Demyelination is typically followed by a remyelination process through mature oligodendrocytes (OLs) differentiated from precursor cells (OPCs) recruited into the lesioned areas, however, this event usually results in uncompleted myelination. Potentiation of the remyelination process is an important target for designing effective therapeutic strategies against white matter loss. Here, it was evaluated the remyelinating effect of different β-carbolines that present differential allosteric modulation on the GABAA receptor expressed in OLs. For this, we used a focalized demyelination model in the inferior cerebellar peduncle (i.c.p.) of rats (DRICP model), in which, demyelination by ethidium bromide (0.05%) stereotaxic injection was confirmed histologically by staining with Black-Gold II (BGII) and toluidine blue. In addition, a longitudinal analysis with diffusion-weighted magnetic resonance imaging (dMRI) was made by computing fractional anisotropy (FA), apparent diffusion coefficient (ADC) and diffusivity parameters to infer i.c.p. microstructural changes. First, dMRI analysis revealed FA decreases together with ADC and radial diffusivity (RD) increases after demyelination, which correlates with histological BGII observations. Then, we evaluated the effect produced by three allosteric GABAA receptor modulators, the N-butyl-β-carboline-3-carboxylate (β-CCB), ethyl 9H-pyrido [3,4-b]indole-3-carboxylate (β-CCE), and 4-ethyl-6,7-dimethoxy-9H-pyrido [3,4-b]indole-3-carboxylic acid methyl ester (DMCM). The results indicated that daily systemic β-CCB (1 mg/Kg) or β-CCE (1 mg/Kg) administration for 2 weeks, but not DMCM (0.35 mg/Kg), in lesioned animals increased FA and decreased ADC or RD, suggesting myelination improvement. This was supported by BGII staining analysis that showed a recovery of myelin content. Also, it was quantified by immunohistochemistry both NG2+ and CC1+ cellular population in the different experimental sceneries. Data indicated that either β-CCB or β-CCE, but not DMCM, produced an increase in the population of CC1+ cells in the lesioned area. Finally, it was also calculated the g-ratio of myelinated axons and observed a similar value in those lesioned animals treated with β-CCB or β-CCE compared to controls. Thus, using the DRICP model, it was observed that either β-CCB or β-CCE, positive modulators of the GABAA receptor in OLs, had a potent promyelinating effect.

中文翻译：

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增强少突胶质细胞中表达的 GABAA 受体反应的 β-咔啉可促进局灶性脱髓鞘体内大鼠模型中的髓鞘再生

脱髓鞘通常伴随着从前体细胞 (OPC) 分化而来的成熟少突胶质细胞 (OL) 的髓鞘再生过程，然而，这一事件通常会导致髓鞘形成不完全。髓鞘再生过程的增强是设计针对白质损失的有效治疗策略的重要目标。在此，评估了对 GABA 具有不同变构调节作用的不同 β-咔啉的髓鞘再生作用AOL 中表达的受体。为此，我们在小脑下脚使用了局灶性脱髓鞘模型（ICP）大鼠（DRICP模型），其中通过黑金II（BGII）和甲苯胺蓝染色，通过组织学证实溴化乙锭（0.05%）立体定位注射脱髓鞘。此外，通过计算分数各向异性（FA）、表观扩散系数（ADC）和扩散率参数，利用扩散加权磁共振成像（dMRI）进行纵向分析，以推断ICP微观结构的变化。首先，dMRI 分析显示，脱髓鞘后 FA 随 ADC 一起下降，径向扩散率 (RD) 增加，这与组织学 BGII 观察结果相关。然后，我们评估了三种变构 GABA 产生的效果A受体调节剂，N-丁基-β-咔啉-3-羧酸酯（β-CCB）、9H-吡啶并[3,4-b]吲哚-3-甲酸乙酯（β-CCE）和4-乙基-6， 7-二甲氧基-9H-吡啶并[3,4-b]吲哚-3-甲酸甲酯（DMCM）。结果表明，每日全身性 β-CCB (1 mg/Kg) 或 β-CCE (1 mg/Kg) 给药 2 周，但 DMCM (0.35 mg/Kg) 不会在病变动物中增加 FA 并降低 ADC 或 RD ，表明髓鞘形成得到改善。 BGII 染色分析证实了这一点，显示髓磷脂含量有所恢复。此外，还通过免疫组织化学对 NG2 进行了定量+和CC1+不同实验场景中的细胞群。数据表明，β-CCB 或 β-CCE（而非 DMCM）导致 CC1 数量增加+病变区域的细胞。最后还计算了G- 有髓轴突的比率，并在用 β-CCB 或 β-CCE 治疗的病变动物中观察到与对照相比相似的值。因此，使用 DRICP 模型，观察到 β-CCB 或 β-CCE（GABA 的正调节剂）AOL 中的受体，具有有效的早髓鞘作用。