salicylates and Infarction--Middle-Cerebral-Artery

The objective of this work is to study the dose-dependent effect of combination therapy with dipyridamole and triflusal over that of triflusal alone on infarct size after middle cerebral artery occlusion (MCAO) ischemia.. Male Wistar rats were subjected to a permanent MCAO in the right hemisphere. Rats received triflusal alone and with dipyridamole via oral route. Three days after surgery, infarct volumes were measured.. The lower dose regime of triflusal (10 mg/kg) and dipyridamole (200 mg/kg) caused the greatest decrease in infarct size compared with higher dose regime of triflusal (30 mg/kg) and dipyridamole (200 mg/kg) (P <.01), triflusal (30 mg/kg) alone (P <.07), and vehicle-treated controls.. The lower dose combination of dipyridamole and triflusal appears to be more effective than triflusal alone after MCAO-induced cerebral ischemia. Therefore, there is a strong rationale to continue to examine the protective effects of triflusal and dipyridamole after cerebral ischemia.

Topics: Animals; Brain; Cytoprotection; Dipyridamole; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Rats, Wistar; Salicylates

Background and Purpose- Although intracellular zinc accumulation has been shown to contribute to neuronal death after cerebral ischemia, the mechanism by which zinc keeps on accumulating to cause severe brain damage remains unclear. Herein the dynamic cause-effect relationships between zinc accumulation and reactive oxygen species (ROS) production during cerebral ischemia/reperfusion are investigated. Methods- Rats were treated with zinc chelator, ROS scavenger, mitochondria-targeted ROS inhibitor, or NADPH oxidase inhibitor during a 90-minute middle cerebral artery occlusion. Cytosolic labile zinc, ROS level, cerebral infarct volume, and neurological functions were assessed after ischemia/reperfusion. Results- Zinc and ROS were colocalized in neurons, leading to neuronal apoptotic death. Chelating zinc reduced ROS production at 6 and 24 hours after reperfusion, whereas eliminating ROS reduced zinc accumulation only at 24 hours. Furthermore, suppression of mitochondrial ROS production reduced the total ROS level and brain damage at 6 hours after reperfusion but did not change zinc accumulation, indicating that ROS is produced mainly from mitochondria during early reperfusion and the initial zinc release is upstream of ROS generation after ischemia. Suppression of NADPH oxidase decreased ROS generation, zinc accumulation, and brain damage only at 24 hours after reperfusion, indicating that the majority of ROS is produced by NADPH oxidase at later reperfusion time. Conclusions- This study provides the direct evidence that there exists a positive feedback loop between zinc accumulation and NADPH oxidase-induced ROS production, which greatly amplifies the damaging effects of both. These findings reveal that different ROS-generating source contributes to ischemia-generated ROS at different time, underscoring the critical importance of spatial and temporal factors in the interaction between ROS and zinc accumulation, and the consequent brain injury, after cerebral ischemia/reperfusion.

Topics: Animals; Antioxidants; Apoptosis; Biphenyl Compounds; Brain; Brain Ischemia; Chelating Agents; Ethylenediamines; Infarction, Middle Cerebral Artery; NADPH Oxidases; Neurons; Onium Compounds; Organometallic Compounds; Pramipexole; Rats; Reactive Oxygen Species; Salicylates; Zinc

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is a metabolite of triflusal (TF), and has been reported to exert anti-inflammatory effect. In this study, the authors investigated whether HTB has a neuroprotective effect against ischemic brain injuries. We showed that intravenous administration of HTB (5mg/kg) 30min before or 1, 3, or 6h after middle cerebral artery occlusion (MCAO) reduced brain infarct to 10.4±3.3%, 16.9±2.3%, 22.2±1.5% and 40.7±7.5%, respectively, of that of treatment-naive MCAO controls, and the therapeutic time window extended to 9h after MCAO (40.7±7.5%). Furthermore, HTB suppressed infarct formation, protected motor activities, and ameliorated neurological deficits more effectively than by TF or salicylic acid (SA). HTB markedly suppressed microglial activation and proinflammatory cytokines expressions in the postischemic brain and in BV2 cells and suppressed LPS-induced nitrite production by inhibiting IkB degradation. In addition, HTB suppressed NMDA-induced neuronal cell death more effectively than TF or SA in primary cortical neuron cultures. Together, these results indicate that HTB has multi-modal protective effects against ischemic brain damage that encompass anti-inflammatory, anti-excitotoxicity, and anti-Zn

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Brain; Brain Ischemia; Cytokines; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; Salicylates

