Current Molecular Pharmacology - Volume 14, Issue 2, 2021

Background: Major depressive disorder (MDD) is a common psychological disorder worldwide. However, one-third of patients with MDD are resistant to the present anti-depressant medicine, which regulates monoamine contents in the brain. Thus, another drug target is strongly required. Much evidence strongly suggests that sirtuin1, which is the key factor in regulating the mitochondrial activity, may be implicated in MDD. Objective: Since it is suggested that royal jelly (RJ) ameliorated depressive-like behavior and affected mitochondrial activity in mice, we hypothesized that RJ could be an alternative medicine against MDD, which acts via sirtuin1 signaling to improve mitochondrial activity. Methods: In the present study, we applied a mouse model of MDD to investigate the effect of RJ on the depressive-like behavior and the sirtuin1 signaling on mitochondrial activity. Results: Our results indicated that either the oral administration of RJ for 12 days or single intracerebroventricular (i.c.v.) injection decreased the duration of immobility in the tail suspension test, which suggested that RJ had an antidepressant-like effect. Moreover, sirtuin1 protein expression increased in mice following RJ treatment in the amygdala region, but not in the other brain regions. Similarly, the expressions of oxidative phosphorylation (OXPHOS) related proteins increased in the amygdala regions, but not in the hippocampal regions. Conclusion: The increase of sirtuin1 and OXPHOS protein expression may at least in part contribute to the antidepressant-like effect of the RJ pathway, and RJ may have the potential to be a novel anti-depressant drug.

Transient receptor potential (TRP) channels, especially canonical TRP channel subfamily members 3 (TRPC3) and 6 (TRPC6), have gained attention as a putative therapeutic target of heart failure. Moreover, TRPC3 and TRPC6 channels are physiologically important for maintaining cellular homeostasis. How TRPC3/C6 channels alter intracellular signaling from adaptation to maladaptation, has been discussed for many years. We have recently shown that the formation of a protein signal complex between TRPC3 and NADPH oxidase (Nox) 2 caused by environmental stresses (e.g., hypoxia, nutritional deficiency, and anti-cancer drug treatment) promotes Nox2-dependent reactive oxygen species production and cardiac stiffness, including myocardial atrophy and interstitial fibrosis, in rodents. In fact, pharmacological prevention of the TRPC3 -Nox2 protein complex can maintain cardiac flexibility in mice after anti-cancer drug treatment. In this mini-review, we discuss the relationship between TRPC3/C6 channels and cardiovascular disease, and propose a new therapeutic strategy by focusing on pathology-specific protein-protein interactions.

Delirium is a very common but annoying clinical state that interferes with the treatment of background disease and delays recovery. Delirium is a troublesome condition that exhausts not only the patient but also his/her family and healthcare professionals. Since aging is a risk factor for delirium, how to control delirium is an extremely important issue in an aging society. Phenotype of delirium is so diverse that it is difficult to elucidate the mechanism of individual symptoms, but it is clinically well known that maintaining sleep quality is important in preventing and improving delirium. Drugs and factors that are known to disrupt the sleep-wake cycle also overlap with the risk factors for delirium, indicating the close connection between delirium and sleep. Although the sleep-wake cycle is tightly regulated by many neurotransmitters and hormones, the role of each substance in this cycle is being elucidated in detail. It is well known that acetylcholine is one of the most important neurotransmitters involved in wakefulness, and anticholinergic drugs reduce rapid eye movement sleep. Anticholinergic drugs are also the major drug causing drug-induced delirium. Several clinical studies have reported that melatonin receptor agonists reduce delirium. Some clinical studies have examined the relationship between delirium and environmental factors that interfere with sleep, such as noise and brightness. The purpose of this review is to organize the cause of poor sleep underlying delirium and propose strategies to prevent delirium, based on rich neurological and pharmacological findings of sleep. We consider that elimination of causes of sleep deprivation underlying delirium is one of the most effective prevention strategies for delirium.

