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BACKGROUND: Several therapeutic strategies to rescue the brain from ischemic injury have improved outcomes after stroke; however, there is no treatment as yet for reperfusion injury, the secondary damage caused by necessary revascularization. Recently we characterized ammonium tetrathiomolybdate (ATTM), a drug used as a copper chelator over many decades in humans, as a new class of sulfide donor that shows efficacy in preclinical injury models. We hypothesized that ATTM could confer neuroprotection in a relevant rodent model of regional stroke. METHODS AND RESULTS: Brain ischemia was induced by transient (90-min) middle cerebral artery occlusion (tMCAO) in anesthetized Wistar rats. To mimic a clinical scenario, ATTM (or saline) was administered intravenously just prior to reperfusion. At 24 h or 7 days post-reperfusion, rats were assessed using functional (rotarod test, spontaneous locomotor activity), histological (infarct size), and molecular (anti-oxidant enzyme capacity, oxidative damage, and inflammation) outcome measurements. ATTM-treated animals showed improved functional activity at both 24 h and 7-days post-reperfusion, in parallel with a significant reduction in infarct size. These effects were additionally associated with increased brain antioxidant enzyme capacity, decreased oxidative damage, and a late (7-day) effect on pro-inflammatory cytokine levels and nitric oxide products. CONCLUSION: ATTM confers significant neuroprotection that, along with its known safety profile in humans, provides encouragement for its development as a novel adjunct therapy for revascularization following stroke.

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Neuropeptide S (NPS) and its receptor were recently discovered in the central nervous system. In rodents, NPS promotes hyperlocomotion, wakefulness, anxiolysis, anorexia, and analgesia and enhances memory when injected intracerebroventricularly (i.c.v.). Herein, NPS at different doses (0.01, 0.1 and 1nmol) was i.c.v. administered in mice challenged with pentylenetetrazole (PTZ; 60mg/kg) repeatedly injected. Aiming to assess behavioral alterations and oxidative damage to macromolecules in the brain, NPS was injected 5min prior to the last dose of PTZ. The administration of NPS only at 1nmol increased the duration of seizures evoked by PTZ, without modifying frequency and latency of seizures. Biochemical analysis revealed that NPS attenuated PTZ-induced oxidative damage to proteins and lipids in the hippocampus and cerebral cortex. In contrast, the administration of NPS to PTZ-treated mice increased DNA damage in the hippocampus, but not cerebral cortex. In conclusion, this is the first evidence of the potential proconvulsive effects of NPS in mice. The protective effects of NPS against lipid and protein oxidative damage in the mouse hippocampus and cerebral cortex evoked by PTZ-induced seizures are quite unexpected. The present findings were discussed analyzing the paradoxical effects of NPS: facilitation of convulsive behavior and protection against oxidative damage to lipids and proteins.

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Activation of adenosine receptors modifies the action of classic neurotransmitters (i.e. dopamine, glutamate and acetylcholine) and other neuromodulators, like vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide S (NPS). Similarly to adenosine, NPS is involved in the regulation of stimulus and response to fear and arousal. Thus, the present study investigates the effects of NPS on locomotor activity in mice treated with or without α,ß-methylene adenosine 5'-diphosphate (AOPCP), the inhibitor of ecto-5'-nucleotidase. Additionally, we evaluate the activity of ecto-5'-nucleotidase in brain slices of mice treated with or without NPS. Male adult CF-1 mice received i.c.v. NPS as 0.1 nmol injection with or without pre-treatment with 1 nmol α,ß-methylene adenosine 5'-diphosphate (AOPCP), the selective inhibitor of ecto-5'-nucleotidase, to evaluate locomotor activity. In another set of experiments, mice received i.c.v. infusion of 0.1 nmol NPS to assay enzymatic activity in brain slices. The results demonstrated that the pre-treatment with AOPCP, which was inactive per se, prevented NPS-induced hyperlocomotion in mice. The dose of 0.1 nmol NPS was efficient to induce hyperlocomotion in animals during the observation period in the activity cage. Regarding enzymatic activity, i.c.v. NPS injection did not induce any significant alterations in ATP and AMP hydrolysis in striatum and hippocampus brain slices of mice. The present study shows that the hyperlocomotor effect of NPS depends on the ecto-5'-nucleotidase activity.

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