Glycine is a strychnine-sensitive inhibitory neurotransmitter in the central nervous system (CNS), especially in the spinal cord, brainstem, and retina. The objective of the present study was to investigate the potential neuroprotective effects of GlyT1 inhibitor N [3-(4'-fluorophenyl)-3-(4'-phenylphenoxy) propyl] sarcosine (NFPS) in the rat model of experimental stroke.. In vivo ischaemia was induced by transient middle cerebral artery occlusion (tMCAO). The methods of Western Blotting, Nissl Staining and Morris water maze methods were applied to analyze the anti-ischaemia mechanism.. The results showed that high dose of NFPS (H-NFPS) significantly reduced infarct volume, neuronal injury and the expression of cleaved caspase-3, enhanced Bcl-2/Bax, and improved spatial learning deficits which were administered three hours after transient middle cerebral artery occlusion (tMCAO) induction in rats, while, low dose of NFPS (L-NFPS) exacerbated the injury of ischaemia. These findings suggested that low and high dose of NFPS produced opposite effects. Importantly, it was demonstrated that H-NFPS-dependent neuronal protection was inverted by salicylate (Sal), a specific GlyR x0251;1 antagonist. Such effects could probably be attributed to the enhanced glycine level in both synaptic and extrasynaptic clefts and the subsequently altered extrasynaptic GlyRs and their subtypes.. These data imply that GlyT1 inhibitor NFPS may be a novel target for clinical treatment of transient focal cerebral ischaemia and reperfusion which are associated with altered GlyR alpha 1 subunits.

Topics: Animals; bcl-2-Associated X Protein; Blotting, Western; Brain; Caspase 3; Disease Models, Animal; Glycine; Glycine Plasma Membrane Transport Proteins; Immunohistochemistry; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Maze Learning; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Salicylates; Sarcosine

Cerebral ischemia leads to brain injury via a complex series of pathophysiological events, and therefore, multi-drug treatments or multi-targeting drug treatments provide attractive options with respect to limiting brain damage. Previously, we reported that a novel multi-functional compound oxopropanoyloxy benzoic acid (OBA-09, a simple ester of pyruvate and salicylic acid) affords robust neuroprotective effects in the postischemic rat brain. OBA-09 exhibited anti-oxidative effects that appeared to be executed by OBA-09 and by the salicylic acid afforded by hydrolysis. Here, we report the anti-inflammatory effects of OBA-09. Microglial activation observed at 2 days post-middle cerebral artery occlusion (MCAO, 90 min) and at 1 day after a LPS injection (0.5 mg/kg, intravenously) in the brains of Sprague-Dawley rats were markedly suppressed by the administration of OBA-09 (10 mg/kg). Inductions of proinflammatory markers (TNF-α, IL-1β, iNOS, and COX-2) were also suppressed by OBA-09 in both the LPS and MCAO models. Moreover, the anti-inflammatory effect of OBA-09 was accompanied by the suppression of infarct formation in the postischemic brain, but appeared to be independent of neuroprotection in LPS-treated rats. The inductions of proinflammatory markers were also inhibited by OBA-09 in LPS-treated BV2 cells (a microglia cell line) and in LPS-treated-primary neutrophils, possibly due to the suppression of NF-κB activity. Interestingly, the anti-inflammatory effect of OBA-09 was greater than that of equivalent co-treatment with pyruvate and salicylic acid. Together these results indicate that OBA-09 is a potent multi-modal neuroprotectant in the postischemic brain, and that its anti-inflammatory effect contributes to its neuroprotective function.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cytokines; Infarction, Middle Cerebral Artery; Male; Microglia; Neuroprotective Agents; NF-kappa B; Pyruvates; Rats; Rats, Sprague-Dawley; Salicylates

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 hypoxic-ischemia. 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 micromol/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.

Topics: Animals; Antioxidants; Aspirin; Benzoates; Brain Ischemia; Cells, Cultured; Excitatory Amino Acid Antagonists; Fluorobenzenes; Infarction, Middle Cerebral Artery; meta-Aminobenzoates; Mice; N-Methylaspartate; Oxidative Stress; Receptors, N-Methyl-D-Aspartate; Salicylates; Sulfasalazine

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E(2) (PGE(2)) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post-ischaemic treatment with nimesulide markedly reduced the increase in PGE(2) levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.

Topics: Animals; Blood-Brain Barrier; Enzyme Inhibitors; Infarction, Middle Cerebral Artery; Leukocytes; Male; Neurologic Examination; Peroxidase; Prostaglandins E; Rats; Rats, Sprague-Dawley; Salicylates; Statistics, Nonparametric; Sulfonamides