Exposure to stress induces alterations in synaptic functions, and increases the risk of stress-related psychiatric disorders, such as major depression and PTSD. To develop new treatments for stress-related psychiatric disorders, it is important to understand the effect of stress on the emotional circuits, such as prefrontal cortex (PFC), amygdala and other limbic regions. The orbitofrontal cortex (OFC, ventral subregion of the PFC) has important roles for processing of negative emotion and has recently been highlighted as a critical region in stress-related psychiatric disorders. However, mechanisms how stress affect OFC circuit and induce psychiatric symptoms were less understood. OFC sends dense projection to the amygdala, which is one of the key nodes for processing of negative emotion. Taken together, there is a possibility that stress affects the information processing in the OFC-amygdala pathway, and it underlies stress-induced emotional alteration. In this article, we introduce our research that examined effects of stress on the excitatory synaptic transmission from OFC to the basolateral nucleus of the amygdala (BLA) using optogenetic and whole-cell patch-clamp methods in mice.
Neurons communicate with other cells via long processes, i.e., axons and dendrites, functionally and morphologically specialized tree-like structures. Formation and maintenance of such processes play a crucial role in neuronal functions. Axons are particularly important for construction of neuronal network, and, together with synapses at the end of them, play a central role in transmission of information. Axonal degeneration, a phenomenon that once formed axons lose structural integrity, is most typically observed as “Wallerian degeneration”, in which injured axonal segment (distal to the site of injury) degenerates. Different forms of axonal degeneration are also observed in a variety of contexts, including pathogenesis and progression of different neurodegenerative disorders, as well as neuronal network formation during development. Thus, understanding of regulatory mechanism of axonal degeneration is important in many aspects, such as for clarification of neuronal morphogenesis mechanism, and for development of neuroprotective therapy against neurological disorders. Here, I discuss recent progress in the research field of axonal degeneration mechanism.
The basal levels of intracellular Zn2+ and extracellular Zn2+ are in the range of ~100 pM and ~10 nM, respectively, in the hippocampus. Extracellular Zn2+ dynamics, which serves bidirectionally and involved in cognitive activity and cognitive decline, is modified by extracellular glutamate signaling and the presence of amyloid-β1-42 (Aβ1-42), a causative peptide in Alzheimer’s disease (AD) pathogenesis. When human Aβ1-42 reaches 100–500 pM in the extracellular compartment of the rat hippocampus, Zn-Aβ1-42 complexes are produced and readily taken up into dentate granule cells in a synaptic activity-independent manner. Furthermore, intracellular Zn-Aβ1-42 complexes release Zn2+ followed by intracellular Zn2+ dysregulation. Aβ1-42-mediated intracellular Zn2+ toxicity is accelerated with aging, because extracellular Zn2+ is age-relatedly increased. We have reported that Aβ1-42 released physiologically from neuron terminals disrupts intracellular Zn2+ homeostasis, resulting in age-related cognitive decline and neurodegeneration. Metallothioneins (MTs), zinc-binding proteins can capture Zn2+ released from intracellular Zn-Aβ1-42 complexes and serve for intracellular Zn2+-buffering under acute intracellular Zn2+ dysregulation. Aβ1-42-induced pathogenesis leads the AD development and its defense strategy may prevent the development. This review summarizes extracellular Zn2+-dependent Aβ1-42 neurotoxicity, which is accelerated with aging, and the potential defense strategy against AD.
Parkinson’s disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.
Recent studies have revealed that neuroimmune system is involved in the brain development and the pathogenesis of neurological diseases. However, it remains unclear how neuroimmune system modulates brain functions at a molecular level. We identified the role of immune cells in brain development and inflammatory neurological diseases. We demonstrated that B cells were abundant in the developing brain, and contribute to myelination by promoting the proliferation of oligodendrocyte precursor cells. In other study, we identified the role of microglia, which are immune cells in central nervous system, in the progression of autoimmune encephalomyelitis. We depleted microglia by PLX3397, an inhibitor of colony-stimulating factor receptor 1 (CSF-1R), in autoimmune encephalomyelitis, and showed that microglia regulate the T cell proliferation and differentiation during disease progression. In this article, we introduce the recent findings of the role of neuroimmune system in the brain development and pathogenesis of neurological diseases.
In 2020, the number of nursing universities in Japan increased to 274. One out of three universities has a nursing school, and the number of nursing universities continues to increase. The Ministry of Education, Culture, Sports, Science and Technology introduced the “Model Core Curriculum for Nursing Science Education in Japan” (MCCNSE) in 2017. The MCCNSE aims to include indispensable nursing competencies to the undergraduate course, enumerating the learning targets that will be useful for students. The MCCNSE includes seven aspects that aim to develop the qualities and abilities of a nurse for a lifetime. A consists of the basic qualities/abilities required by nursing professionals. B comprises social and nursing science. C consists of the basic knowledge necessary for understanding the objectives of nursing, including pharmacological science. D includes basic knowledge of the specialty underlying nursing practice. E comprises the basic knowledge necessary for nursing practice in various settings. F relates to clinical and regional training practice, and G includes research in nursing science. Nursing universities are required to comply with both the School Education Act and the Act on Public Health Nurses, Midwives, and Nurses. Nursing universities are expected to formulate a more complete and original curriculum based on the revision of Rules for the Designation of Public Health Nurses, Midwives, Nursing Schools, and Training Schools.
