Systemic Administration of Porphyromonas Gingivalis Lipopolysaccharide Induces Glial Activation and Depressive-Like Behavior in Rats.

BACKGROUND: Periodontitis is one of the most common chronic inflammatory disorders in adults. Although clinical studies have suggested a causal relationship between periodontitis and major depression (MD), the biological mechanisms by which periodontitis instigates MD are unknown. We investigated whether a systemic administration of lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg), a major Gram-negative pathogen of periodontitis, causes depressive-like behavior and glial activation in the hippocampus and the prefrontal cortex (PFC), which are MD-related brain regions. MATERIALS AND METHODS: Eight-week-old male Sprague Dawley rats were randomly divided into a behavioral test group and an immunohistochemistry group. The rats in each group were further assigned to the sham injection (saline) and Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) injection protocols. The rats received an intraperitoneal injection of saline or Pg-LPS with gradually increasing doses (day 1: 0.5, day 2: 0.5, day 3: 0.75, day 4: 0.75, day 5: 1.0, day 6: 1.0, and day 7: 1.0 mg/kg of body weight) for seven consecutive days. After the systemic administration, the behavior test group underwent the forced swimming test (FST) and Y-maze test. For the immunohistochemistry group, we quantified the immunoreactivity for microglial Iba-1 (ionized calcium-binding adapter molecule 1) and astrocytic glial fibrillary acidic protein (GFAP) in the hippocampus (dentate gyrus [DG], cornu ammonis [CA1 and CA3]) and PFC (prelimbic [PrL] and the infralimbic [IL]) areas. RESULTS: The FST immobility time in the Pg-LPS group was significantly longer than that in the sham group. In the Y-maze test, a significant decline in spontaneous alternation behavior was observed in the Pg-LPS group compared to the sham group. The peripheral administration of Pg-LPS significantly increased the immunoreactivity for Iba-1 in the CA3 and PrL. Pg-LPS injection significantly increased the immunoreactivity for GFAP in the DG, CA1, and CA3. CONCLUSIONS: The major result of this study is that a repeated systemic administration of Pg-LPS caused depressive-like behavior and both microglial and astrocytic activation in rats. This finding may comprise biological evidence of a causal relationship between periodontitis and MD.

Video polysomnographic analysis of elevated EMG activity and rapid eye movements before abnormal behaviors in REM sleep behavior disorder.

The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is unclear. According to the cortical hypothesis, severe RBD episode (RBDE) occurs when spinal motoneurons are less inhibited and cortical and limbic systems are more active. We made this study to prove the hypothesis for the development of RBDE using video-polysomnography (VPSG). VPSG records of 35 patients with RBD were analyzed. According to severity, RBDEs were classified into three motor events (MEs): ME 1; small movements or jerks, ME 2; proximal movements including violent behavior, and ME 3; axial movements including bed falls. For each ME, we measured the number of MEs preceded or not preceded by both REM sleep without atonia (RWA) and REMs during the 10-s-period immediately before ME onset. In severe RBDE (ME 3), the number of MEs preceded by both RWA and REMs was significantly higher than that of MEs not preceded by both (0.8 vs. 0.2, P = 0.033). This was not the case for mild RBDE (ME 1) and moderate RBDE (ME 2). Our results suggest that both RWA and REMs are associated with the development of severe RBDE.

Normalizing hyperactivity of the Gunn rat with bilirubin-induced neurological disorders via ketanserin.

BACKGROUND: Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear. METHODS: The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses. RESULTS: Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat. CONCLUSIONS: It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations. IMPACT: We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations. Ketanserin normalizes hyperlocomotion of Gunn rats. To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

Urinary biopyrrins and free immunoglobin light chains are biomarker candidates for screening at-risk mental state in adolescents.

BACKGROUND: Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. AIM: In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. METHODS: Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. RESULTS: Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. CONCLUSION: Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.

Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease.

