The anomalously large Ham effect observed in pyrene has been studied in various solvents at room temperature by measuring the fluorescence and absorption spectra. As in the case of benzene, the Ham bands of pyrene were assigned to the 0–0 and ag-vibration bands. This was confirmed by fluorescence polarization measurement. The correlation of the intensities of the fluorescence and absorption bands to solvent polarities is discussed.

Tumor necrosis factor-␣ (TNF-␣

Increasing evidence suggests that the elevation of ␤-amyloid (A␤) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signalregulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates A␤-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble A␤ 1-40 and A␤ 1-42 in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-A␤ antibody, it was evidently shown that the administration of nobiletin decreased the A␤ burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.Long-term potentiation (LTP) in the hippocampus is an activity-dependent modification of synaptic strength and considered a potential cellular mechanism underlying learning and memory (Bliss and Collingridge 1993). Brain-derived neurotrophic factor (BDNF) is implicated in synaptic plasticity such as LTP (Barde et al. 1982;Leibrock et al. 1989;Patterson et al. 1992;Figurov et al. 1996). Recently, we have demonstrated that BDNF mRNA in the hippocampus increased after a radial maze training, and treatment with an antisense BDNF oligonucleotide led to impairment of not only the acquisition, but also the maintenance and/or recall of spatial memory (Mizuno et al. 2000). Although these findings imply an essential role for BDNF in spatial learning and memory, the molecular mechanisms by which BDNF regulates spatial memory processes remain to be determined .N-Methyl-D-aspartate (NMDA) receptors are heteromeric glutamate-gated ion channels in the central nervous system, which are constructed by two families of an essential subunit NR1 and other subunits NR2A-D (Hollmann and Heinemann 1994), and are involved in synaptic plasticity (Collingridge 1987). Activation of NMDA receptors generates LTP, whereas inhibition and deletion of NMDA receptors impair LTP and spatial learning and memory (Morris et al. 1986;Sakimura et al. 1995;Tsien et al. 1996). NMDA receptor activity is modulated by the phosphorylation catalyzed by several protein kinases including protein kinase A, protein kinase C, and calcium/calmodulin-dependent protein kinase II (Omkumar et al. 1996;Tingley et al. 1997;Gardoni et al. 1999).Phosphorylation at tyrosine residues leads to an increase in NMDA current (Chen and Leonard 1996). Compelling evidence has been provided that NMDA receptors are substrates of protein tyrosine kinases. Fyn is a nonreceptor Src-family tyrosine kinase expressed abund...