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Significance Chronic neurodegeneration, a major cause of the long-term disabilities that afflict survivors of traumatic brain injury (TBI), is linked to an increased risk for late-life neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, vascular dementia, and chronic traumatic encephalopathy. Here, we report on the restoration of blood–brain barrier (BBB) structure and function by P7C3-A20 when administered 12 mo after TBI. This pharmacotherapy was associated with cessation of chronic neurodegeneration and recovery of normal cognitive function, benefits that persisted long after treatment cessation. Pharmacologic renewal of BBB integrity may thus provide a new treatment option for patients who have suffered a remote TBI, or other neurological conditions associated with BBB deterioration., Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood–brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer’s disease, Parkinson’s disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.

Chronic stress during pregnancy harms both the mother and developing child, and there is an urgent unmet need to understand this process in order to develop protective treatments. Here, we report that chronic gestational stress (CGS) causes aberrant maternal care behavior in the form of increased licking and grooming, decreased nursing, and increased time spent nest building. Treatment of CGS-exposed dams with the NAD(+)-stabilizing agent P7C3-A20 during pregnancy and postpartum, however, preserved normal maternal care behavior. CGS also caused abnormally low weight gain during gestation and postpartum, which was partially ameliorated by maternal treatment with P7C3-A20. Dams also displayed hyperactive locomotion after CGS, which was not affected by P7C3-A20. Although dams did not display a classic depressive-like phenotype after CGS, some changes in anxiety- and depressive-like behaviors were observed. Our results highlight the need for further characterization of the effects of chronic gestational stress on maternal care behavior and provide clues to possible protective mechanisms.

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.

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer’s disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 (K(i) = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.

IMPORTANCE: Use of electronic cigarettes (often called e-cigarettes) has increased considerably among young people in the past 5 years. Use of e-cigarettes has been associated with higher rates of marijuana use, which is associated with several adverse health outcomes in youth. OBJECTIVE: To characterize and quantify the association between e-cigarette and marijuana use among youth using a meta-analysis. DATA SOURCES: PubMed, Embase, and Web of Science & ProQuest Dissertations and Theses were searched from inception to October 2018. A gray-literature search was also conducted on conference abstracts, government reports, and other sources. STUDY SELECTION: Included studies compared rates of marijuana use among youth aged 10 to 24 years who had used e-cigarettes vs those who had not used e-cigarettes. Two reviewers independently assessed studies for inclusion; disagreements were discussed with a third reviewer and resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent reviewers following Meta-analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines and pooled using a random-effects analysis. The Newcastle-Ottawa Scale was used to assess data quality and validity of individual studies. MAIN OUTCOMES AND MEASURES: Adjusted odds ratios (AORs) of self-reported past or current marijuana use by youth with vs without past or current e-cigarette use. RESULTS: Twenty-one of 835 initially identified studies (2.5%) met selection criteria. The meta-analysis included 3 longitudinal and 18 cross-sectional studies that included 128 227 participants. Odds of marijuana use were higher in youth who had an e-cigarette use history vs those who did not (AOR, 3.47 [95% CI, 2.63-4.59]; I(2), 94%). Odds of marijuana use were significantly increased in youth who used e-cigarettes in both longitudinal studies (3 studies; AOR, 2.43 [95% CI, 1.51-3.90]; I(2), 74%) and cross-sectional studies (18 studies; AOR, 3.70 [95% CI, 2.76-4.96]; I(2), 94%). Odds of using marijuana in youth with e-cigarette use were higher in adolescents aged 12 to 17 years (AOR, 4.29 [95% CI, 3.14-5.87]; I(2), 94%) than young adults aged 18 to 24 years (AOR, 2.30 [95% CI, 1.40-3.79]; I(2), 91%). CONCLUSIONS AND RELEVANCE: This meta-analysis found a significant increase in the odds of past or current and subsequent marijuana use in adolescents and young adults who used e-cigarettes. These findings highlight the importance of addressing the rapid increases in e-cigarette use among youths as a means to help limit marijuana use in this population.

Development of the brain prenatally is affected by maternal experience and exposure. Prenatal maternal psychological stress changes brain development and results in increased risk for neuropsychiatric disorders. In this review, multiple levels of prenatal stress mechanisms (offspring brain, placenta, and maternal physiology) are discussed and their intersection with cellular stress mechanisms explicated. Heat shock factors and oxidative stress are closely related to each other and converge with the inflammation, hormones, and cellular development that have been more deeply explored as the basis of prenatal stress risk. Increasing evidence implicates cellular stress mechanisms in neuropsychiatric disorders associated with prenatal stress including affective disorders, schizophrenia, and child-onset psychiatric disorders. Heat shock factors and oxidative stress also have links with the mechanisms involved in other kinds of prenatal stress including external exposures such as environmental toxicants and internal disruptions such as preeclampsia. Integrative understanding of developmental neurobiology with these cellular and physiological mechanisms is necessary to reduce risks and promote healthy brain development.