Protective effect of the alpha2-adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat.

The alpha2-adrenoceptor antagonist, dexefaroxan, has been shown in the rat to have neuroprotective and plastic effects against degenerative structural changes in elements of the basalocortical cholinergic system that result from cortical devascularization [Neuroscience 115 (2002) 41]. The present study, using the same experimental protocol, examined the functional consequences of cortical devascularization and dexefaroxan treatment in the Morris water maze memory test. Rats were first trained to find the hidden platform in the test, and then subjected to the devascularization procedure. Thirty-one days later, lesioned rats exhibited a significant deficit in recalling the platform location, compared with sham control animals. A 28-day subcutaneous infusion with dexefaroxan (0.63, 2.5, and 10 mg rat(-1) day(-1)), starting from the moment of the devascularization, protected against this spatial memory deficit.

F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.

Benzamide, an inhibitor of poly(ADP-ribose) polymerase, attenuates methamphetamine-induced dopamine neurotoxicity in the C57B1/6N mouse.

Previous studies have indicated that the activation of poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA plasticity-related phenomena, is an early event occurring in glutamate-induced neurotoxicity in vitro, and that inhibitors of PARP, including benzamide, are protective against both glutamate- and methamphetamine (METH)-induced neurotoxicity in vitro. To evaluate a central neuroprotective potential of benzamide in vivo, the present study examined the effect of benzamide on the nigrostriatal dopamine toxicity (i.e., long-lasting striatal dopamine depletion) induced by METH in the C57B1/6N mouse. Intraperitoneal injection of METH at 2-h intervals (4 injections of 5 mg/kg, 4 injections of 10 mg/kg, or 2 injections of 20 mg/kg) dose-dependently reduced the levels of striatal dopamine in male C57B1/6N mice by up to 53% at 7 days post-treatment. Administration of benzamide (2 injections of 160 mg/kg spaced by a 4 interval) during the different METH treatment protocols partially and significantly attenuated the METH-induced dopamine depletions. Benzamide (160 mg/kg i.p.) by itself had no acute effect on striatal dopamine metabolism and did not reduce body temperature. The concentrations of benzamide measured in the striatum at different times following this same dose of drug were in a range (0.09-0.64 mM) reported in in vitro studies to be both neuroprotective and effective in inhibiting PARP activity. These results indicate a neuroprotective potential of benzamide in vivo and suggest a role of PARP in METH neurotoxicity.