There are a wide variety of drugs used in acute care hospitals. When giving medication, the nurse must first understand the instructions and decide whether the instructions are safe for the patient or can be implemented by the nurse. Then, after the work of preparing the drug, he plays the role of giving the drug by using nursing techniques such as injection, infusion, and tube injection as the final performer. In addition, it plays a role in observing the patient’s reaction and promptly responding to any abnormalities. The medication by nurses is a very important, responsible and complex task. In clinical field, we are working to improve knowledge about drugs and simplify work in order to avoid medical accidents caused by medication. However, incidents of medication by nurses have not diminished, and serious medical accidents have not disappeared. In clinical field, we are exploring how to improve the education system and working environment. Appropriate judgment and reliable medication technology are required to safely administer medication. The basis for this is understanding of treatment and knowledge of drugs. What we hope for basic nursing education from the clinical field is to deepen our understanding of the pathophysiology and treatment methods of diseases, the various actions of drugs and their mechanisms, and to practice learning about the dangers hidden in medications performed by nurses.
Midwives are responsible professionals who support the sexual and reproductive health, rights, and welfare of individuals, families, and communities. In particular, midwives work in partnership with women to provide the necessary support, care and advice needed during pregnancy, childbirth and the postpartum period. Midwives conduct normal births on her own responsibility, support breastfeeding, provide care for newborns and infants, and fully release mother-infant’s latent strengths. Midwives also contribute in adopting appropriate preventative measures to promote normal birth and breastfeeding, detecting early signs of complications, and carrying out emergency measures or transferring the patient to other medical care or assistance as needed. In order to provide the best care to mother and infant, midwives should first learn the biological foundations of women’s health, pregnancy, childbirth, postpartum, breastfeeding, and infant health. They must also understand the in vivo mechanisms and actions of the key hormones and neurotransmitters in play during the reproductive period. Additionally, midwives need to learn pharmaceutical treatments to complement and support biological function in cases of disorders or impairments occurring in women and infants. Midwives should also be competent in life support skills in obstetrics and neonatal cardiopulmonary resuscitation. The directors of Japanese Maternity Centers sign a contract with obstetricians that permits them to purchase and use emergency medicines. We facilitate midwifery students in their studies of medicine and pharmacology in order to train them to cope with such emergency situations. In this revision of the midwifery curriculum and the continuing education, we hope to create a new midwifery educational program focusing on personalized, client-centered pharmacology, with the ultimate objective to support and maintain the health of women, mothers, infants, child-rearing families, and communities.
In nursing degree course education, it is needed to enhance contents of pharmacology education for acquiring nursing practice ability in the nursing education model core curriculum and revision of designation regulations. Therefore, it is intended to consider pharmacology education in nursing degree course in universities in the current study in order to cultivate nurses skilled in drug therapy. We have conducted a survey on knowledge required for students of universities of nursing as well as an analysis on contents of inquiries made by nurses on drugs. As a result, it has been revealed that students have recognized effect and side effects of drugs as basic knowledge required for a nurse. With less recognition required on pharmacokinetics and practical contents, however, the knowledge held by students was dissociated with practical knowledge often required for nurses when administering drugs. A possibility has been also revealed by the current survey that nurses may not be able to make use of pharmacokinetics as pharmacological knowledge for patients’ treatment management. From results of the survey and previous study, it is believed to be necessary in university education to extend pharmacological knowledge from its basic to clinical stage and build up adequate basic knowledge and thinking power of pharmacology in nursing degree course as well as to sufficiently learn and understand necessity of pharmacokinetics for conducting evaluation of drug efficacy.
Predicting drug-induced side effects in central nervous system is important because they can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although many efforts are made, evaluation system using animals have not been highly predictive in humans. In addition, animal experiments are time-consuming and costly. To address these issues, in vitro evaluation methods, such as the use of New Approach Methodologies (NAM) have been explored. Human iPS cell technology has already been applied to assess drug-induced cardiotoxicity. In addition, the use of human iPS cell technology and in silico has been promoted for neurotoxicity assessment during the developmental neurotoxicity in terms of chemical safety issues. Organization for Economic Cooperation and Development (OECD) guidance regarding developmental neurotoxicity is under preparation. In this review, we will review the current trends in safety assessment methods for the central nervous system in light of these international trends.
Orexin receptor antagonists have been approved for insomnia, and the insomnia pharmacotherapy is being greatly progressed. Orexin is a neuropeptide produced in the lateral hypothalamic area, and its physiological role has been suggested to be a key mediator controlling the sleep-wake state. Orexin receptor antagonists are thought to induce physiological sleep by acting specifically on the sleep-wake cycle. Lemborexant is a dual antagonist acting on both two orexin receptors, the orexin 1 (OX1R) and 2 receptor (OX2R), with stronger inhibitory effects on OX2R. Since it binds to and dissociates from orexin receptors rapidly, the pharmacokinetics of its blood concentration may have an impact on its pharmacological action. In rats, lemborexant exhibited a sleep-inducing effect without altering sleep architecture. In the phase III studies in patients with insomnia, lemborexant significantly improved difficulties in falling asleep and maintaining sleep. While somnolence occurred as treatment-related adverse events in a dose-dependent manner, lemborexant was generally well-tolerated. Also, the effects on body sway and driving skills 8–9 hours after administration did not differ from those in the placebo group, suggesting little next morning residual effects. Subgroup analysis has shown that efficacy and safety of lemborexant were similar in patients with insomnia with comorbidities, suggesting lemborexant may also be useful for those patients. Based on the above results and others, lemborexant has been approved for the indication of insomnia in January 2020 in Japan. Lemborexant will give a new treatment option for patients with insomnia.