Neurosignals最新文献

The antiaging protein Klotho is encoded by the Klotho gene first identified as an 'aging suppressor', in mice. Klotho deficiency is involved in premature aging and early death, while its overexpression is related to longevity. Klotho is mostly expressed in the kidney, but also in the brain, and in other organs. Two forms of Klotho, the cell membrane and secreted form, have pleiotropic activities that include regulation of general metabolism, oxidative stress, and mineral metabolism that correlates with its effect on accelerating aging. Membrane Klotho serves as an obligate co-receptor for the fibroblast growth factor (FGF), while secreted Klotho plays its role as a humoral factor. Klotho protein participates in the regulation of several biological activities, including regulation of calcium-phosphate homeostasis and PTH as well as vitamin D metabolism. The active form of vitamin D, 1,25(OH)₂D₃ (1,25-dihydroxy-vitamin D3 = calcitriol), acts as a neurosteroid that participates in the regulation of multiple brain functions. It provides neuroprotection and suppresses oxidative stress, inhibits inflammation and inflammatory mediators, and stimulates various neurotrophins. Calcitriol is involved in many brain-related diseases, including multiple sclerosis, Alzheimer´s disease, Parkinson´s disease, and schizophrenia. This review covers the most recent advances in Klotho research and discusses Klotho-dependent roles of calcitriol in neuro-psycho-pathophysiology.

Background/aims: Neuroendocrine dysregulation has been associated with rheumatoid arthritis (RA). Tyrosine hydroxylase (TH), a rate-limiting enzyme for synthesis of neuroendocrine hormones such as epinephrine, is also expressed in T lymphocytes and regulates balance between helper T (Th) 17 cells and regulatory T (Treg) cells. Herein, we aimed to show that TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in collagen-induced arthritis (CIA), an animal model of RA, and these effects may be implemented by the mechanism of epinephrine action on α1-adrenoreceptor (α1-AR) in T cells.

Methods: CIA was prepared by intradermal injection of collagen type II in tail base of DBA1/J mice. On the 33rd day post-immunization, lentiviral vectors encoding TH or TH shRNA were injected into ankle joints of CIA mice. Limb inflammation of the mice was assessed beginning from day 21 until day 69 post-immunization by measurement of limb swelling, erythema and rigidity. Th17 and Treg differentiation and function in ankle joints were assessed on day 69 post-immunization by test of the expression of Th17 transcriptional factor ROR-γt and the levels of proinflammatory cytokines interleukin (IL)-17 and IL-22 as well as the expression of Treg transcriptional factor Foxp3 and the levels of antiinflammatory cytokines transforming growth factor (TGF)-β1 and IL-10. T cells were obtained from the spleen of mice that had been immunized with collagen type II 41 day earlier and treated with epinephrine or α1-AR agonist phenylephrine in vitro. Flow cytometry was used to analyze the percentages of CD25^-IL-17⁺ cells and CD25⁺Foxp3⁺ cells in CD4⁺ T cells.

Results: TH gene overexpression in ankle joints of CIA mice reduced limb inflammation and Th17-related transcription factor expression and inflammatory cytokine production but increased Treg-related antiinflammatory cytokine production in the joints. In contrast, TH gene silence in ankle joints of CIA mice enhanced limb inflammation and Th17 cell activity but decreased Treg cell function in the joints. Epinephrine upregulated α1-AR expression in T cells derived from CIA mice. Both epinephrine and phenylephrine reduced CIA-induced Th17 transcription factor expression and inflammatory cytokine production but enhanced Treg antiinflammatory cytokine production in vitro.

Conclusion: Upregulating TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in CIA at least partially by enhancing epinephrine action on α1-AR in T cells.

The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson's disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson's disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson's disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca²⁺ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)₂D₃ (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)₂D₃ production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)₂D₃ formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)₂D₃ formation, an effect requiring Klotho. 1,25(OH)₂D₃ is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)₂D₃ and excessive 1,25(OH)₂D₃ formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)₂D₃ is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)₂D₃ suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)₂D₃ is considered to favorably influence the clinical course of Parkinson's disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson's disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)₂D₃ in the pathophysiology of Parkinson's disease and its sensitivity to milk consumption.

Background/aims: Fluids of the human body such as serum, cerebrospinal fluid and saliva contain a wide variety of proteins. Because kynurenic acid (KYNA) has been detected in human saliva, we wondered if KYNA could be produced in saliva by KYNA-synthesising enzymes, namely the kynurenine aminotransferases KAT I, KAT II and KAT III.

Methods: Thirty samples of human saliva from control volunteers were investigated. KAT activity was measured in the presence of 1 mM pyruvate and 2 µM or 100 µM L-kynurenine and KYNA production was assessed by high-performance liquid chromatography.

Results: Saliva dose- and time-dependently produced KYNA. KAT activity ranged between 900 and 1050 pmol/mg protein/h: 900 for KAT I, 950 for KAT III and 1050 for KAT II. KYNA was synthesised in saliva at a physiological concentration of 2 µM L-kynurenine and at a higher concentration of 100 µM. Investigation of the distributions of the enzymes in saliva revealed that KAT I, KAT II and KAT III activity in a centrifuge-obtained pellet ranged from ~100% to 120%; in the supernatant, the percentage was between 0% and 20%. We observed a nonsignificant tendency for lower KAT activity in women's saliva than in men's. KATs present in saliva were sensitive to the GABA-transaminase inhibitor γ-acetylenic GABA, with a concentration of 100 µM γ-acetylenic GABA significantly blocking the formation of KYNA (50% of control, p < 0.05). Furthermore, KATs in saliva were sensitive to anti-dementia drugs, such as D-cycloserine and cerebrolysin, in an in vitro study.

Conclusion: Our data revealed for the first time the presence of KAT I, KAT II and KAT III proteins in human saliva. KAT activity was found mostly in pelleted cells, suggesting their presence in salivary gland cells. KAT proteins in saliva are sensitive to drugs blocking KYNA formation. Our data indicate the presence of cells in saliva involved in the biochemical machinery of the kynurenine pathway. Their role in the digestive process remains to be clarified. We speculate that modulation of KYNA formation in the mouth by food and/or drugs might affect glutamate neurotransmission and cholinergic activity in the CNS and/or periphery and play a role under physiological as well as pathological conditions.

While the role of interferon during systemic disease is well known and its immune modulating functions and its role in antiviral activity were extensively studied, the role of IFN-I in the brain is less clear. Here we summarize the most important literature on IFN in homeostasis of the CNS and induction of an IFN response during viral infection in the brain. Furthermore, we present work on the roles of IFN in the developing brain as well as during inflammation in the brain. Lastly, we aim to enlighten the functions of IFN on the blood-brain barrier as well as circulation and in cognitive and psychological functions and degeneration. In short, CNS astrocytes produce IFN-β, which is of high relevance for homeostasis in the brain. IFN-β regulates phagocytic removal of myelin debris by microglia. IFN-I limits the permeability of the blood-brain barrier. Disruption of the blood-brain barrier facilitates entrance of peripheral lymphocytes and inflammation. Viral infections during vulnerable phases of embryonic development cause severe fetal pathology and debilitating impairments to human infants. The roles of IFN in these scenarios are diverse and include deficits due to overproduction of IFN during the developmental stage of the brain as seems to be the case in pseudo-TORCH2.

Background/aims: Normal pressure hydrocephalus (NPH) is a potentially reversible neurological syndrome commonly characterized by gait disturbance, urinary incontinence, and dementia. Hydrocephalus e-vacuo (He-v) is also characterized by the occurrence of dementia but does not show gait disturbance or urinary incontinence and has no evident cerebrospinal fluid (CSF) pressure elevation. Kynurenic acid (KYNA), an endogenous metabolite of the L-kynurenine (L-KYN) pathway of L-tryptophan (L-TRP) degradation, is an antagonist of glutamate N-methyl-D-aspartic acid and alpha-7 nicotinic cholinergic receptors that have been linked to dementia. We investigated KYNA, L-KYN, and L-TRP levels in human CSF and serum during the aging process in 30 healthy control individuals. In addition, clinical parameters and L-TRP metabolites in CSF and serum were evaluated in four patients with NPH and five with He-v.

Methods: KYNA, L-KYN, and L-TRP levels in CSF and serum were determined using highperformance liquid chromatography.

Results: Healthy controls showed a significant decrease in serum albumin with age. Compared with their corresponding controls and unlike patients with He-v, patients with NPH (age ≤ 50 years) had significant increases in CSF protein (241%, p < 0.001), CSF albumin (246%, p < 0.001), CSF IgG (328%, p < 0.001), and CSF:serum IgG (321%, p < 0.001) and CSF:serum albumin (257%, p < 0.001) ratios. Controls had significant increases in KYNA, L-KYN, and L-TRP levels in the CSF with advancing age but not in the serum. Compared with the corresponding controls, KYNA levels were significantly increased in the CSF of patients with NPH (141%, p < 0.05) and He-v (225%; p < 0.01). Additionally, the serum levels of KYNA were increased in patients with NPH and He-v to 161% and 156% of controls, respectively (both p < 0.01). The serum levels of L-KYN and L-TRP were significantly reduced in patients with He-v but not in patients with NPH. C-reactive protein, as a marker of inflammation, was significantly increased in the serum of patients with He-v but not in patients with NPH, compared with the corresponding controls.

