Neuroprotective agent; NAMPT

当暴露于 LPS 时，P7C3 可阻止 BV2 细胞产生促炎因子 [3]。在用 100 ng/mL LPS 处理的 BV2 细胞中，P7C3 显着且剂量依赖性地降低 iNOS 和 COX-2 的蛋白质水平，而不影响细胞活力 [3]。在 BV2 细胞中，P7C3 阻止 LPS 诱导的 NF-κB p65 亚基的核转位 [3]。通过阻止 IκB 激酶 (IKK) 激活，P7C3 可以阻止 LPS 诱导的抑制性 κB α (IκBα) 降解 [3]。

体内 P7C3（20 mg/kg/d；腹腔注射；每天两次；持续 21 天）可防止小胶质细胞和小胶质细胞激活介导的多巴胺能 (DA) 神经元的损失 [3]。

蛋白质印迹分析[3]
细胞类型： BV2 细胞
测试浓度： 0.1 μM、1 μM、10 μM
孵育时间：2小时
实验结果：降低iNOS、COX-2的蛋白质水平。

Animal/Disease Models: 6-8 weeks male C57BL/6 mice (25-30 g)[3]
Doses: 20 mg/kg/d
Route of Administration: intraperitoneal (ip)injection, twice (two times) daily, for 21 days
Experimental Results: Strikingly diminished the expressions of (a microglia marker) and GFAP (an astrocyte marker) LPS-induced in the substantia nigra pars compacta (SNpc).

[1]. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51.

[2]. P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. Chem Soc Rev. 2014 Oct 7;43(19):6716-26.

[3]. P7C3 Inhibits LPS-Induced Microglial Activation to Protect Dopaminergic Neurons Against Inflammatory Factor-Induced Cell Death in vitro and in vivo. Front Cell Neurosci. 2018; 12: 400.

[4]. Blaya MO, Wasserman JM, Pieper AA, Sick TJ, Bramlett HM, Dietrich WD. Neurotherapeutic capacity of P7C3 agents for the treatment of Traumatic Brain Injury. Neuropharmacology. 2019;145(Pt B):268-282.

An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging.[1]

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A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders.[2]

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Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although its pathogenesis remains unclear, growing evidencce suggests that microglia-mediated neuroinflammation contributes greatly to the progression of PD. P7C3, an aminopropyl carbazole, possesses significant neuroprotective effects in several neurodegenerative disease animal models, including PD. In this study, we designed to investigate the effects of P7C3 on neuroinflammation. We showed that P7C3 specially suppressed the expression of lipopolysaccharide (LPS)-induced pro-inflammatory factors but not influenced the anti-inflammatory factors in microglia. The inhibition of the nuclear factor κB (NF-κB) signaling pathway was involved in the mechanisms of the anti-inflammatory effects by P7C3. LPS-induced activation of IκB kinase (IKK), degradation of the inhibitory κB alpha (IκBα) and nuclear translocation of NF-κB can be attenuated by the pretreatment of P7C3 in microglia. Furthermore, in LPS-treated microglia, P7C3-pretreatment decreased the toxicity of conditioned media to MES23.5 cells (a dopaminergic (DA) cell line). Most importantly, the anti-inflammatory effects of P7C3 were observed in LPS-stimulated mouse model. In general, our study demonstrates that P7C3 inhibits LPS-induced microglial activation through repressing the NF-κB pathway both in vivo and in vitro, providing a theoretical basis for P7C3 in anti-inflammation.[3]

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Traumatic brain injury (TBI) is a significant public health problem around the world. A promising area of research is the characterization of small, drug-like molecules that have potent clinical properties. One pharmacotherapeutic agent in particular, an aminopropyl carbazole called P7C3, was discovered using an in vivo screen to identify new agents that augmented the net magnitude of adult hippocampal neurogenesis. P7C3 greatly enhanced neurogenesis by virtue of increasing survival rates of immature neurons. The potent neuroprotective efficacy of P7C3 is likely due to enhanced nicotinamide phosphoribosyltransferase (NAMPT) activity, which supports critical cellular processes. The scaffold of P7C3 was found to have favorable pharmacokinetic properties, good bioavailability, and was nontoxic. Preclinical studies have shown that administration of the P7C3-series of neuroprotective compounds after TBI can rescue and reverse detrimental cellular events leading to improved functional recovery. In several TBI models and across multiple species, P7C3 and its analogues have produced significant neuroprotection, axonal preservation, robust increases in the net magnitude of adult neurogenesis, protection from injury-induced LTP deficits, and improvement in neurological functioning. This review will elucidate the exciting and diverse therapeutic findings of P7C3 administration in the presence of a complex and multifactorial set of cellular and molecular challenges brought forth by experimental TBI. The clinical potential and broad therapeutic applicability of P7C3 warrants much needed investigation into whether these remedial effects can be replicated in the clinic. P7C3 may serve as an important step forward in the design, understanding, and implementation of pharmacotherapies for treating patients with TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".[4]

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C21H18BR2N2O

474.19

471.978

C, 53.19; H, 3.83; Br, 33.70; N, 5.91; O, 3.37

301353-96-8

P7C3-A20;1235481-90-9

2836187

White to off-white solid powder

1.6±0.1 g/cm3

656.4±55.0 °C at 760 mmHg

350.8±31.5 °C

0.0±2.1 mmHg at 25°C

1.687

6.6

37.19

2

2

5

26

433

0

BrC1C([H])=C([H])C2=C(C=1[H])C1C([H])=C(C([H])=C([H])C=1N2C([H])([H])C([H])(C([H])([H])N([H])C1C([H])=C([H])C([H])=C([H])C=1[H])O[H])Br

FZHHRERIIVOATI-UHFFFAOYSA-N

InChI=1S/C21H18Br2N2O/c22-14-6-8-20-18(10-14)19-11-15(23)7-9-21(19)25(20)13-17(26)12-24-16-4-2-1-3-5-16/h1-11,17,24,26H,12-13H2

1-anilino-3-(3,6-dibromocarbazol-9-yl)propan-2-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.39 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.39 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。