Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.
Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.
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将Pomalidomide重新利用为神经保护药物：帕金森氏病的基于α-核蛋白模型中的功效。
DOI：
10.1007/s13311-022-01182-2
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发表时间：
2022-01
影响因子：
5.7
通讯作者：
Carta, Anna R.
中科院分区：
文献类型：
--
作者：
Palmas, Maria Francesca;Ena, Anna;Burgaletto, Chiara;Casu, Maria Antonietta;Cantarella, Giuseppina;Carboni, Ezio;Etzi, Michela;De Simone, Alfonso;Fusco, Giuliana;Cardia, Maria Cristina;Lai, Francesco;Picci, Luca;Tweedie, David;Scerba, Michael T.;Coroneo, Valentina;Bernardini, Renato;Greig, Nigel H.;Pisanu, Augusta;Carta, Anna R.
帕金森病（PD）的市售药物治疗疾病运动症状，但在阻止或减缓疾病进展方面无效。在寻求可能靶向疾病进展的新型药理学方法时，药物再利用提供了一种策略，以加速已批准用于其他医学适应症的药物的临床前和临床试验。在此，我们针对PD病理学的炎症成分，首次在PD神经病理学转化大鼠模型中测试了免疫调节酰亚胺药物（IMiD）泊马度胺的疾病修饰特性，该模型基于双侧黑质内输注人α-突触核蛋白（H-αSynOs）的毒性预制寡聚体。在疾病进展的第一阶段，当观察到已经持续的神经炎症时，通过从H-αSynOs输注后1个月开始的2个月慢性给药，检测泊马度胺（20 mg/kg; i. p.，每周3次，间隔48 h）的神经保护作用。脑内输注H-α SynO诱导运动和协调能力受损，通过输注后3个月的一系列运动测试评估，泊马度胺完全缓解了该损伤。此外，通过TH +和Nissl染色的神经元的体视学计数，H-α SynOs灌注大鼠显示双侧黑质内40-45%的细胞损失，这在很大程度上被泊马度胺消除。在CNS受累区域和外周血清中评价了对H-αSynOs输注和泊马度胺治疗的炎症反应。在H-αSynOs输注后3个月以及H-α SynOs+泊马度胺治疗后，黑质中存在反应性小胶质细胞增生（测量为小胶质细胞标志物Iba-1所占的体积）。然而，实验组之间的小胶质细胞的表型不同。在H-αSynOs输注后，小胶质细胞显示出促炎特征，产生大量促炎细胞因子TNF-α。相反，泊马度胺抑制TNF-α的过度产生，并升高抗炎细胞因子IL-10。此外，H-αSynOs输注诱导了全身性炎症，血清促炎细胞因子和趋化因子过度产生，泊马度胺在很大程度上减轻了这种炎症。结果提供了泊马度胺在PD神经病理啮齿动物模型中的疾病改善潜力的证据，并支持将该药物重新用于PD患者的临床试验。在线版本包含补充材料，可通过10.1007/s13311-022-01182-2获得。
Marketed drugs for Parkinson’s disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients. The online version contains supplementary material available at 10.1007/s13311-022-01182-2.
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影响因子：
2.1
作者：
Decourt B;Drumm-Gurnee D;Wilson J;Jacobson S;Belden C;Sirrel S;Ahmadi M;Shill H;Powell J;Walker A;Gonzales A;Macias M;Sabbagh MN
通讯作者：
Sabbagh MN
影响因子：
7.3
作者：
Chen X;Hu Y;Cao Z;Liu Q;Cheng Y
通讯作者：
Cheng Y
影响因子：
5.6
作者：
Boi L;Pisanu A;Palmas MF;Fusco G;Carboni E;Casu MA;Satta V;Scherma M;Janda E;Mocci I;Mulas G;Ena A;Spiga S;Fadda P;De Simone A;Carta AR
通讯作者：
Carta AR
DOI：
10.1002/bdrb.20115
发表时间：
2007-06-01
影响因子：
--
作者：
Christian, Mildred S.;Laskin, Oscar L.;Latriano, Louise
通讯作者：
Latriano, Louise
影响因子：
7.6
作者：
Edison, Paul;Ahmed, Imtiaz;Brooks, David J.
通讯作者：
Brooks, David J.