Chloride extrusion enhancers as novel therapeutics for neurological diseases.
Chloride extrusion enhancers as novel therapeutics for neurological diseases.
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作者：
K+-Cl−协同转运蛋白KCC 2负责维持中枢神经系统（CNS）神经元中的低Cl−浓度，这对于通过GABAA和甘氨酸受体进行突触后抑制至关重要。虽然没有CNS疾病与KCC 2突变相关，但这种转运蛋白活性的丧失已成为几种神经和精神疾病的关键机制，包括癫痫、运动痉挛、应激、焦虑、精神分裂症、吗啡诱导的痛觉过敏和慢性疼痛。最近的报告表明，增强KCC 2活性可能是在涉及Cl−转运受损的病理条件下恢复抑制和正常功能的首选治疗策略。我们设计了一种用于高通量筛选的测定方法，该方法鉴定了可降低[Cl−]i的KCC 2激活剂。对一类芳基亚甲基化合物家族的优化产生了降低[Cl−]i的KCC 2选择性类似物（CLP 257）。CLP 257恢复了受损的Cl−转运神经元中的KCC 2活性降低。该化合物挽救了KCC 2质膜表达，使神经损伤后致敏的脊髓伤害性通路中的刺激诱发反应重新正常化，并减轻了神经性疼痛大鼠模型中的超敏反应。使用CLP 257前体药物可实现与普瑞巴林相当但无运动损伤的口服镇痛功效。这些结果验证了KCC 2作为CNS疾病的药物靶标。
The K+-Cl− cotransporter KCC2 is responsible for maintaining low Cl− concentration in neurons of the central nervous system (CNS), essential for postsynaptic inhibition through GABAA and glycine receptors. While no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favoured therapeutic strategy to restore inhibition and normal function in pathological condition involving impaired Cl− transport. We designed an assay for high-throughput screening which led to the identification of KCC2 activators that reduce [Cl−]i. Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl−]i. CLP257 restored impaired Cl− transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalised stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of Pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.
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影响因子：
4.3
作者：
Doyon N;Prescott SA;Castonguay A;Godin AG;Kröger H;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
5.3
作者：
Cordero-Erausquin, M;Coull, JAM;De Koninck, Y
通讯作者：
De Koninck, Y
影响因子：
16.2
作者：
Kuner, T;Augustine, GJ
通讯作者：
Augustine, GJ
影响因子：
25
作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
3.3
作者：
Labrakakis C;Lorenzo LE;Bories C;Ribeiro-da-Silva A;De Koninck Y
通讯作者：
De Koninck Y