title: Neuroprotection against excitotoxic and ischemic insults by bis(12)-hupyridone, a novel anti-acetylcholinesterase dimer, possibly via acting on multiple targets.
abstract: The activation of N-methyl-d-aspartate (NMDA) receptors by excessive release of glutamate is involved in the pathogenesis of ischemic stroke. Thus the NMDA receptor has become an attractive therapeutic target for the development of neuroprotectants, especially from antagonists with moderate to low affinity. In the current study, NMDA receptor blockage and neuroprotective effects of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor derived from a naturally occurring monomeric analog huperzine A, were investigated in vitro and in vivo. In primary rat cerebellar granule neurons, B12H (0.1 nM to 1 μM) prevented glutamate-induced apoptosis in a concentration- and time-dependent manner. Receptor-ligand binding analysis showed that B12H competed with [(3)H]MK801 with a K(i) value of 7.7 μM. In the 2-hour middle cerebral artery occlusion rat model, B12H (0.4 and 0.8 mg/kg, 30 min before-ischemia and 15 min post-ischemia, i.p.) significantly attenuated ischemia-induced apoptosis in the penumbra region, improved neurological behavior impairment, and decreased cerebral infarct volume, cerebral edema and neuronal apoptosis in the stroke model. Together, these results showed that B12H moderately blocks NMDA receptors at MK801 site and exerts neuroprotection against excitotoxic and ischemic insults in vitro and in vivo. Combined with our previous publications, we conjecture that B12H might exert neuroprotection via acting on multiple targets.
authors: Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong.
authors: Yuming
authors: Y
authors: Zhao
authors: Juan
authors: J
authors: Dou
authors: Jialie
authors: J
authors: Luo
authors: Wenming
authors: W
authors: Li
authors: Hugh H N
authors: HH
authors: Chan
authors: Wei
authors: W
authors: Cui
authors: Huan
authors: H
authors: Zhang
authors: Renwen
authors: R
authors: Han
authors: Paul R
authors: PR
authors: Carlier
authors: Xuejun
authors: X
authors: Zhang
authors: Yifan
authors: Y
authors: Han
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C528260:bis(12)-hupyridone; D000110:Acetylcholinesterase