Bis(7)-tacrine, a promising anti-Alzheimer's dimer, affords dose- and time-dependent neuroprotection against transient focal cerebral ischemia.
Bis(7)-tacrine, a promising anti-Alzheimer's dimer, has been shown to have multiple neuroprotective activities in vitro. Here, we investigate whether bis(7)-tacrine attenuates focal cerebral ischemic impairment in vivo. Cerebral ischemia was induced in Sprague-Dawley rats by transient (2h) middle cerebral artery occlusion (MCAO) followed by 24h of reperfusion. Bis(7)-tacrine administered intraperitoneally 15 min after ischemia dose-dependently improved neurological behavior deficits and reduced both cerebral infarct volume and edema. The TUNEL staining assay showed that bis(7)-tacrine attenuated neuronal apoptosis in the penumbral region. Compared with that for memantine, a moderately effective N-methyl-d-aspartate (NMDA) receptor antagonist with a similar affinity and potency to bis(7)-tacrine in blocking NMDA receptors, the therapeutic window for bis(7)-tacrine was wider and lasted up to 6h after the onset of ischemia. Bis(7)-tacrine did not affect physiological parameters or regional cerebral blood flow during either the occlusion period or the early reperfusion stage. In conclusion, bis(7)-tacrine dose- and time-dependently protected against acute focal cerebral ischemic insults, possibly through the drug's anti-apoptotic effects during multiple events in the ischemic cascade.
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China.
Yuming
Y
Zhao
Wenming
W
Li
Peter C Y
PC
Chow
Dickson T K
DT
Lau
Nelson T K
NT
Lee
Yuanping
Y
Pang
Xuejun
X
Zhang
Xiaoliang
X
Wang
Yifan
Y
Han
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013619:Tacrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D018696:Neuroprotective Agents; D013619:Tacrine