Astrocytes contribute to brain development and homeostasis and support diverse functions of neurons. These cells also respond to the pathological processes in Alzheimer's disease (AD). There is still considerable debate concerning the overall contribution of astrocytes to AD pathogenesis since both the protective and harmful effects of these cells on neuronal survival have been documented. This review focuses exclusively on the neurotoxic potential of astrocytes while acknowledging that these cells can contribute to neurodegeneration through other mechanisms, for example, by lowered neurotrophic support. We identify reactive oxygen and nitrogen species, tumor necrosis factor α (TNF-α), glutamate, and matrix metalloproteinase (MMP)-9 as molecules that can be directly toxic to neurons and are released by reactive astrocytes. There is also considerable evidence suggesting their involvement in AD pathogenesis. We further discuss the signaling molecules that trigger the neurotoxic response of astrocytes with a focus on human cells. We also highlight microglia, the immune cells of the brain, as critical regulators of astrocyte neurotoxicity. Nuclear imaging and magnetic resonance spectroscopy (MRS) could be used to confirm the contribution of astrocyte neurotoxicity to AD progression. The molecular mechanisms discussed in this review could be targeted in the development of novel therapies for AD.

Magnetic Resonance Spectroscopy in the Ventral Tegmental Area Distinguishes Responders to Suvorexant Prior to Treatment: A 4-Week Prospective Cohort Study.

Background: The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant. Methods: A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration). Results: Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders (p = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio (p = 0.297) between the two groups. Conclusions: Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells.

Psychosis in a primary hyperparathyroidism patient with mild hypercalcemia: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

Prompt improvement of difficulty with sleep initiation and waking up in the morning and daytime somnolence by combination therapy of suvorexant and ramelteon in delayed sleep-wake phase disorder: a case series of three patients.

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients.

Glia-Driven Neuroinflammation and Systemic Inflammation in Alzheimer's Disease.

The neuroinflammatory hypothesis of Alzheimer's disease (AD) was proposed more than 30 years ago. The involvement of the two main types of glial cells microglia and astrocytes, in neuroinflammation, was suggested early on. In this review, we highlight that the exact contributions of reactive glia to AD pathogenesis remain difficult to define, likely due to the heterogeneity of glia populations and alterations in their activation states through the stages of AD progression. In the case of microglia, it is becoming apparent that both beneficially and adversely activated cell populations can be identified at various stages of AD, which could be selectively targeted to either limit their damaging actions or enhance beneficial functions. In the case of astrocytes, less information is available about potential subpopulations of reactive cells; it also remains elusive whether astrocytes contribute to the neuropathology of AD by mainly gaining neurotoxic functions or losing their ability to support neurons due to astrocyte damage. We identify L-type calcium channel blocker, nimodipine, as a candidate drug for AD, which potentially targets both astrocytes and microglia. It has already shown consistent beneficial effects in basic experimental and clinical studies. We also highlight the recent evidence linking peripheral inflammation and neuroinflammation. Several chronic systemic inflammatory diseases, such as obesity, type 2 diabetes mellitus, and periodontitis, can cause immune priming or adverse activation of glia, thus exacerbating neuroinflammation and increasing risk or facilitating the progression of AD. Therefore, reducing peripheral inflammation is a potentially effective strategy for lowering AD prevalence.

Real-World Preventive Effects of Suvorexant in Intensive Care Delirium: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown. METHODS: A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay. RESULTS: There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013). CONCLUSIONS: The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

Drug offenses in the Tokyo Metropolitan Area: Trends for 2016-2018.

In Japan over the past few years, approximately 13,000 individuals were arrested for drug offenses each year. It is useful to know the trends in drug offenses, in order to devise the most effective countermeasures and addiction treatment programs. Herein, we have revealed the trends in drug offenses in the Tokyo Metropolitan Area. This report was researched the number of individuals arrested for drug offenses in Tokyo during the 3-year study period 2016-2018. The drugs are classified into the six categories: stimulants, narcotics, psychoactive drugs, opium, cannabis, and designated substances. We also calculated the percentages of individuals arrested for various drug offenses based on these six categories. Approximately 86% of the arrests for drug offenses in Tokyo during the 3-year period were for stimulants or cannabis. A higher percentage of individuals were arrested for stimulants, but the percentage of individuals arrested for cannabis increased each year. Given the percentage of individuals arrested for designated substances or narcotics, preventive measures for drug offenses involving stimulants and cannabis should be promptly implemented. Further campaigns to prevent drug offenses and public lectures are also needed. Public education must be provided to prevent drug offenses involving designated substances and narcotics.

Low Serum Levels of Fibroblast Growth Factor 2 in Gunn Rats: A Hyperbilirubinemia Animal Model of Schizophrenic Symptoms.

BACKGROUND: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons. METHOD: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. RESULTS: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. CONCLUSION: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.