Debeir Thomas, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, Raisman-Vozari R
INSERM U289, Neurologie et Thérapeutique Expérimentale, Hôpital de la Salpêtrière, Paris, France.
Exp Neurol. 2004 Dec;190(2):384-95. doi: 10.1016/j.expneurol.2004.08.023.
We have previously reported that the alpha2-adrenoceptor antagonist dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since nerve growth factor (NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of dexefaroxan in the devascularization model was associated with regional induction of NGF biosynthesis. Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or sham operation procedures. In vehicle-treated devascularized rats, NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation; NGF levels in NbM remained unchanged during this time. In dexefaroxan-treated devascularized rats, increases in NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of NGF's actions, including increases in choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM cholinergic cell numbers. Dexefaroxan also increased NGF protein levels in sham-operated rats, but without any significant consequence to the otherwise normal NbM cholinergic phenotype in these animals. Results indicate that activation of endogenous NGF systems could contribute to the cholinergic protective effect of dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of dexefaroxan in neurodegenerative diseases where central cholinergic function is progressively compromised.
我们之前曾报道，α2-肾上腺素能受体拮抗剂地昔法罗生可保护成年大鼠大脑皮质缺血后基底核大细胞部（NbM）胆碱能神经元的退变。由于神经生长因子（NGF）对成年大脑中NbM胆碱能神经元的存活至关重要，且已知其合成受去甲肾上腺素能机制调控，我们研究了地昔法罗生在缺血模型中的保护作用是否与NGF生物合成的区域诱导有关。在缺血或假手术操作后，通过皮下微型泵给大鼠注射地昔法罗生或赋形剂，持续28天。在接受赋形剂治疗的缺血大鼠中，皮质中的NGF蛋白水平在术后5天升高，但在术后2周恢复正常；在此期间，NbM中的NGF水平保持不变。在接受地昔法罗生治疗的缺血大鼠中，在术后整个28天期间，皮质和NbM中的NGF蛋白水平（增加2倍）和免疫反应性均持续升高；这些升高与NGF作用的功能标志物变化一致，包括胆碱乙酰转移酶（ChAT）、p75和TrkA免疫反应性增加，以及NbM胆碱能细胞数量的保留。地昔法罗生还增加了假手术大鼠中的NGF蛋白水平，但对这些动物原本正常的NbM胆碱能表型没有任何显著影响。结果表明，内源性NGF系统的激活可能有助于地昔法罗生在皮质缺血模型中的胆碱能保护作用，并为地昔法罗生在中枢胆碱能功能逐渐受损的神经退行性疾病中的潜在治疗效用提供了进一步支持。
