The Novel Neuroprotective Action of Sulfasalazine through Blockade of NMDA Receptors

Abstract

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

Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons

“…Our previous observations indicated that SULFA non-competitively prevents NMDA receptor-mediated neuronal death (Ryu et al, 2003). Our present data support this notion and further confirm it at the molecular level.…”

“…SULFA was further shown to significantly reduce the degeneration of cortical and retinal neurons following transient ischemic insults, but did not generate any neuronal damage in normal rat brain and retina (Choi et al, 2000). The neuroprotective actions of SULFA have been attributed to prevention of Ca 2C influx and accumulation through the NMDA receptor (Ryu et al, 2003). Thus, SULFA is considered a strong candidate drug for the safe and effective treatment of glutamate neurotoxicity.…”

“…For example, acetyl salicylic acid attenuates ischemic neuronal death, cognitive deficits in Alzheimer's disease and motor deficits in amyotrophic lateral sclerosis (Rich et al, 1995;Barneoud and Curet, 1999;Khayyam et al, 1999). It was recently reported (Ryu et al, 2003) that sulfasalazine (SULFA, a conjugate of 5-aminosalicylic acid and sulfapyridine) prevents NMDA-induced neuronal cell death at the therapeutic doses generally applied to treat inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. SULFA was further shown to significantly reduce the degeneration of cortical and retinal neurons following transient ischemic insults, but did not generate any neuronal damage in normal rat brain and retina (Choi et al, 2000).…”

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…Neu2000 acts as an NR2B-receptor-specific, low-affinity gating modifier in an uncompetitive manner that enhances NMDA desensitization and stabilizes the closed state of NMDA receptors [74]. Sulfasalazine, another anti-inflammatory drug, also functions as a scavenger of free radicals [75,76]. Neu2000 was generated by combining these two compounds, resulting in dual neuroprotective actions by functioning as an uncompetitive NMDA receptor antagonist and a free radical scavenger.…”

Marked Prevention of Ischemic Brain Injury by Neu2000, an NMDA Antagonist and Antioxidant Derived from Aspirin and Sulfasalazine

“…However, the therapeutic potential of aspirin in the brain may be limited given that high doses (as much as 10 mmol/L) of the drug are needed to prevent NMDA and Zn 2 + neurotoxicity in primary cortical cell cultures. The antiinflammatory drug sulfasalazine, a conjugate of 5-aminosalicylic acid and sulfapyridine, inhibits NMDA neurotoxicity more potently than aspirin and in addition offers neuroprotection against free radical injury (Gionchetti et al, 1990;Ryu et al, 2003).…”