Tatsuhiro Akaishi

Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory

Small molecules that activate signaling pathways used by neurotrophic factors could be useful for treating CNS disorders. Here we show that the flavonoid fisetin activates ERK and induces cAMP response element-binding protein (CREB) phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice. Together, these data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders.

A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimers disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimers disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

A pyrazole derivative of curcumin enhances memory

Reduced cognitive function is associated with Alzheimers and Parkinsons diseases as well as brain trauma and ischemia. However, there are few compounds that enhance memory and are also orally active. We recently synthesized a pyrazole derivative of curcumin called CNB-001 that enhances the activity of Ca(2+)/calmodulin dependent protein kinase II (CaMKII). Since CaMKII plays a central role in long-term potentiation (LTP) and memory, it was asked if CNB-001 can facilitate the induction of LTP in rat hippocampal slices and enhance memory in a rat object recognition test. It is shown that CNB-001 enhances both LTP and memory.

β2-Adrenoceptor-Mediated Tracheal Relaxation Induced by Higenamine from Nandina domestica Thunberg

The fruit of Nandina domestica Thunberg (ND, Berberidaceae) has been used to improve cough and breathing difficulties in Japan for many years, but very little is known about the constituent of ND responsible for this effect. We have recently reported that the crude extract from ND (NDE) inhibits histamine- and serotonin-induced contraction of isolated guinea pig trachea, and the inhibitory activity was not explained by nantenine, a well-known alkaloid isolated from ND. To explore other constituent(s) of NDE with tracheal smooth muscle relaxant activity, we fractionated NDE and assessed the pharmacological effects of the fractions using isolated guinea pig tracheal ring preparations. NDE was introduced into a polyaromatic absorbent resin column and stepwise eluted to yield five fractions, among which only the 40 % methanol fraction was active in relaxing tracheal smooth muscle precontracted with histamine. Further separation of the 40 % methanol fraction with high-performance liquid chromatography yielded multiple subfractions, one of which was remarkably active in relaxing histamine-precontracted trachea. Chemical analysis with a time-of-flight mass spectrometer and nuclear magnetic resonance spectrometer identified the constituent of the most active subfraction as higenamine, a benzyltetrahydroisoquinoline alkaloid. The potency and efficacy of the active constituent from NDE in relaxing trachea were almost equivalent to synthetic higenamine. In addition, the effect of the active constituent from NDE was competitively inhibited by the selective beta (2)-adrenoceptor antagonist ICI 118,551. These results indicate that the major constituent responsible for the effect of NDE is higenamine, which probably causes the tracheal relaxation through stimulation of beta (2) adrenoceptors.

Stimulation of basolateral amygdaloid serotonin 5-HT2C receptors promotes the induction of long-term potentiation in the dentate gyrus of anesthetized rats

We have previously found that the induction of hippocampal long-term potentiation (LTP) is modulated by neuron activities in the basolateral amygdala (BLA). However, little is known about what neurotransmitter system in the BLA contributes to modulation of hippocampal LTP. In the present study, we investigated possible involvement of BLA serotonergic system in the induction of LTP at the perforant path (PP)-dentate gyrus (DG) granule cell synapses of anesthetized rats. The induction of PP-DG LTP was significantly inhibited by intra-BLA injection of the 5-HT(2) receptor antagonist cinanserin (25-50nmol), but not by intra-BLA injection of the 5-HT(1,7) receptor antagonist methiothepin (50nmol), the 5-HT(3) receptor antagonist ondansetron (50nmol) or the 5-HT(4) receptor antagonist RS23597-190 (100nmol). In addition, intra-BLA injection of the 5-HT(2C) receptor agonist MK212 (50nmol) facilitated the induction of PP-DG LTP. These results suggest that the induction of PP-DG LTP is promoted by activation of 5-HT(2C) receptors in the BLA.

Basolateral amygdala D1- and D2-dopaminergic system promotes the formation of long-term potentiation in the dentate gyrus of anesthetized rats

We have previously found that the induction of hippocampal long-term potentiation (LTP) is modulated by neuron activities in the basolateral amygdala (BLA). However, little is known about what neurotransmitter system in the BLA contributes to modulation of hippocampal LTP. In the present study, we investigated possible involvement of BLA dopaminergic system in the induction of LTP at the perforant path (PP)-dentate gyrus (DG) granule cell synapses of anesthetized rats. The induction of PP-DG LTP was significantly attenuated by intra-BLA injection of the D(1) receptor antagonist SCH23390 (2 or 6 nmol) or the D(2) receptor antagonists, chlorpromazine (30 or 100 nmol) or haloperidol (4.4 or 13.3 nmol). The effects of SCH23390 and haloperidol were abolished by concomitant intra-BLA injection of the D(1) receptor agonist SKF38393 (17 nmol) and the D(2) receptor agonist quinpirole (3 nmol), respectively. Furthermore, lesioning with 6-hydroxydopamine of the ventral tegmental area, the origin of the dopaminergic system projecting to the BLA, resulted in attenuated PP-DG LTP, which was restored by intra-BLA injection of SKF38393 or quipirole. These results suggest that the induction of PP-DG LTP is promoted by the BLA dopaminergic system via both D(1) and D(2) receptors.

