Although exogenously administered acetyl-l-carnitine (ALCAR, (2-acetoxy-3-carboxypropyl)-trimethylammonium) and l-carnitine (LC, (3-carboxy-2-hydroxypropyl)-trimethylammonium) prevent brain damage in several ischemic models, the protective mechanism of these compounds remains unclear. Here, we evaluated the effect of ALCAR and LC in primary cultured neurons from the cerebral cortex, striatum and thalamus of 18-day-old rat embryos. Deprivation of the serum from cultured medium for 3 days reduced the number of viable cells and mitochondrial activity and induced cell death with characteristics of apoptosis such as DNA fragmentation, nuclear condensation and histone-DNA release into the cytoplasm. ALCAR (1 - 100 microM) and LC (1 - 100 microM) promoted neuronal survival and mitochondrial activity in a concentration-dependent manner. Moreover, these compounds attenuated DNA fragmentation and nuclear condensation in cultured neurons and significantly decreased histone-DNA release into the cytoplasm. These results indicate that anti-apoptotic actions of ALCAR and LC contribute to their neuroprotective effect.

Abstract. The effect of T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl] amino]methyl]-[1,1'-biphenyl]-4-carbonitrile dihydrochloride}, a novel tachykinin NK 1 -receptor antagonist, was examined on cisplatin-induced emesis in ferrets. Cisplatin induced acute emesis in 24 h and delayed emesis during 24 and 72 h, respectively. Ondansetron, a 5-HT 3 antagonist, almost completely blocked the acute emesis and transiently reduced the delayed emesis. In contrast, T-2328 elicited long-lasting anti-emetic effects on both acute and delayed phases by a single intravenous administration. Suppression of delayed emesis was not due to elimination of the acute phase because the delayed emesis was also suppressed by administration after the onset of delayed emesis. Persistent blockade of NK 1 receptors in the brain was demonstrated by inhibition of the NK 1 agonist-induced foot tapping response for over 24 h. An appreciable amount of T-2328 was present in the brain 32 and 72 h after the injection. The NK 1 agonistinduced contractions of isolated ileum in guinea pigs was antagonized with IC 50 values of 1.4 nM in an insurmountable manner. It is likely that T-2328 exerts the long-lasting anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of NK 1 receptors.

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Abstract. The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK 1 ) receptor. T-2328 inhibited the specific binding of [ 3 H][Sar 9 ,Met(O 2 ) 11 ]substance P to tachykinin NK 1 receptors in human lymphoblastic IM9 cells with K i of 0.08 nM. In the same assay, K i for aprepitant, a brain-penetrating NK 1 antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK 1 receptors since the affinities for human NK 2 , NK 3 receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK 1 receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK 1 receptor. T-2328 (0.03 -0.1 mg / kg, i.v.) and aprepitant (1 -3 mg / kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1 -0.3 mg/ kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg / kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK 1 antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapyinduced emesis.