Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxicischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 lmol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.
Sulfasalazine is widely used to treat inflammatory diseases. Besides anti-inflammatory actions such as blockade of nuclear factor-B and cyclooxygenases, we found that 30 to 1000 M sulfasalazine dose dependently blocked N-methyl-D-aspartate receptor-mediated excitotoxicity without intervening kainate or ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid neurotoxicity. The neuroprotective effects of sulfasalazine were attributable to prevention of Ca 2ϩ influx and accumulation through N-methyl-D-aspartate receptors as a low-affinity antagonist. The systemic administration of sulfasalazine reduced neuronal death following transient cerebral and retinal ischemia in adult rat. The present findings suggest that the neuroprotective action of sulfasalazine can be therapeutically applied to halt devastating neuronal death following hypoxic ischemia, trauma, and neurodegenerative diseases.Accumulating evidence suggests that inflammatory processes play a role in degeneration of neuronal cells in acute and chronic neurodegenerative diseases. For example, the inducible enzyme cyclooxygenase-2 (COX-2) is up-regulated in ischemic brain areas following focal cerebral ischemia and global forebrain ischemia (Planas et al., 1995;Nakayama et al., 1998), which converts arachidonic acid into the proinflammatory mediators such as prostaglandins. Selective inhibitors and genetic knockout of COX-2 reduce ischemic neuronal death (Sasaki et al., 1988;Iadecola et al., 2001). Increased expression of COX-2 is observed in Alzheimer's disease and traumatized brain and spinal cord and probably contributes to progress of diseases (Oka and Takashima, 1997;Resnick et al., 1998;Dash et al., 2000).The transcription factor nuclear factor-B (NF-B) regulates expression of proinflammatory cytokines such as tumor necrosis factor and interleukins, cell adhesion molecules, and the inducible enzymes such as nitric oxide synthase, COXs, and manganese superoxide dismutase (Baeuerle and Baltimore, 1996;O'Neill and Kaltschmidt, 1997) and modulates degeneration of neurons and non-neuronal cells (Beg and Baltimore, 1996;Scatena et al., 1998). Activation of NF-B is observed in basal forebrain cholinergic neurons of patients with Alzheimer's disease and in vulnerable brain areas after ischemic injury (Boissiere et al., 1997;Clemens et al., 1997;Stephenson et al., 2000). Activation of NF-B mediates Nmethyl-D-aspartate (NMDA) receptor-mediated neuronal death but can protect neurons from oxidative stress and apoptosis (Mattson et al., 1997;Taglialatela et al., 1997;Qin et al., 1998;Won et al., 1999). Acetylsalicylate (aspirin), an inhibitor of COXs and NF-B, holds multiple therapeutic effects, including anti-inflammatory, analgesic, and antipyretic effects (Kopp and Ghosh, 1994;Vane and Botting, 1998). Aspirin reduces platelet aggregation and the risk of recurrent stroke (Diez-Tejedor et al., 1995). Acetyl salicylate also attenuates ischemic neuronal death, cognitive deficiency in Alzheimer's disease, and
Evidence has accumulated showing that pharmacological inhibition of proteasome activity can both induce and prevent neuronal apoptosis. We tested the hypothesis that these paradoxical effects of proteasome inhibitors depend on the degree of reduced proteasome activity and investigated underlying mechanisms. Murine cortical cell cultures exposed to 0.1 lM MG132 underwent widespread neuronal apoptosis and showed partial inhibition of proteasome activity down to 30-50%. Interestingly, administration of 1-10 lM MG132 almost completely blocked proteasome activity but resulted in reduced neuronal apoptosis. Similar results were produced in cortical cultures exposed to other proteasome inhibitors, proteasome inhibitor I and lactacystin. Administration of 0.1 lM MG132 led to activation of a mitochondria-dependent apoptotic signaling cascade involving cytochrome c, caspase-9, caspase-3 and degradation of tau protein; such activation was markedly reduced with 10 lM MG132. High doses of MG132 prevented the degradation of inhibitor of apoptosis proteins (IAPs) cIAP and X chromosome-linked IAP, suggesting that complete blockade of proteasome activity interferes with progression of apoptosis. In support of this, addition of high doses of proteasome inhibitors attenuated apoptosis of cortical neurons deprived of serum. Taken together, the present results indicate that inhibition of proteasome activity can induce or prevent neuronal cell apoptosis through regulation of mitochondria-mediated apoptotic pathways and IAPs. Keywords: inhibitor of apoptosis protein, MG132, mitochondria, neuronal apoptosis, proteasome.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.