P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice

Alzheimer’s disease (AD), the most common type of dementia is a progressive neurodegenerative disorder characterized by a decline in cognitive function and memory impairment. Characteristic neuropathological features of AD are accumulation of amyloid plaques, formation of neurofibrillary tangles, induction of oxidative stress and inflammatory responses, and disturbance in neurotransmission. Particularly, the impairment of memory and cognitive dysfunction in AD is associated with cholinergic (acetylcholine-producing) hypofunction by increasing the acetyl-cholinesterase (AchE) activity. Conversely, the major treatment for AD is AchE inhibitors, which improve the levels of acetylcholine by delaying its degradation at cholinergic synapses. However, due to the limitation of current medications for treating AD such as relatively low efficacy, severe adverse effects for the long-term use, and in-effectiveness in the late stage of AD, it is very necessary to develop novel and safe anti-amnesic compounds with neuroprotective properties. In this regard, one promising new candidate of interest in this study is P7C3.

Previous studies have showed that learning and memory is controlled by a lot of proteins and signaling pathways, especially the BDNF signaling pathway. BDNF is a neurotrophic factor closely involved in memory consolidation, and the dysfunction of BDNF disrupts the hippocampusdependent memory formation . CREB is a transcription factor coupled to the activation of BDNF, and plays important roles in many developmentally regulated processes, such as cell survival, hippocampal neurogenesis and long-term memory.

P7C3 is an identified proneurogenic and neuroprotective aminopropyl carbazole. Pieper et al. reported that the intraperitoneal injection of P7C3 could significantly enhance the hippocampal neurogenesis at a dose of 20 mg/kg, while hippocampal neurogenesis is closely correlated with learning and memory. By now, this compound has already been demonstrated to treat several brain disorders in animal models, including the Parkinson’s disease, amyotrophic lateral sclerosis and traumatic brain injury. Here, the author speculated that P7C3 may have anti-amnesic effects and exhibit a preventive/therapeutic potential for treating AD.

Scopolamine is a muscarinic acetylcholine receptor (mAChR) antagonist which impairs learning acquisition and short-term memory in rodents and humans. The scopolamine-induced amnesia has been widely used to generate experimental animal models for the screening of anti-amnesic drugs. In this study, the author have utilized the scopolamine model to assess the anti-amnesic effects of P7C3, and furthermore, the actions of P7C3 were extended to the molecular levels by examining the expression of brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus and cortex.

In this study, the major findings of this study are as follows. First, P7C3 produces anti-amnesic effects in multiple animal models screening for anti-amnesic activity, including the passive avoidance task, Y-maze test and Morris water maze. Second, the anti-amnesic effects of P7C3 require the BDNF signaling pathway, since it could be prevented by selective inhibition of BDNF system in the hippocampus and cortex. Together, these data identify a novel function of P7C3 suggesting it could be developed as a potential treatment for AD.

AD is the most common form of age-related neurodegenerative disorder that is characterized with an insidious loss of memory, associated functional decline, and behavioral disturbances. Cholinergic deficit is a major feature that is associated with memory loss and cognitive dysfunction in AD, and so it is well known that the anti-cholinergic agent scopolamine-induced memory deficits are similar to those found in age-related senile central nervous system dysfunction. Therefore, scopolamine challenge could serve as a useful tool for selecting compounds with therapeutic potential for treating AD. The compound, P7C3, was selected in our study by virtue of the knowledge that it demonstrates robust proneurogenic activity as neurogenesis is closely involved in learning and memory, and this compound also has neuroprotective effects while AD is always accompanied with neuronal loss. P7C3 is orally bioavailable, endowed with a relatively long half life, capable of crossing the blood brain barrier, and safely tolerated by mice. Here, the author investigated whether P7C3 has anti-AD potential in the scopolamine-induced memory impairment animal model, and conducted a series of behavior tests. Firstly, in the passive avoidance test, scopolamine treatment reduced the step-through latency, which was effectively restored by intraperitoneal injection of P7C3. Secondly, in the Y-maze test, the scopolamine-treated mice showed decreased spontaneous alternation compared with that of vehicle-treated mice, which was significantly improved by P7C3 pretreatment. Lastly, in the Morris water-maze task, the scopolamine-treated animals took longer time to find the platform than those animals in the control group, and P7C3? scopolamine-treated animals easily found the location of the hidden platform. Collectively, these data strongly suggest that P7C3 could be a novel anti-AD compound.

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Bo Jiang • Lu Song, • Chao Huang • Wei Zhang. P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice