Effect of NXY‐059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window

Abstract

1 The ecacy of the free radical trapping agent NXY-059 in reducing the infarct volume following both transient and permanent focal ischaemia has been examined in rats. 2 In the transient ischaemia model, rats were subjected to a 2 h occlusion of the middle cerebral artery (MCA). Intravenous infusion of NXY-059 (1, 10 and 30 mg kg 71 h) for 21.75 h starting 2.25 h after the occlusion, produced a dose-dependent decrease in both neurological impairment and the histologically measured infarct volume (a mean 59% decrease at 10 mg kg 71 h). 3 In the permanent ischaemia model, animals were injected (s.c.) with a loading dose of NXY-059 of 32.5, 53.8 or 75.4 mg kg 71 and osmotic minipumps were implanted which had been primed to deliver respectively 30, 50 or 70 mg kg 71 h. When treatment was initiated 5 min after MCA occlusion there was a dose dependent protection of both cortical and sub-cortical tissue (cortex: 63% at the mid-range dose). Protection was related linearly to plasma concentration (plasma unbound NXY-059 concentration at 1 h: 37+16 mmol l 71 at the mid-range dose). 4 When the mid range dose was administered between 5 min ± 4 h after MCA occlusion, a marked and statistically signi®cant protection was seen at all time points (44% protection in cortex at 4 h). 5 These data demonstrate the substantial neuroprotective ecacy of NXY-059 at plasma concentrations that can be achieved clinically and indicate that NXY-059 also has a therapeutic window of opportunity that is clinically relevant.

Neuroprotection for ischemic stroke: Past, present and future

“…Even when started at 3 h of recirculation (i.e., 5 h after the onset of ischemia), neurologic deficits were still improved and infarct volume was still reduced by approximately two-thirds. Other workers confirmed these effects in similar models (Sydserff et al, 2002) Neuroprotective effects were also described in rat models of permanent MCA occlusion: In one such study, higher-dose NXY-059 treatment begun at 5 min after onset of permanent MCA occlusion in spontaneously hypertensive (SHR) rats led to a 36% reduction in cortical infarct volume ). In another permanent-occlusion model in rats, 44% infarct reduction was observed even when treatment was initiated at 4 h after stroke onset (Sydserff et al, 2002).…”

The Nitrone Disodium 2,4-Sulphophenyl-N-Tert-Butylnitrone is Without Cytoprotective Effect on Sodium Nitroprusside-Induced Cell Death in N1E-115 Neuroblastoma Cells in vitro

“…In contrast, NXY-059 was ineffective at a concentration (300 mmol/L), which both markedly exceeds that required in plasma for a maximum neuroprotective effect in animal models of stroke in vivo (150 mmol/L; Sydserff et al, 2002) and is also greater than the targeted steady-state concentration (260 mmol/L) in the recent Phase III trials of NXY-059 in acute stroke (Lees et al, 2006). Direct nitration of amino acid tyrosine by peroxynitrite was also abolished by the antioxidant cocktail, but was unaffected by NXY-059.…”

“…a-Phenyl-N-tert-butylnitrone (PBN) has been extensively studied in both permanent and transient focal ischaemia models in rats, and its close congener 2-sulphophenyl-N-tertbutylnitrone (S-PBN) is also an established neuroprotective agent . Disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059) is another derivative of PBN that has showed an impressive neuroprotective profile in both rodent and primate models of acute ischaemic stroke (Sydserff et al, 2002;Marshall et al, 2003;Green and Ashwood, 2005). Surprisingly, evidence for nitrones having cytoproprotective activity in vitro is sparse.…”

Treatment Targets in Intracerebral Hemorrhage

“…Several nitrone free radical-trapping agents (i.e., spin-trap agents) have demonstrated neuroprotection in rodent models of both transient and permanent focal ischemia [111,112]. NXY-059 (disodium 4-[(tert-butylimino) methyl] benzene-1,3-disulfonate N-oxide) is a novel nitrone-based compound that has free radical-trapping properties.…”