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. 2011;4(2):125-30.
doi: 10.3980/j.issn.2222-3959.2011.02.03. Epub 2011 Apr 18.

Bis(7)-tacrine protects retinal ganglion cells against excitotoxicity via NMDA receptor inhibition

Zu-Hai Zhang  1 , Yu-Wei Liu, Fa-Gang Jiang, Xiang Tian, Yan-Hua Zhu, Jing-Bo Li, Qi Wang, Jia-Hua Fang
Affiliations

Bis(7)-tacrine protects retinal ganglion cells against excitotoxicity via NMDA receptor inhibition

Zu-Hai Zhang et al. Int J Ophthalmol. 2011.

Abstract

Aim: To investigate whether bis(7)-tacrine, a multifunctional drug, inhibits N-methyl-D-aspartate (NMDA) -activated current in retinal ganglion cells(RGC) and provides neuroprotection against retinal cell damage.

Methods: Purified RGC cultures were obtained from retinas of 1-3 days old Sprague-Dawley(SD) rats, following a two-step immunopanning procedure. After 7 days of cultivation, the inhibition of NMDA-activated current by bis(7)-tacrine was measured by using patch-clamp recording techniques. In animal experiments, RGCs were damaged after intravitreal injection of NMDA (5µL, 40nmol) in adult rats. Bis(7)-tacrine(0.05, 0.1, 0.2mg/kg) or memantine(20mg/kg) was intraperitoneal administered to the rats fifteen minutes before intravitreally injection of NMDA. RGC damage was analyzed by histologic techniques, TUNEL and retrograde labeling techniques.

Results: Whole-cell patch-clamp recordings demonstrated that NMDA (30µmol/L) resulted in approximately -50 pA inward currents that were blocked by bis(7)-tacrine(1µmol/L). Histological examination and retrograde labeling analysis revealed that bis(7)-tacrine induced a significant neuroprotective effect against NMDA-induced cell damage 7 days after NMDA injection. TUNEL staining showed that pretreatment with bis(7)-tacrine was effective in ameliorating NMDA-induced apoptotic cell loss in the retinal ganglion cell layer 18 hours after injection.

Conclusion: Bis(7)-tacrine possesses remarkable neuroprotective activities against retinal excitotoxicity through inhibition of NMDA receptors.

Keywords: N-methyl-D-aspartate receptors; bis(7)-tacrine; excitotoxicity; neuroprotection.

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Figures

Figure 1
Figure 1. Inhibition of NMDA-activated current by bis(7)-tacrine in RGC in vitro
Bis(7)-tacrine: 30µmol/L; NMDA: 1µmol/L
Figure 2
Figure 2. Protective effects of bis(7)-tacrine on retinal damage induced by intravitreal injection of NMDA(40nmol)
aP<0.05, bP<0.01 vs NMDA; Scale bar, 100µm
Figure 3
Figure 3. Bis(7)-tacrine reduces NMDA-induced apoptosis of ganglion cell layer(GCL) cells in vivo
A: Representative photographs of retina in the vehicle group, the NMDA group and the NMDA group with peritoneal injection of bis(7)-tacrine(0.2mg/kg) or memantine(20mg/kg); B: The number of TUNEL-positive cells in GCL was counted. NMDA treatment plus NMDA receptor blocker was tested vs NMDA treatment alone bP<0.01 vs NMDA; Scale bar, 100µm
Figure 4
Figure 4. Protective effects of bis(7)-tacrine on retinal ganglion cells(RGC) following intravitreal injection of NMDA (40nmol)
aP<0.05, bP<0.01 vs NMDA; Scale bar, 100µm
See this image and copyright information in PMC

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