Biphasic Tracheal Relaxation Induced by Higenamine and Nantenine From Nandina domestica THUNBERG

We compared the effects of the extract from fruits of Nandina domestica THUNBERG (NDE) and its constituents, higenamine and nantenine, on contractile responses in isolated guineapig trachea. NDE (1 mg/ml) caused biphasic relaxation of the trachea precontracted with high-K+ stimulation: the fast component was blocked by propranolol and mimicked by higenamine; and the slow was resistant to propranolol and mimicked by nantenine. Ca2+-induced contraction under high-K+ stimulation was antagonized by nantenine or NDE + propranolol. These results suggest that NDE relaxes the trachea quickly through β-adrenoceptor stimulation by higenamine and slowly through Ca2+ antagonism by nantenine.

Involvement of dopamine D2 receptors in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats.

We have previously found that synaptic pathway from the basolateral amygdala (BLA) to the dentate gyrus (DG) displays N-methyl-D-aspartate (NMDA) receptor-independent form of long-term potentiation (LTP), which should be a valuable model for elucidating neural mechanisms linking emotion and memory. To explore its cellular mechanisms, we investigated possible involvement of the beta-adrenergic, muscarinic cholinergic and dopaminergic systems on LTP in this pathway of anesthetized rats. The induction of BLA-DG LTP was not affected by administration of the beta-adrenoceptor antagonist propranolol (50-150nmol, i.c.v.), the muscarinic receptor antagonist scopolamine (2-6mg/kg, i.p.), the cholinesterase inhibitor physostigmine (50 nmol, i.c.v.) or the dopamine D(1) receptor antagonist SCH23390 (100nmol, i.c.v.), but significantly inhibited by the dopamine D2 receptor antagonists, chlorpromazine (15nmol, i.c.v.) and haloperidol (0.15-0.5mg/kg, i.p.), and significantly promoted by the dopamine D2 receptor agonist quinpirole (78nmol, i.c.v.). Furthermore, lesioning with 6-hydroxydopamine of the ventral tegmental area (VTA), the origin of mesolimbic dopaminergic neurons, resulted in attenuated BLA-DG LTP. These results suggest that the D2-dopaminergic system, but not the beta-adrenergic, muscarinic or D1-dopaminergic system, is involved in the induction of BLA-DG LTP. In addition, inhibition of BLA-DG LTP by haloperidol or VTA lesion was abolished by blockade of GABAergic inhibition with picrotoxin. It is probable that the D2-dopaminergic system promotes the induction of BLA-DG LTP by suppressing GABAergic inhibition.

Modulatory role of dopamine D2 receptors and fundamental role of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats

We have previously found that the induction of long-term potentiation in the synaptic pathway from the basolateral amygdala to the dentate gyrus (BLA-DG LTP) is regulated by L-type Ca(2+) channels, dopamine D(2) receptors and GABAergic inhibition. In the present study, we investigated possible relations among the three mechanisms by using anesthetized rats. Blockade of GABAergic inhibition with picrotoxin abolished both the inhibitory effect of the dopamine D(2) receptor antagonist chlorpromazine and the promoting effect of the dopamine D(2) receptor agonist quinpirole on the induction of BLA-DG LTP. However, the inhibitory effect of the L-type Ca(2+) channel blocker verapamil on BLA-DG LTP was not affected by picrotoxin. These results suggest that the role of dopamine D(2) receptors in the induction of BLA-DG LTP is modulatory and depends on GABAergic inhibition, whereas the role of L-type Ca(2+) channels is fundamental.

CNB-001, a synthetic pyrazole derivative of curcumin, suppresses lipopolysaccharide-induced nitric oxide production through the inhibition of NF-κB and p38 MAPK pathways in microglia

ABSTRACT CNB‐001, a pyrazole derivative of curcumin, has been found to exert neuroprotective and memory‐enhancing effects that may be effective for the treatment of Alzheimers disease. Since aberrant activation of microglia is involved in the pathogenesis of Alzheimers disease, the present study was undertaken to investigate the effect of CNB‐001 on microglia‐mediated inflammatory responses. In primary cultured rat microglia, CNB‐001 (1–10 &mgr;M) suppressed the lipopolysaccharide (LPS)‐induced nitric oxide (NO) production and expression of inducible NO synthase (iNOS), and the potency of CNB‐001 was stronger than curcumin. CNB‐001 also suppressed the LPS‐induced nuclear translocation of nuclear factor &kgr;B (NF‐&kgr;B), which is essential for the expression of iNOS. LPS treatment promoted phosphorylation of extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (MAPK). CNB‐001 significantly suppressed the LPS‐induced phosphorylation of p38 MAPK, but not ERK and JNK. The suppressive effect of CNB‐001 on NO production was mimicked by blockade of the p38 MAPK signaling pathway with SB203580. These results suggest that CNB‐001 exerts anti‐inflammatory effects through inhibition of NF‐&kgr;B and p38 MAPK pathways in microglia.