintenance (in 79% N 2 /21% O 2 ), and after drilling a small hole in the temporal bone, the middle cerebral artery (MCA) was compressed for 60 min with a 30-G needle using a micromanipulator.…”

“…The grip strength test is designed to assess the maximum force in the mouse’s forelimbs using a metal grid connected to a force sensor (Bioseb, Vitrolles, France). The test was performed as described previously [26,33,34] and a total of 6 trials were carried out in each test session, calculating the strength (in grams) as the mean of these trials.…”

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

“…In our current program targeted to identify new nitrones for the therapy of stroke 11 , we have already investigated nitrones derived from (hetero)aromatic aldehydes 12,13 , quinolylnitrones [14][15][16][17] , and cholesteronitrones 18 . More recently, we have designed bis-nitrones derived from alpha-phenyl-N-tert-butylnitrone (PBN) ( Fig.…”

5-Aryl-2-(3,5-dialkyl-4-hydroxyphenyl)-4,4-dimethyl-4H-imidazole 3-Oxides and Their Redox Species: How Antioxidant Activity of 1-Hydroxy-2,5-dihydro-1H-imidazoles Correlates with the Stability of Hybrid Phenoxyl–Nitroxides

“…During the last decade, Marco-Contelles at al. have synthesized and tested a large series of acyclic nitrones that hold promise for the treatment of neurodegenerative diseases: (a) PBN analogs containing isovanillin moieties (RP-6) 1d [ 14 ], (b) 3- and 4-nitronylquinolines 5 (RP-19 and QN-23) [ 15 , 16 ] and 6 (QN-6) [ 17 ], and (c) heteroatomic C -phosphoryl derivative 3c [ 18 ] ( Scheme 1 ). Moreover, very recently, a new cholesterol derivative containing exocyclic nitrone function 4 (ISQ-201) was obtained by the same group of researchers [ 19 ].…”