Cacna1c: Protecting young hippocampal neurons in the adult brain

Jesús-Cortés, Héctor De; Rajadhyaksha, Anjali M.; Pieper, Andrew A.

doi:10.1080/23262133.2016.1231160

Cited by 14 publications

(7 citation statements)

References 46 publications

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“…This form of injury and its associated behavioral deficits can be recapitulated in rodent models, which may therefore be useful for discovery and validation of new therapeutic approaches (Goldstein et al, 2012; Mohan et al, 2013; Yin et al, 2014). Pharmcologic agents shown to enhance flux of the nicotinamide adenine dinucleotide (NAD) salvage pathway in normal mammalian cells and facilitate NAD rebound following doxorubicin exposure (Pieper et al, 2010, 2014; MacMillan et al, 2011; Wang et al, 2014) confer protective efficacy on pathology and behavior in a rodent model of blast-mediated TBI (Yin et al, 2014), as well as other models of neurodegeneration in the central and peripheral nervous systems (De Jesús-Cortés et al, 2012, 2015,2016; Tesla et al, 2012; Blaya et al, 2014; Dutca et al, 2014; Naidoo et al, 2014; Kemp et al, 2015; Walker et al, 2015; Lee et al, 2016). In addition, treatment with NAD and NAD precursors, including nicotinamide, nicotonic acid mononucleotide, and nicotinamide mononucleotide (NMN), or overexpression of nicotinamide phosphoribosyltransferase protect axons in vitro (Araki et al, 2004; Wang et al, 2005; Sasaki et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice

Yin

Voorhees

Genova

et al. 2016

eNeuro

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Axonal degeneration is a prominent feature of many forms of neurodegeneration, and also an early event in blast-mediated traumatic brain injury (TBI), the signature injury of soldiers in Iraq and Afghanistan. It is not known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. The Wallerian degeneration slow strain (WldS) of mice is resistant to some forms of axonal degeneration because of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1). Here, we demonstrate that resistance of WldS mice to axonal degeneration after blast-mediated TBI is associated with preserved function in hippocampal-dependent spatial memory, cerebellar-dependent motor balance, and retinal and optic nerve–dependent visual function. Thus, early axonal degeneration is likely a critical driver of subsequent neurobehavioral complications of blast-mediated TBI. Future therapeutic strategies targeted specifically at mitigating axonal degeneration may provide a uniquely beneficial approach to treating patients suffering from the effects of blast-mediated TBI.

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Section: Introductionmentioning

confidence: 99%

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice

Yin

Voorhees

Genova

et al. 2016

eNeuro

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“…P7C3 compounds were first identified through an unbiased screen of hippocampal neurogenesis in rodents 17 , and subsequently shown to have neuroprotective properties for a number of CNS relevant rodent models 18 – 35 . Here we establish the next step in advancing P7C3 along the translational pipeline into a species more closely related to humans—the rhesus macaque.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…CaBP1 also prolongs Ca 2+ currents mediated by Ca v 1.2 L-type channels (Zhou et al, 2004, Zhou et al, 2005, Tippens and Lee, 2007). Ca v 1.2 is thought to be the dominant L-type calcium channel in the brain (Clark et al, 2003), and mediates somatodendritic Ca 2+ signals coupled to gene transcription (Ma et al, 2013), LTP and spatial memory (Moosmang et al, 2005), and neurogenesis (De Jesus-Cortes et al, 2016, Temme et al, 2016, Volkening et al, 2017). While presynaptic Ca v 2.1 Ca 2+ signals would be potentiated in C-KO mice, postsynaptic Ca v 1 currents would be more transient.…”

Section: Discussionmentioning

confidence: 99%

Ca2+-Binding Protein 1 Regulates Hippocampal-dependent Memory and Synaptic Plasticity

et al. 2018

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Ca-binding protein 1 (CaBP1) is a Ca-sensing protein similar to calmodulin that potently regulates voltage-gated Ca channels. Unlike calmodulin, however, CaBP1 is mainly expressed in neuronal cell-types and enriched in the hippocampus, where its function is unknown. Here, we investigated the role of CaBP1 in hippocampal-dependent behaviors using mice lacking expression of CaBP1 (C-KO). By western blot, the largest CaBP1 splice variant, caldendrin, was detected in hippocampal lysates from wild-type (WT) but not C-KO mice. Compared to WT mice, C-KO mice exhibited mild deficits in spatial learning and memory in both the Barnes maze and in Morris water maze reversal learning. In contextual but not cued fear-conditioning assays, C-KO mice showed greater freezing responses than WT mice. In addition, the number of adult-born neurons in the hippocampus of C-KO mice was ∼40% of that in WT mice, as measured by bromodeoxyuridine labeling. Moreover, hippocampal long-term potentiation was significantly reduced in C-KO mice. We conclude that CaBP1 is required for cellular mechanisms underlying optimal encoding of hippocampal-dependent spatial and fear-related memories.

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Cacna1c: Protecting young hippocampal neurons in the adult brain

Cited by 14 publications

References 46 publications

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice

Neuroprotective efficacy of P7C3 compounds in primate hippocampus

Ca2+-Binding Protein 1 Regulates Hippocampal-dependent Memory and Synaptic Plasticity

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