Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo.
Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo.
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DOI：
10.1167/iovs.05-0754
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发表时间：
2006-02
影响因子：
4.4
通讯作者：
Cordeiro MF
中科院分区：
文献类型：
--
作者：
Guo L;Salt TE;Maass A;Luong V;Moss SE;Fitzke FW;Cordeiro MF
评估不同谷氨酸调节策略对青光眼相关视网膜神经节细胞（RGC）凋亡的神经保护作用，使用非选择性（MK801）和选择性（伊芬地尔）NMDA受体拮抗剂和代谢性谷氨酸受体激动剂（mGluR Group II, LY354740）。staurosporine （SSP）诱导大鼠RGC凋亡。单药MK801、伊芬普罗地尔或LY354740，或MK801和LY354740联合以不同剂量静脉注射。使用最近建立的技术对眼睛进行活体成像，结果在组织学上得到证实。然后在慢性高眼压（OHT）大鼠模型中评估MK801和LY354740最有效的联合治疗方案，分别在OHT手术后0、1和2周应用，并按照上述方法评估效果。与对照组相比，所有谷氨酸调节策略均以剂量依赖的方式减少了ssp诱导的rgc凋亡：MK801 (R2 = 0.8863), ifenprodil （R2 = 0.4587）和LY354740 (R2 = 0.9094)， ec50分别为0.074,0.0138和19纳米摩尔。MK801与LY354740的最有效联合剂量分别为0.06纳摩尔和20纳摩尔（P < 0.05），最佳治疗时间为OHT术后0周（P < 0.05）。这种新的SSP模型被证实是一种有用的工具，用于筛选体内的神经保护策略。II组mGluR调节可能是治疗RGC死亡的有效方法。限制MK801神经毒性作用的优化联合治疗可能是视网膜退行性疾病的有效神经保护方法。此外，减少继发性RGC变性的治疗可能对青光眼最有用。
To assess the neuroprotective effects of different glutamate modulation strategies, with a nonselective (MK801) and a selective (ifenprodil) NMDA receptor antagonist and a metabotropic glutamate receptor agonist (mGluR Group II, LY354740), in glaucoma-related in vivo rat models of retinal ganglion cell (RGC) apoptosis. RGC apoptosis was induced in Dark Agouti (DA) rats by staurosporine (SSP) treatment. Single agents MK801, ifenprodil, or LY354740, or MK801 and LY354740 combined, were administrated intravitreally at different doses. Eyes were imaged in vivo using a recently established technique and the results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before. All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2 = 0.8863), ifenprodil (R2 = 0.4587), and LY354740 (R2 = 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively. The most effective combination dose of MK801 and LY354740 was 0.06 and 20 nanomoles (P < 0.05), respectively, and the optimal timing of the therapy was 0 weeks after OHT surgery (P < 0.05). This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment for RGC death. Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, treatments that minimize secondary RGC degeneration may be most useful in glaucoma.
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影响因子：
4.4
作者：
Hare, WA;WoldeMussie, E;Wheeler, L
通讯作者：
Wheeler, L
影响因子：
1.7
作者：
Bond, A;O'Neill, MJ;Lodge, D
通讯作者：
Lodge, D
影响因子：
3.4
作者：
HARTVEIT, E;BRANDSTATTER, JH;WASSLE, H
通讯作者：
WASSLE, H
影响因子：
1.9
作者：
Higgs, MH;Lukasiewicz, PD
通讯作者：
Lukasiewicz, PD
青光眼中的视网膜神经节细胞凋亡与眼内压和IOP诱导的细胞外基质有关。
影响因子：
4.4
作者：
Guo L;Moss SE;Alexander RA;Ali RR;Fitzke FW;Cordeiro MF
通讯作者：
Cordeiro MF