Chemistry:P7C3-A20
P7C3-A20 is a synthetic chemical compound belonging to the carbazole class. It was developed as a more potent analog of P7C3. It functions as an activator of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway.[1] P7C3-A20 exhibits proneurogenic and neuroprotective properties in preclinical models, crossing the blood-brain barrier and demonstrating efficacy in various models of brain injury and neurodegeneration. Research has investigated its potential to treat Alzheimer's disease, where it reversed pathological features and restored cognitive function in mice.[1] As of 2025, P7C3-A20 remains an experimental compound with no established clinical use in humans.
Mechanism of action
P7C3-A20 acts as a small-molecule activator of NAMPT, enhancing the conversion of nicotinamide to nicotinamide mononucleotide (NMN), a precursor to NAD+. This increases intracellular NAD+ levels, supporting cellular energy metabolism, mitochondrial function, and resistance to stress-induced cell death.[1] Additional pathways reported in models include activation of PI3K/AKT/GSK3β signaling and restoration of NAD+ homeostasis without elevating NAD+ to supraphysiologic levels.[2]
Research
P7C3-A20 has shown efficacy in preclinical animal models, including:
- Traumatic brain injury (TBI): Repairs blood-brain barrier, arrests chronic neurodegeneration, and restores cognition even when administered one year post-injury.[3][4]
- Hypoxic-ischemic encephalopathy: Neuroprotective via PI3K/AKT/GSK3β pathway.[2]
- Alzheimer's disease models: Reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, neuroinflammation; enhances neurogenesis and synaptic plasticity; achieves full cognitive recovery.[1][5]
- Other models: Protects against ischemic stroke, optic nerve injury, intracerebral hemorrhage, and chemotherapy-induced peripheral neuropathy.[6]
References
- ↑ 1.0 1.1 1.2 1.3 Chaubey, Kalyani et al. (2025). "Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain". Cell Reports Medicine. doi:10.1016/j.xcrm.2025.102535. PMID 41435831.
- ↑ 2.0 2.1 Bai, Junjie; Zeng, Shanshan; Zhu, Jinjin; Fu, Changchang; He, Minzhi; Zhu, Jianghu; Chen, Shangqing; Fu, Xiaoqin et al. (2020). "The Small Molecule P7C3-A20 Exerts Neuroprotective Effects in a Hypoxic–ischemic Encephalopathy Model via Activation of PI3K/AKT/GSK3β Signaling". Neuroscience 441: 197–208. doi:10.1016/j.neuroscience.2020.05.051. PMID 32504794.
- ↑ Vázquez-Rosa, Edwin; Shin, Min-Kyoo; Dhar, Matasha; Chaubey, Kalyani; Cintrón-Pérez, Coral J.; Tang, Xinmiao; Liao, Xudong; Miller, Emiko et al. (2020). "P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition". Proceedings of the National Academy of Sciences 117 (44): 27667–27675. doi:10.1073/pnas.2010430117. PMID 33087571. Bibcode: 2020PNAS..11727667V.
- ↑ Yang, Zhiqing; Wang, Zhenchao; Deng, Xiaoqi; Zhu, Lingxin; Song, Zhaomeng; Cao, Changyu; Li, Xinran (2024). "P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis". Neural Regeneration Research 19 (5): 1078–1083. doi:10.4103/1673-5374.380910. PMID 37862211.
- ↑ "Scientists reverse Alzheimer's in mice and restore memory". December 24, 2025. https://www.sciencedaily.com/releases/2025/12/251224032354.htm.
- ↑ Wang, Shu-Na; Xu, Tian-Ying; Wang, Xia; Guan, Yun-Feng; Zhang, Sai-Long; Wang, Pei; Miao, Chao-Yu (2016). "Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3-A20 in Ischemic Stroke". CNS Neuroscience & Therapeutics 22 (9): 782–788. doi:10.1111/cns.12576. PMID 27333812.
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