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Yifan Han - One of the best experts on this subject based on the ideXlab platform.
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evaluation of acute bis 7 Tacrine treatment on behavioral functions in 17 day old and 30 day old mice with attention to drug toxicity
Pharmacology Biochemistry and Behavior, 2007Co-Authors: Siyuan Pan, Hang Dong, Nelson Tsz Kin Lee, Hui Wang, Wang Fun Fong, Yifan HanAbstract:Bis(7)-Tacrine was evaluated for efficacy on memory retention in mice 17 days of age and 30 days of age. The tests used were a passive-avoidance response test and a measure of spontaneous motor activity. Also, possible drug-induced hepatotoxicity and acute drug toxicity were evaluated. Behavioral studies were performed using a step-through task and an open-field test with a 24-h interval between training and evaluation tests. Bis(7)-Tacrine (0.06−20 μmol/kg) was subcutaneously injected 30 min prior to the first session of both test types. During the training session of the step-through task, bis(7)-Tacrine treatment reduced (by 46%, P < 0.01) the number of avoidable electric shocks (footshocks) only at a high dose of 20 μmol/kg in mice 17 days of age, but dose-dependently decreased the number of footshocks (10–56%, P < 0.001) in mice 30 days of age. Bis(7)-Tacrine treatment at all doses tested did not produce any detectable changes in retention latency in mice 17 days of age, but the drug significantly prolonged retention latency at low doses (1.25 and 2.50 μmol/kg), and not high doses (5–20 μmol/kg), in mice 30 days of age. In the open-field test, bis(7)-Tacrine decreased spontaneous motor activity in the acquisition session only at a high dose of 20 μmol/kg in mice 17 days of age and 30 days of age (by 28 and 45%, respectively), but did not affect spontaneous motor activity in the recall session. Bis(7)-Tacrine treatment at a dose of 20 μmol/kg produced a more potent hepatotoxic effect in mice 30 days of age than in mice 17 days of age, (P < 0.05), and the drug caused acute toxicity with comparable potencies in mice of both age groups. In conclusion, mice 30 days of age seemed to be more sensitive than mice 17 days of age to bis(7)-Tacrine-induced cognitive function enhancement and hepatotoxicity. Bis(7)-Tacrine appears to be more potent and more selective as a cognitive function-enhancing agent than Tacrine.
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evaluation of acute Tacrine treatment on passive avoidance response open field behavior and toxicity in 17 and 30 day old mice
Pharmacology Biochemistry and Behavior, 2006Co-Authors: Siyuan Pan, Yifan Han, Rong Yang, Hang DongAbstract:Abstract The potential of Tacrine in altering cognitive/behavioral function as well as in causing toxicity was evaluated in mice of 17 and 30 days of age. Cognitive and behavioral studies were performed using a step-through passive avoidance task and a habituation open-field test with a 24-h retention interval. Tacrine was subcutaneously injected (1.25−80 μmol/kg) 30 min prior to the first session of both tests. During the training session in step-through task, Tacrine treatment dose-dependently decreased the number of footshocks, with IC 50 values being 7.8 and 23.3 μmol/kg in 17- and 30-day-old mice, respectively. Treatment with Tacrine at a low dose (5 μmol/kg) significantly prolonged the retention latency in 17-day-old mice only, but it shortened the retention latency at high doses of 20 and 40 μmol/kg in 17- and 30-day-old, respectively. During the acquisition session in the open-field test, Tacrine treatment dose-dependently decreased the locomotor activity in 17- and 30-day-old mice, with IC 50 values being 15.1 and 24.7 μmol/kg, respectively. High doses of Tacrine invariably increased the locomotor activity during the recall session. Tacrine treatment at a dose of 40 μmol/kg caused a significant increase in serum alanine aminotransferase activity in 17- and 30-day-old mice at 6 h post-dosing, with the extent of stimulation in 30-day-old mice being more prominent. In conclusion, Tacrine was more potent in enhancing/disrupting the cognitive function, inhibiting locomotor activity as well as in causing hepatotoxicity in 17-day-old than in 30-day-old mice.
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bis 7 Tacrine attenuates β amyloid induced neuronal apoptosis by regulating l type calcium channels
Journal of Neurochemistry, 2006Co-Authors: Yuanzhi Lao, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Karl Wah Keung Tsim, Kelvin K W Kan, Yifan HanAbstract:Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-Tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-Tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-Tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-Tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-Tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-Tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
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heterodimeric Tacrine based acetylcholinesterase inhibitors investigating ligand peripheral site interactions
Journal of Medicinal Chemistry, 1999Co-Authors: Paul R Carlier, Yifan Han, E S H Chow, Jing Liu, El J Yazal, Yuan Ping PangAbstract:Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (Tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to Tacrine itself. AChE IC50 values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > Tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC50 values, suggesting the importance of ligand hydrophobicity for effective cation−π interaction with the peripheral site.
