Recent results have demonstrated that the spin trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg x kg(-1) followed by 0.30, 3.0, or 30 mg x kg(-1) x h(-1) for 24 or 48 hours. Dose-response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg x kg(-1) had a small and 30 mg x kg(-1) a marked effect on infarct volume. At equimolar doses (3.0 mg x kg(-1) for NXY-059 and 1.4 mg x kg(-1) for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood-endothelial interface.
a b s t r a c tWe have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-a, IL-2, IFN-c, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.
As the leading cause of dementia, Alzheimer's disease (AD) 1 is characterized by a loss of memory and neurons. These characteristics have been associated with brain lesions known as neurofibrillary tangles composed of Tau protein and amyloid plaques, which consist of amyloid  (A) peptide. In a small number of families, mutations in the genes for the amyloid peptide precursor (APP, chromosome 21) to A peptide for presenilin-1 (PSEN-1, chromosome 14), presenilin-2 (PSEN-2, chromosome 1) and for an anonymous gene on chromosome 12 have been associated with AD. In contrast, Saunders and colleagues (1) discovered that a significant percentage of patients inheriting one or more of the epsilon-4 alleles of apolipoprotein-E (APOE4, chromosome 19) were at risk of acquiring AD at an earlier age than their counterparts expressing the more common epsilon-3 allele of APOE. The observation that AD patients with mutant genes for APP, PSEN-1, or PSEN-2 have higher levels of A peptide than non-diseased controls (2, 3) argues that A peptide may cause AD. Further supporting this idea is the observation that APOE4 patients with AD display more amyloid plaques than those with APOE3 (4). Based on neuropathological, genetic, and biochemical associations, the presence of amyloid  peptide is a key component of AD.A crucial link between A peptide and AD was provided by Yankner and colleagues (5), who showed that fibrillar aggregates of A peptide were toxic to neurons. This seminal observation inspired a global quest to define the mechanism by which fibrillar A peptide mediated neurotoxicity. One of the mechanisms proposed suggests that neurons exposed to A peptide suffer severe oxidative stress that may lead to their death. Clear evidence of oxidative stress in Alzheimer's disease has been provided by Smith et al. (6), who found that neurons of AD patients contained nitrotyrosine modifications of proteins, which were not detected in age-matched control brains. Increased levels of lipid peroxides (7), reactive aldehydes such as hydroxynonenal (8), and oxidized DNA (9) have also been reported in AD brains, providing additional evidence of an oxidative stress component in the disease.The exact nature of the radical species generated in Alzheimer's diseased brains is unknown. In one line of investigation, Behl et al. (10) demonstrated that cells exposed to fibrillar A peptide responded by releasing hydrogen peroxide and dying, a process that could be inhibited by the application of catalase to degrade the released peroxide. Subsequent reports have demonstrated cellular release of superoxide (11) and nitric oxide (12) in response to A peptide treatment. The effect of these radicals may be potentiated since A peptides also appear to inhibit the cellular redox mechanisms that normally protect cells from oxidative stress (13).In a provocative hypothesis, Hensley et al. (14) suggest that the A peptide itself spontaneously generates free radicals that can damage cells. By mixing the spin trap N-tert-butyl-␣-phenylnitrone (PBN) with ...
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