We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δGABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.

Background: Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the body and then mediates several physiological functions. The pharmacological effects of melatonin can be mediated through its direct antioxidant activity and receptor-dependent signaling. Objective: This article will mainly review receptor-dependent signaling. Human melatonin receptors include melatonin receptor type 1 (MT1) and melatonin receptor type 2 (MT2), which are widely distributed throughout the brain. Result: Several lines of evidence have revealed the involvement of the melatonergic system in different neurodegenerative diseases. Alzheimer’s disease pathology negatively affects the melatonergic system. Melatonin effectively inhibits β-amyloid (Aβ) synthesis and fibril formation. These effects are reversed by pharmacological melatonin receptor blockade. Reductions in MT1 and MT2 expression in the amygdala and substantia nigra pars compacta have been reported in Parkinson’s disease patients. The protective roles of melatonin against ischemic insults via its receptors have also been demonstrated. Melatonin has been reported to enhance neurogenesis through MT2 activation in cerebral ischemic/reperfusion mice. The neurogenic effects of melatonin on mesenchymal stem cells are particularly mediated through MT2. Conclusion: Understanding the roles of melatonin receptors in neuroprotection against diseases may lead to the development of specific analogs with specificity and potency greater than those of the original compound. These successfully developed compounds may serve as candidate preventive and disease-modifying agents in the future.

Objective: Osteoarthritis is a common disease of the joint cartilage. Since the molecular pathogenesis of osteoarthritis is not clearly understood, early diagnostic markers and effective therapeutic agents have not been developed. Methods and Results: In recent years, there are several studies to elucidate the molecular aspects based on mouse genetics by using a stress-induced mechanical load model. Chondrocyte hypertrophy, which is usually seen in growth plate chondrocyte, is also induced in articular cartilage and involved in the onset of osteoarthritis. Additionally, signal molecules involved in inflammatory cytokine and matrix proteinase are expected to be target molecules for the fundamental treatment of early osteoarthritis. Some additional signal molecules, transcription factors and compounds have been reported to be involved in cartilage homeostasis. Conclusion: This review sheds light on the current status of various signal molecules for the management of osteoarthritis.

Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors.

In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine- glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.

Arterial atherosclerosis is the main pathological cause of coronary artery disease and peripheral arterial disease. Atherosclerosis is a chronic condition characterized by the presence of cholesterol-rich macrophages in the arterial intima. Accumulation of cholesterol in these macrophages is due to increased oxidation of low-density lipoprotein (LDL) and its uptake via scavenger receptors on the macrophages. Cholesterol efflux from the cholesterol-laden macrophages into high-density lipoprotein (HDL) is also a key process in maintaining cholesterol homeostasis and preventing cholesterol accumulation. Four pathways for the efflux of cholesterol to HDL exist in macrophages, including passive and active pathways. Several HDL characteristics determine cholesterol efflux capacity, namely composition, oxidative status, and HDL size. Oxidation of LDL and HDL, as well as an imbalance in cholesterol uptake and efflux, could lead to the accumulation of cholesterol in macrophages and initiation of atherosclerogenesis. Epidemiological studies have demonstrated that polyphenol-rich foods reduce cardiovascular events in the general population and in patients at risk of cardiovascular diseases. Many studies have reported that polyphenols in polyphenol-rich foods have anti-atherosclerotic properties by preventing cholesterol accumulation in macrophages through the suppression of lipoproteins oxidation and regulation of cholesterol uptake and efflux.