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Potent, easily synthesized huperzine A-Tacrine hybrid acetylcholinesterase inhibitors.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul R Carlier, Yifan Han, Jing Liu, Yuan Ping PangAbstract:Hybrid acetylcholinesterase inhibitors composed of a key fragment of huperzine A and an intact Tacrine unit were prepared. The syntheses are quite direct, proceeding in a maximum of 4 linear steps from commercially available starting materials. The optimum hybrid inhibitor (+/-)-9g is 13-fold more potent than (-)-huperzine A, and 25-fold more potent than Tacrine.
Yuan Ping Pang - One of the best experts on this subject based on the ideXlab platform.
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synergistic neuroprotection by bis 7 Tacrine via concurrent blockade of n methyl d aspartate receptors and neuronal nitric oxide synthase
Molecular Pharmacology, 2007Co-Authors: Jian Xue, Yuan Ping Pang, Jialie Luo, Kelvin K W Kan, Nelson Tsz Kin Lee, Chunying Niu, Colin S C Lam, Hugh H Chan, Huaiguo Xue, Karl Wah Keung TsimAbstract:The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis(7)-Tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate. Moreover, like L-NMMA but not like 5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and memantine, bis(7)-Tacrine showed greater neuroprotection and inhibition on NO release when neurons were pretreated for a prolonged time between 0 and 24 h and remained quite potent even when neurons were post-treated 1 h after the glutamate challenge. Bis(7)-Tacrine was additionally found to be as moderately potent as memantine in competing with [(3)H]MK-801, inhibiting NMDA-evoked currents and reducing glutamate-triggered calcium influx, which eventually reduced neuronal NOS activity. More importantly, at neuroprotective concentrations, bis(7)-Tacrine substantially reversed the overactivation of neuronal NOS caused by glutamate without interfering with the basal activity of NOS. Furthermore, in vitro pattern analysis demonstrated that bis(7)-Tacrine competitively inhibited both purified neuronal and inducible NOS with IC(50) values at 2.9 and 9.3 microM but not endothelial NOS. This result was further supported by molecular docking simulations that showed hydrophobic interactions between bis(7)-Tacrine and three NOS isozymes. Taken together, these results strongly suggest that the substantial neuroprotection against glutamate by bis(7)-Tacrine might be mediated synergistically through the moderate blockade of NMDAR and selective inhibition of neuronal NOS.
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bis 7 Tacrine attenuates β amyloid induced neuronal apoptosis by regulating l type calcium channels
Journal of Neurochemistry, 2006Co-Authors: Yuanzhi Lao, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Karl Wah Keung Tsim, Kelvin K W Kan, Yifan HanAbstract:Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-Tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-Tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-Tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-Tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-Tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-Tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
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novel dimeric acetylcholinesterase inhibitor bis 7 Tacrine but not donepezil prevents glutamate induced neuronal apoptosis by blocking n methyl d aspartate receptors
Journal of Biological Chemistry, 2005Co-Authors: Hugh H N Chan, Hong Xue, Paul R Carlier, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Keming Xiong, Karl Wah Keung TsimAbstract:The neuroprotective properties of bis(7)-Tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 M glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-Tacrine treatment (0.01–1 M) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 M bis(7)-Tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro--erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-Tacrine, suggesting that the neuroprotection of bis(7)-Tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-D-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-Tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca 2 imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-Tacrine was found effectively to buffer the intracellular Ca 2 increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [ 3 H]MK-801 with an IC50 value of 0.763 M in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-Tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.
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heterodimeric Tacrine based acetylcholinesterase inhibitors investigating ligand peripheral site interactions
Journal of Medicinal Chemistry, 1999Co-Authors: Paul R Carlier, Yifan Han, E S H Chow, Jing Liu, El J Yazal, Yuan Ping PangAbstract:Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (Tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to Tacrine itself. AChE IC50 values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > Tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC50 values, suggesting the importance of ligand hydrophobicity for effective cation−π interaction with the peripheral site.
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Potent, easily synthesized huperzine A-Tacrine hybrid acetylcholinesterase inhibitors.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul R Carlier, Yifan Han, Jing Liu, Yuan Ping PangAbstract:Hybrid acetylcholinesterase inhibitors composed of a key fragment of huperzine A and an intact Tacrine unit were prepared. The syntheses are quite direct, proceeding in a maximum of 4 linear steps from commercially available starting materials. The optimum hybrid inhibitor (+/-)-9g is 13-fold more potent than (-)-huperzine A, and 25-fold more potent than Tacrine.
