Abstract. Adenosine A 1 receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A 1 receptor antagonist, FR194921 (2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone), and characterized the pharmacological activity in the present study. FR194921 showed potent and selective affinity for the adenosine A 1 receptor without affinity for A 2A and A 3 receptors and did not show any species differences in binding affinity profile among human, rat, and mouse. Pharmacokinetic study in rats revealed that FR194921 was orally active and highly brain penetrable. Oral administration of FR194921 dose-dependently ameliorated the hypolocomotion induced by the A 1 receptor agonist N 6 -cyclopentyladenosine in rats, indicating this compound exerts A 1 -antagonistic action in vivo. In the passive avoidance test, scopolamine (1 mg / kg)-induced memory deficits were significantly ameliorated by FR194921 (0.32, 1 mg / kg). In two animal models of anxiety, the social interaction test and elevated plus maze, FR194921 showed specific anxiolytic activity without significantly influencing general behavior. In contrast, FR194921 did not show antidepressant activity even at a dose of 32 mg / kg in the rat forced swimming test. These results indicate that the novel, potent, and selective adenosine A 1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.

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Global ischemia, induced in Mongolian gerbils by bilateral occlusion of the carotid arteries for 5 min, produced a significant increase in locomotor activity at 1 day post-occlusion and a severe loss of hippocampal CA1 neurons at 4 days post-occlusion. To explore the pharmacological relationship between ischemia-induced hypermotility and CA1 cell death in the hippocampus, we evaluated the efficacy of diverse classes of putative neuroprotective agents for preventing hypermotility and delayed neuronal death. Administration of any drug 30 min before global ischemia dose-dependently, and with similar potency, ameliorated both hippocampal delayed neuronal death and locomotor hyperactivity, with a rank order: tacrolimus (FK506)>nizofenone>clonindine>dizocilpine (MK-801)>6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K)>phencyclidine>pentobarbital>2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride (E-2001)>cis-(+/-)-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755)>3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488H)>piroxicam>eliprodil>vinpocetine. Furthermore, potencies of the protective effect on delayed neuronal death and inhibitory effects on hypermotility were closely correlated (r=0.98). These results suggest that post-ischemic CA1 injury and hypermotility share common mechanisms, and further imply that it is possible to predict the neuroprotective efficacy of drugs more easily by examining the inhibitory effects on post-ischemic hypermotility in global ischemia model in gerbils.

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.