IL-19 is a type of anti-inflammatory cytokine. Since the receptor for IL-19 is common to IL-20 and IL-24, it is important to clarify the role of each of the three cytokines. If three different cytokines bind to the same receptor, these three may have been produced to complement the other two. However, perhaps it is unlikely. Recently, the existence of a novel receptor for IL-19 was suggested. The distinction between the roles of the three cytokines still makes sense. On the other hand, because T cells do not produce IL-19, their role in acquired immunity is limited or indirect. It has been reported that IL-19 causes inflammation in some diseases but does not have an anti-inflammatory effect. In this review, we introduce the current role of IL-19 in each disease. In addition, we will describe the molecular mechanism of IL-19 and its development for the prevention of diseases. IL-19 was previously considered an anti-inflammatory cytokine, but we would like to propose it as an immunoregulatory cytokine.

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder commonly found in children, which is recognized by hyperactivity and aggressive behavior. It is known that the pathophysiology of ADHD is associated with neurobiological dysfunction. Although psychostimulants are recognized as the therapeutic drugs of choice for ADHD patients, the side effects might be of great concern. Ginkgo biloba is a promising herbal, complementary supplement that may modulate the neuronal system in an ADHD-like condition. The beneficial effect of Ginkgo biloba on ADHD-like symptoms may be related to the modulation of the system by novel molecular mechanisms. Ginkgo biloba is known to modulate dopamine, serotonin, and norepinephrine signaling. Flavonoid glycosides and terpene trilactones are the two major phytochemical components present in the Ginkgo biloba preparations, which can exhibit antioxidant and neuroprotective activities. The pharmacological mechanisms of the phytochemical components may also contribute to the neuroprotective activity of Ginkgo biloba. In this review, we have summarized recent findings on the potential of various Ginkgo biloba preparations to treat ADHD-like symptoms. In addition, we have discussed the pharmacological mechanisms mediated by Ginkgo biloba against an ADHD-like condition.

Among the various orphan G protein-coupled receptors, apelin receptor (APJ), originally identified in the human genome as an orphan G-protein-coupled receptor, was deorphanised in 1998 with the discovery of its endogenous ligand, apelin. Apelin and APJ mRNA are widely expressed in peripheral tissues and the central nervous system in mammals. In this review, we discuss the characteristics, pharmacology, physiology, and pathology of the apelin/APJ system in mammals. Several physiological roles of the apelin/APJ system have been reported, including in homeostasis, cardiovascular maintenance, angiogenesis, and neuroprotection. In cellular signaling, apelin has been shown to drive the PI3K/Akt, MAPK, and PKA signaling pathways, leading to cell proliferation and protection from excitotoxicity. Apelin is also found in breast milk; therefore, apelin is believed to contribute to the establishment of the infant immune system. Furthermore, activation of the apelin/APJ system is reported to restore muscular weakness associated with aging. Thus, the apelin/APJ system represents a novel target for the prevention of several important cardiovascular and neurodegenerative diseases and the maintenance of health during old age.

Background: The enhancement of learning and memory through food-derived ingredients is of great interest to healthy individuals as well as those with diseases. Ergothioneine (ERGO) is a hydrophilic antioxidant highly contained in edible golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), and systemically absorbed by its specific transporter, carnitine/organic cation transporter OCTN1/SLC22A4. Objective: This study aims to examine the possible enhancement of object recognition memory by oral administration of ERGO in normal mice. Methods: Novel object recognition test, spatial recognition test, LC-MS/MS, Golgi staining, neuronal culture, western blotting, immunocytochemistry, and quantitative RT-PCR were utilized. Result: After oral administration of ERGO (at a dose of 1–50 mg/kg) three times per week for two weeks in ICR mice, the novel object recognition test revealed a longer exploration time for the novel object than for the familiar object. After oral administration of ERGO, the spatial recognition test also revealed a longer exploration time for the spatially moved object than the unmoved one in mice fed ERGO-free diet. The discrimination index was significantly higher in the ERGO-treated group than the control in both behavioral tests. ERGO administration led to an increase in its concentration in the plasma and hippocampus. The systemic concentration reached was relevant to those found in humans after oral ERGO administration. Golgi staining revealed that ERGO administration increased the number of matured spines in the hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I. This elevation of synapsin I was inhibited by the tropomyosin receptor kinase inhibitor, K252a. Treatment with ERGO also increased the expression of neurotrophin-3 and -5, and phosphorylated mammalian target of rapamycin in hippocampal neurons. Conclusion: Oral intake of ERGO may enhance object recognition memory at its plasma concentration achievable in humans, and this enhancement effect could occur, at least in part, through the promotion of neuronal maturation in the hippocampus.

