Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3‐A20 in Ischemic Stroke

Wang, Shu-Na; Xu, Tao; Wang, Xia; Guan, Yongjun; Zhang, Sai-Long; Wang, Pei; Miao, Chao‐Yu

doi:10.1111/cns.12576

Cited by 37 publications

(34 citation statements)

References 48 publications

(76 reference statements)

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“…Middle cerebral artery occlusion (MCAO) surgery in rats was performed as described [23]. The rats were anesthetized with a combination of ketamine (50 mg/kg), xylazine (2.6 mg/kg), and acepromazine (0.50 mg/kg) by intraperitoneal injection.…”

Section: Middle Cerebral Artery Occlusion Modelmentioning

confidence: 99%

Cerebral Organoids Repair Ischemic Stroke Brain Injury

Wang

et al. 2019

Transl. Stroke Res.

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Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.

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Section: Middle Cerebral Artery Occlusion Modelmentioning

confidence: 99%

Cerebral Organoids Repair Ischemic Stroke Brain Injury

Wang

et al. 2019

Transl. Stroke Res.

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“…Stem cells have the ability of self‐renewing and differentiating into various cell lineages, and stem cell‐based strategies hold promise in curing traumatic brain injury and stroke . Our group has done much work in identifying therapeutic targets and screening effective neuroprotective drugs against stroke . Recently, we have demonstrated that nicotinamide phosphoribosyltransferase‐NAD cascade which is particularly important for the proliferation, self‐renewal, and differentiation of neural stem cells can promote regenerative neurogenesis after ischemic stroke .…”

Section: Applications and Advantages Of Brain Organoid Technologymentioning

confidence: 99%

“…[40][41][42] Our group has done much work in identifying therapeutic targets and screening effective neuroprotective drugs against stroke. [43][44][45] Recently, we have demonstrated that nicotinamide phosphoribosyltransferase-NAD cascade which is particularly important for the proliferation, self-renewal, and differentiation of neural stem cells can promote regenerative neurogenesis after ischemic stroke. [46][47][48] In addition to promoting tissue regeneration by stimulating endogenous stem cells, progress in stem cell transplantation also enhances the development of regenerative medicine.…”

Section: Regenerative Medicinementioning

confidence: 99%

Organoid technology for brain and therapeutics research

Wang

et al. 2017

CNS Neurosci Ther

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Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics.

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“…Aged rats that underwent prolonged administration of P7C3 also performed better on cognitive tasks and exhibited decreased cell death in the hippocampus 17 . Subsequently, the neuroprotective effects of P7C3 and its derivative compounds have been further demonstrated in broad preclinical rodent models of CNS disease and injury, including environmental stress-related hippocampal cell death 18 – 20 , amyotrophic lateral sclerosis 21 , Parkinson’s disease 22 – 25 , traumatic brain injury 26 – 28 , peripheral nerve crush 29 , chemotherapy-induced peripheral neuropathy 30 , optic nerve injury 31 , 32 , Alzheimer’s disease 33 , stroke 34 – 36 , and recently expanded to acetaminophen-induced liver toxicity 37 . Mechanistically, P7C3 increases nicotinamide adenine dinucleotide (NAD) flux in mammalian cells under conditions of otherwise overwhelming energy crisis that would normally lead to cell death 38 .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective efficacy of P7C3 compounds in primate hippocampus

et al. 2018

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There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2–11, monkeys received weekly injection of 5′-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.

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Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3‐A20 in Ischemic Stroke

Abstract: P7C3-A20 has neuroprotective effect in cerebral ischemia. The study contributes to the development of NAMPT activators against ischemic stroke and expands the horizon of the neuroprotective effect of aminopropyl carbazole chemicals.

Cited by 37 publications

References 48 publications

Cerebral Organoids Repair Ischemic Stroke Brain Injury

Cerebral Organoids Repair Ischemic Stroke Brain Injury

Organoid technology for brain and therapeutics research

Neuroprotective efficacy of P7C3 compounds in primate hippocampus

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