Conclusion: The aging process is related to elevated CSF levels of KYNA, L-KYN, and L-TRP levels. There are significant differences in clinical parameters between the two forms of hydrocephalus and these differences might have diagnostic utility. The occurrence of dementia in patients with either form of hydrocephalus might be at least partly related to elevated KYNA levels in the CNS and/or periphery.

Sphingomyelin synthases (SMS) catalyze the conversion of ceramide and phosphatidylcholine to sphingomyelin and diacylglycerol and are thus crucial for the balance between synthesis and degradation of these structural and bioactive molecules. SMS thereby play an essential role in sphingolipid metabolism, cell signaling, proliferation and differentiation processes. Although tremendous progress has been made toward understanding the involvement of SMS in physiological and pathological processes, literature in the area of neuropsychiatry is still limited. In this review, we summarize the main features of SMS as well as the current methodologies and tools used for their study and provide an overview of SMS in the central nervous system and their implications in neurological as well as psychiatric disorders. This way, we aim at establishing a basis for future mechanistic as well as clinical investigations on SMS in neuropsychiatric health and diseases.

Extracellular vesicles (EVs), referred as membranous vesicles released into body fluids from all cell types, represent a novel model to explain some aspects of the inter-cellular cross talk. It has been demonstrated that the EVs modify the phenotype of target cells, acting through a large spectrum of mechanisms. In the central nervous system, the EVs are responsible of the wide range of physiological processes required for normal brain function and neuronal support, such as immune signaling, cellular proliferation, differentiation, and senescence. Growing evidences link the EV functions to the pathogenic machinery of the neurological diseases, contributing to the disease progression and spreading. Extracellular vesicles are involved in the brain injury by multimodal ways; they propagate inflammation across the blood brain barrier (BBB), mediate neuroprotection and modulate regenerative processes. For these reasons, extracellular vesicles represent a promising biomarker in neurological disorders as well as an interesting starting point for the development of novel therapeutic strategies. Herein, we review the role of the EVs in the pathogenesis of neurological disease, discussing their potential clinical applications.

Nearly 30 years ago hypoxia-inducible factor (HIF) was described as a protein complex bound to regulatory DNA sequences termed hypoxia response elements because HIF binding induced transcription of the erythropoietin gene under hypoxia. However, it soon became clear that HIF is part of a ubiquitous cellular oxygen sensing system, which ensures finely tuned control of HIF abundance and activity in dependence of the cellular oxygen tension. For their discoveries of how cells sense and adapt to oxygen availability Gregg L. Semenza, William G. Kaelin Jr. and Sir Peter J. Ratcliffe received the Nobel Prize in Physiology or Medicine 2019. The Nobel laureates' pioneering work on cellular oxygen sensing has unraveled that HIF has numerous target genes reflecting its multiple functions in cellular metabolism and adaptation to different levels of oxygen. Importantly, HIF is also crucial for the development of the nervous system. HIF has an influence on different neural cell types regarding neurogenesis, maturation and apoptosis. Furthermore, HIF is involved in pathophysiological processes of the brain like stroke and Alzheimer's disease resulting in the development of HIF-related therapeutic approaches.

Background/aims: Human pregnancy goes along with decreasing gray matter volume in the brain of the mother. Whether these reductions remain for years or renormalize shortly after delivery is unclear. The present study used a longitudinal control group design to investigate postpartal neural plasticity.

Methods: 24 healthy young women were assessed with cognitive and hormonal measures in late pregnancy and underwent a brain scan within the first two months after delivery (TP1). They were compared to 24 naturally cycling women. A follow-up cognitive and imaging measurement was performed three months after the first scan in both groups (TP2, 4-5 months postpartally in the mothers).

Results: Compared to the control group, widespread gray matter volume increases from the first to second scan were observed in the new mothers (TP2 > TP1, whole-brain analysis). These were especially pronounced in frontal and cerebellar regions. The time by group interaction pattern of gray matter indicated a postpartal renormalization process, most likely following pregnancy-related decreases. Age was negatively correlated to postpartal gray matter increase in most of the regions. Despite pronounced changes in brain structure, the two groups did not reliably differ in cognitive performance.

Conclusion: The results reveal the potential for plasticity in the adult female brain following pregnancy. They support the assumption that the volume reductions during pregnancy renormalize at least partly in the early postpartal phase. The course of renormalization seems to differ between participants of different ages. Future studies are needed to further investigate inter-individual variability and the time course of postpartal neural change.