Karl Wah Keung Tsim - One of the best experts on this subject based on the ideXlab platform.
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synergistic neuroprotection by bis 7 Tacrine via concurrent blockade of n methyl d aspartate receptors and neuronal nitric oxide synthase
Molecular Pharmacology, 2007Co-Authors: Jian Xue, Yuan Ping Pang, Jialie Luo, Kelvin K W Kan, Nelson Tsz Kin Lee, Chunying Niu, Colin S C Lam, Hugh H Chan, Huaiguo Xue, Karl Wah Keung TsimAbstract:The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis(7)-Tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate. Moreover, like L-NMMA but not like 5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and memantine, bis(7)-Tacrine showed greater neuroprotection and inhibition on NO release when neurons were pretreated for a prolonged time between 0 and 24 h and remained quite potent even when neurons were post-treated 1 h after the glutamate challenge. Bis(7)-Tacrine was additionally found to be as moderately potent as memantine in competing with [(3)H]MK-801, inhibiting NMDA-evoked currents and reducing glutamate-triggered calcium influx, which eventually reduced neuronal NOS activity. More importantly, at neuroprotective concentrations, bis(7)-Tacrine substantially reversed the overactivation of neuronal NOS caused by glutamate without interfering with the basal activity of NOS. Furthermore, in vitro pattern analysis demonstrated that bis(7)-Tacrine competitively inhibited both purified neuronal and inducible NOS with IC(50) values at 2.9 and 9.3 microM but not endothelial NOS. This result was further supported by molecular docking simulations that showed hydrophobic interactions between bis(7)-Tacrine and three NOS isozymes. Taken together, these results strongly suggest that the substantial neuroprotection against glutamate by bis(7)-Tacrine might be mediated synergistically through the moderate blockade of NMDAR and selective inhibition of neuronal NOS.
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bis 7 Tacrine attenuates β amyloid induced neuronal apoptosis by regulating l type calcium channels
Journal of Neurochemistry, 2006Co-Authors: Yuanzhi Lao, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Karl Wah Keung Tsim, Kelvin K W Kan, Yifan HanAbstract:Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-Tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-Tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-Tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-Tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-Tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-Tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
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novel dimeric acetylcholinesterase inhibitor bis 7 Tacrine but not donepezil prevents glutamate induced neuronal apoptosis by blocking n methyl d aspartate receptors
Journal of Biological Chemistry, 2005Co-Authors: Hugh H N Chan, Hong Xue, Paul R Carlier, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Keming Xiong, Karl Wah Keung TsimAbstract:The neuroprotective properties of bis(7)-Tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 M glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-Tacrine treatment (0.01–1 M) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 M bis(7)-Tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro--erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-Tacrine, suggesting that the neuroprotection of bis(7)-Tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-D-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-Tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca 2 imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-Tacrine was found effectively to buffer the intracellular Ca 2 increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [ 3 H]MK-801 with an IC50 value of 0.763 M in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-Tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.
Akinori Akaike - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective effects of galanthamine and Tacrine against glutamate neurotoxicity
European Journal of Pharmacology, 2006Co-Authors: Yuki Takadatakatori, Toshiaki Kume, Mitsuhiro Sugimoto, Hiroshi Katsuki, Tetsuhiro Niidome, Hachiro Sugimoto, Takeshi Fujii, Susumu Okabe, Akinori AkaikeAbstract:We examined the mechanisms of the neuroprotective effects of two central-type acetylcholinesterase inhibitors, galanthamine and Tacrine, on nitric oxide-mediated glutamate neurotoxicity using primary cultures from the cerebral cortex of fetal rats. Galanthamine and Tacrine showed prominent protective effects against glutamate neurotoxicity. Mecamylamine, a nicotinic acetylcholine receptor antagonist, but not scopolamine, a muscarinic acetylcholine receptor antagonist, inhibited the protective effects of these inhibitors on glutamate neurotoxicity. Furthermore, dihydro-β-erythroidine, an α4-nicotinic receptor antagonist, and methyllycaconitine, an α7-nicotinic receptor antagonist, inhibited the neuroprotective effects of galanthamine but not Tacrine. Next, we investigated the site of action where galanthamine and Tacrine prevent glutamate neurotoxicity. Both these acetylcholinesterase inhibitors prevented glutamate- and ionomycin-induced neurotoxicity, but only Tacrine prevented S-nitrosocysteine-induced neurotoxicity. These results suggest that galanthamine and Tacrine protect cortical neurons from glutamate neurotoxicity via different mechanisms.
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acetylcholinesterase inhibitors used in treatment of alzheimer s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3 kinase cascade
Neuropharmacology, 2006Co-Authors: Yuki Takadatakatori, Toshiaki Kume, Mitsuhiro Sugimoto, Hiroshi Katsuki, Hachiro Sugimoto, Akinori AkaikeAbstract:Abstract We show here that donepezil, galanathamine and Tacrine, therapeutic acetylcholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-β-erythroidine and methyllycaconitine, antagonists for α4-nAChR and α7-nAChR, respectively, antagonized the protective effect of donepezil and galanthamine, but not that of Tacrine. Previous reports suggest the involvement of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway in the nicotine-induced neuroprotection. Inhibitors for a non-receptor type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galanthamine, but not that of Tacrine. Furthermore, LY294002, a PI3K inhibitor, also suppressed the neuroprotective effect of donepezil and galanthamine, but not that of Tacrine. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galanthamine treatment, but not with Tacrine treatment. These results suggest that donepezil and galanthamine prevent glutamate neurotoxicity through α4- and α7-nAChRs, followed by the PI3K–Akt pathway, and that Tacrine protects neuronal cells through a different pathway.
Jialie Luo - One of the best experts on this subject based on the ideXlab platform.
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synergistic neuroprotection by bis 7 Tacrine via concurrent blockade of n methyl d aspartate receptors and neuronal nitric oxide synthase
Molecular Pharmacology, 2007Co-Authors: Jian Xue, Yuan Ping Pang, Jialie Luo, Kelvin K W Kan, Nelson Tsz Kin Lee, Chunying Niu, Colin S C Lam, Hugh H Chan, Huaiguo Xue, Karl Wah Keung TsimAbstract:The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis(7)-Tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate. Moreover, like L-NMMA but not like 5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and memantine, bis(7)-Tacrine showed greater neuroprotection and inhibition on NO release when neurons were pretreated for a prolonged time between 0 and 24 h and remained quite potent even when neurons were post-treated 1 h after the glutamate challenge. Bis(7)-Tacrine was additionally found to be as moderately potent as memantine in competing with [(3)H]MK-801, inhibiting NMDA-evoked currents and reducing glutamate-triggered calcium influx, which eventually reduced neuronal NOS activity. More importantly, at neuroprotective concentrations, bis(7)-Tacrine substantially reversed the overactivation of neuronal NOS caused by glutamate without interfering with the basal activity of NOS. Furthermore, in vitro pattern analysis demonstrated that bis(7)-Tacrine competitively inhibited both purified neuronal and inducible NOS with IC(50) values at 2.9 and 9.3 microM but not endothelial NOS. This result was further supported by molecular docking simulations that showed hydrophobic interactions between bis(7)-Tacrine and three NOS isozymes. Taken together, these results strongly suggest that the substantial neuroprotection against glutamate by bis(7)-Tacrine might be mediated synergistically through the moderate blockade of NMDAR and selective inhibition of neuronal NOS.
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bis 7 Tacrine attenuates β amyloid induced neuronal apoptosis by regulating l type calcium channels
Journal of Neurochemistry, 2006Co-Authors: Yuanzhi Lao, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Karl Wah Keung Tsim, Kelvin K W Kan, Yifan HanAbstract:Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-Tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-Tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-Tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-Tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-Tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-Tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
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novel dimeric acetylcholinesterase inhibitor bis 7 Tacrine but not donepezil prevents glutamate induced neuronal apoptosis by blocking n methyl d aspartate receptors
Journal of Biological Chemistry, 2005Co-Authors: Hugh H N Chan, Hong Xue, Paul R Carlier, Yuan Ping Pang, Nelson T K Lee, Hing Wai Tsang, Donald C Chang, Jialie Luo, Keming Xiong, Karl Wah Keung TsimAbstract:The neuroprotective properties of bis(7)-Tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 M glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-Tacrine treatment (0.01–1 M) on CGNs markedly reduced glutamate-induced apoptosis in dose- and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 M bis(7)-Tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro--erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis(7)-Tacrine, suggesting that the neuroprotection of bis(7)-Tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-D-aspartate (NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-Tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca 2 imaging, patch clamp, and receptor-ligand binding techniques, bis(7)-Tacrine was found effectively to buffer the intracellular Ca 2 increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [ 3 H]MK-801 with an IC50 value of 0.763 M in rat cerebellar cortex membranes. These findings strongly suggest that bis(7)-Tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.