Background: Mutations in the brain-derived neurotrophic factor (BDNF) gene and its receptor, tyrosine receptor kinase B (TrkB), have been reported to cause severe obesity in rodents. Our previous study demonstrated that the oral administration of 5% Eucommia leaf extract (ELE) or ELE aroma treatment (ELE aroma) produced anti-obesity effects. Objective: In this study, we investigated the effects of ELE on glycolysis and lipid metabolism in male Sprague–Dawley rats, as well as the effects of ELE on BDNF in rat hypothalamus. Methods and Results: A significant reduction and a reduction tendency in the respiratory quotient were observed in association with 5% ELE and ELE aroma treatment, respectively. Furthermore, RT-qPCR results showed significant increases in Cpt2, Acad, Complex II, and Complex V mRNA levels in the liver with both treatments. In addition, in rat hypothalamus, significant elevations in BDNF, Akt, PLCγ proteins and CREB phosphorylation were observed in the 5% ELE group and the ELE aroma group. Furthermore, the Ras protein was significantly increased in the ELE aroma group. On the other hand, significant dephosphorylation of ERK1/2 was observed by the western blotting in the 5% ELE group and the ELE aroma group. Conclusion: These findings suggest that the ELE treatment enhances the lipid metabolism and increases the aerobic glycolytic pathway, while ELE-induced BDNF may affect such energy regulation. Therefore, ELE has the possibility to control metabolic syndrome.

Background: Decreases in female hormones not only affect bone metabolism and decrease bone mass, but also affect the central nervous system, causing brain disorders such as depression and dementia. Administration of estradiol by hormone replacement therapy can improve dementia, while reduced estradiol in ovariectomized (OVX) model rats can reduce both bone density and locomotor activity. The antidepressant fluvoxamine, which is widely used in clinical practice, can improve this effect on locomotor reduction. Similarly, lactoferrin (LF) can reportedly improve inhibitory locomotion due to stress. Objective: In this study, we examined the effect of LF on neurite outgrowth

Aims: To show that acetate attenuates neuroinflammatory responses in activated microglia. Background: Dietary acetate supplementation alleviates neuroglial activation in a rat model of neuroinflammation induced by intraventricular administration of lipopolysaccharide (LPS). However, the precise mechanism(s) underlying the anti-inflammatory effect of acetate, is not fully understood. Objective: To determine whether acetate has inhibitory effects on LPS-induced neuroinflammatory responses in microglia. Methods: We examined LPS-stimulated nitric oxide (NO) production in primary rat microglia and BV-2 cells. Protein expression of inducible NO synthase (iNOS) was determined by western blot analysis. The intracellular generation of reactive oxygen species (ROS) and glutathione (GSH) were also evaluated. Results: In primary microglia, acetate decreased LPS-stimulated NO production in a dose-dependent manner, reaching significance at greater than 10 mM, and cell viability was not affected. Acetate suppressed LPS-induced expression of iNOS protein concomitantly with the decrease in NO. The LPS-induced increase in intracellular ROS production was attenuated by acetate. In addition, acetate prevented LPS-induced reduction of GSH. Notably, such suppressive effects of acetate on NO and ROS production were not observed in BV-2 cells. Conclusion: These findings suggest that acetate may alleviate neuroinflammatory responses by attenuating NO and ROS production in primary microglia but not in BV-2 cells. Other: All animals received humane care, and the animal protocols used in this study were approved by the Ethics Committees for Animal Experimentation.