Application of P7C3 Compounds to Investigating and Treating Acute and Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading worldwide cause of disability, and there are currently no medicines that prevent, reduce, or reverse acute or chronic neurodegeneration in TBI patients. Here, we review the target-agnostic discovery of nicotinamide adenine dinucleotide (NAD+)/NADH-stabilizing P7C3 compounds through a phenotypic screen in mice and describe how P7C3 compounds have been applied to advance understanding of the pathophysiology and potential treatment of TBI. We summarize how P7C3 compounds have been shown across multiple laboratories to mitigate disease progression safely and effectively in a broad range of preclinical models of disease related to impaired NAD+/NADH metabolism, including acute and chronic TBI, and note the reported safety and neuroprotective efficacy of P7C3 compounds in nonhuman primates. We also describe how P7C3 compounds facilitated the recent first demonstration that chronic neurodegeneration 1 year after TBI in mice, the equivalent of many decades in people, can be reversed to restore normal neuropsychiatric function. We additionally review how P7C3 compounds have facilitated discovery of new pathophysiologic mechanisms of neurodegeneration after TBI. This includes the role of rapid TBI-induced tau acetylation that drives axonal degeneration, and the discovery of brain-derived acetylated tau as the first blood-based biomarker of neurodegeneration after TBI that directly correlates with the abundance of a therapeutic target in the brain. We additionally review the identification of TBI-induced tau acetylation as a potential mechanistic link between TBI and increased risk of Alzheimer's disease. Lastly, we summarize historical accounts of other successful phenotypic-based drug discoveries that advanced medical care without prior recognition of the specific molecular target needed to achieve the desired therapeutic effect.

Comparing learning retention in medical students using mixed-reality to supplement dissection: a preliminary study.

Objectives: To evaluate student impressions of learning anatomy with mixed-reality and compare long-term information retention of female breast anatomy between students who learned with a mixed-reality supplement and their classmates who dissected cadavers. Methods: In Part 1, 38 first-year medical student volunteers, randomly divided into two groups, completed a mixed-reality module and cadaveric dissection on the female breast in a counterbalanced design. Participants also completed post-quizzes and surveys. Part 2 was a non-randomized controlled trial, 8-months after completing Part 1 and 6-months after a final exam on this content. The performance of twenty-two Part 1 participants and 129 of their classmates, who only dissected, was compared on a delayed post-quiz. Wilcoxon signed-rank test, Mann-Whitney U test, and 95% confidence intervals were used to analyze the data. Results: In Part 1, the Wilcoxon signed-rank test determined that participants expressed significantly more positive responses to mixed-reality and found mixed-reality easier for learning and teamwork. In Part 2, the Mann-Whitney U test found mixed-reality participants scored significantly higher on a delayed-post quiz than their classmates who only dissected (U = 928, p < .009). Conclusions:   This study suggests that medical students may prefer mixed-reality and that it may be an effective modality for learning breast anatomy while facilitating teamwork. Results also suggest that supplementing cadaveric dissection with mixed-reality may improve long-term retention for at least one anatomical topic. It is recommended that similar studies evaluate a larger sample and additional anatomical regions to determine the generalizability of these findings.

Maternal P7C3-A20 Treatment Protects Offspring from Neuropsychiatric Sequelae of Prenatal Stress.

Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511-530.

Loss of Cav1.2 channels impairs hippocampal theta burst stimulation-induced long-term potentiation.

CACNA1 C, which codes for the Cav1.2 isoform of L-type Ca2+ channels (LTCCs), is a prominent risk gene in neuropsychiatric and neurodegenerative conditions. A role forLTCCs, and Cav1.2 in particular, in transcription-dependent late long-term potentiation (LTP) has long been known. Here, we report that elimination of Cav1.2 channels in glutamatergic neurons also impairs theta burst stimulation (TBS)-induced LTP in the hippocampus, known to be transcription-independent and dependent on N-methyl D-aspartate receptors (NMDARs) and local protein synthesis at synapses. Our expansion of the established role of Cav1.2channels in LTP broadens understanding of synaptic plasticity and identifies a new cellular phenotype for exploring treatment strategies for cognitive dysfunction.