Calatrava-Ferreras Lucía, Gonzalo-Gobernado Rafael, Reimers Diana, Herranz Antonio S, Jiménez-Escrig Adriano, Díaz-Gil Juan José, Casarejos María José, Montero-Vega María Teresa, Bazán Eulalia
Service of Neurobiology, Ramón y Cajal Institute for Health Research (IRYCIS), Madrid 28034, Spain.
Service of Neurology, Ramón y Cajal Hospital, Madrid 28034, Spain.
Int J Mol Sci. 2014 Oct 21;15(10):19056-73. doi: 10.3390/ijms151019056.
Cerebellar ataxias (CA) comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the survival and differentiation of selected types of neurons. Liver growth factor (LGF) is a hepatic mitogen that shows biological activity in neuroregenerative therapies. We investigate the potential therapeutic activity of LGF in the 3-acetylpiridine (3-AP) rat model of CA. This model of CA consists in the lesion of the inferior olive-induced by 3-AP (40 mg/kg). Ataxic rats were treated with 5 µg/rat LGF or vehicle during 3 weeks, analyzing: (a) motor coordination by using the rota-rod test; and (b) the immunohistochemical and biochemical evolution of several parameters related with the olivo-cerebellar function. Motor coordination improved in 3-AP-lesioned rats that received LGF treatment. LGF up-regulated NeuN and Bcl-2 protein levels in the brainstem, and increased calbindin expression and the number of neurons receiving calbindin-positive projections in the cerebellum. LGF also reduced extracellular glutamate and GABA concentrations and microglia activation in the cerebellum. In view of these results, we propose LGF as a potential therapeutic agent in cerebellar ataxias.
小脑性共济失调（CA）是一组异质性神经退行性疾病，其特征为运动协调障碍。它们由小脑及其相关神经回路的紊乱引起，因此主要治疗目标是纠正小脑功能障碍。神经营养因子可增强特定类型神经元的存活和分化。肝生长因子（LGF）是一种肝脏有丝分裂原，在神经再生治疗中显示出生物活性。我们研究了LGF在CA的3-乙酰吡啶（3-AP）大鼠模型中的潜在治疗活性。该CA模型在于由3-AP（4０mg/kg）诱导的下橄榄核损伤。对共济失调大鼠用5μg/只LGF或赋形剂治疗3周，分析：（a）使用转棒试验评估运动协调性；（b）与橄榄小脑功能相关的几个参数的免疫组化和生化变化。接受LGF治疗的3-AP损伤大鼠的运动协调性得到改善。LGF上调了脑干中NeuN和Bcl-2蛋白水平，并增加了小脑中小脑钙结合蛋白的表达以及接受小脑钙结合蛋白阳性投射的神经元数量。LGF还降低了小脑中细胞外谷氨酸和GABA浓度以及小胶质细胞的激活。鉴于这些结果，我们提出LGF作为小脑性共济失调的一种潜在治疗药物。
