Showing papers in "Molecular Neurobiology in 2016"
TL;DR: The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.
Abstract: One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.
1,319 citations
TL;DR: The effects of the drug-induced modulation of oxidative balance, and pharmacotherapeutic strategies for OS reduction are analyzed, and they are explored.
Abstract: The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.
463 citations
TL;DR: It is suggested that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction.
Abstract: Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca(2+) influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.
322 citations
TL;DR: Mechanical explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer’s disease.
Abstract: Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer’s disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer’s brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer’s disease.
226 citations
TL;DR: Activated microglia were found surrounding lesions of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease, muscular amyotrophic lateral sclerosis, and multiple sclerosis and inhibiting the activity of microglian appropriately may be an effective way for the treatment of neurodegenersative diseases.
Abstract: Microglia are the main effectors in the inflammatory process of the central nervous system. As the first line of defense, microglia play an important role in the inflammatory reaction. When there is pathogen invasion or cell debris, microglia will be activated rapidly and remove it, while releasing the inflammatory cytokines to mediate inflammatory reaction. Activated microglia were found surrounding lesions of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, muscular amyotrophic lateral sclerosis, and multiple sclerosis. Microglia, the effectors of neuronal degeneration and necrosis, are involved in the removal of necrotic neurons. But over activated microglia may accelerate the process of some neurodegenerative diseases. Activated microglia can release cytotoxic factor and cytokines. Some of them may cause further damage to neuron, and some of them can regulate inflammatory cells to gather to the lesion. Microglia-mediated inflammation was considered to be the possible mechanism for the occurrence or deterioration of neurodegenerative diseases. Therefore, inhibiting the activity of microglia appropriately may be an effective way for the treatment of neurodegenerative diseases.
218 citations
TL;DR: This review provides a comprehensive overview about the construction of exosomes, their targeting and their fusion mechanisms to the recipient cells, and the design of artificial exosome with a clearly defined therapeutic active cargo and surface marker ensuring the specific targeting to the recipients cells is proposed as a promising approach.
Abstract: Since the beginning of the last decade, exosomes have been of increased interest in the science community. Exosomes represent a new kind of long distance transfer of biological molecules among cells. This review provides a comprehensive overview about the construction of exosomes, their targeting and their fusion mechanisms to the recipient cells. Complementarily, the current state of research regarding the cargo of exosomes is discussed. A particular focus was placed on the role of exosomes in the central nervous system. An increasing number of physiological processes in the brain could be associated with exosomes. In this context, it is becoming more apparent that exosomes are involved in several neurological and specifically neurodegenerative diseases. The treatment of these kinds of diseases is often difficult not least because of the blood-brain barrier. Exosomes are very stable, can pass the blood-brain barrier and, therefore, reveal bright perspectives towards diagnosis and therapeutic treatments. A prerequisite for clinical applications is a standardised approach. Features necessary for a standardised diagnosis using exosomes are discussed. In therapeutic terms, exosomes represent a promising drug delivery system able to pass the blood-brain barrier. One option to overcome the disadvantages potentially associated with the use of endogenous exosomes is the design of artificial exosomes. The artificial exosomes with a clearly defined therapeutic active cargo and surface marker ensuring the specific targeting to the recipient cells is proposed as a promising approach.
186 citations
TL;DR: The existing and developing therapeutic options aimed to reduce ER stress to protect the CNS after acute injuries are discussed, highlighting the diverse molecular mechanisms associated with ER stress and its relation to oxidative stress and autophagy.
Abstract: Endoplasmic reticulum (ER) stress induces a variety of neuronal cell death pathways that play a critical role in the pathophysiology of stroke. ER stress occurs when unfolded/misfolded proteins accumulate and the folding capacity of ER chaperones exceeds the capacity of ER lumen to facilitate their disposal. As a consequence, a complex set of signaling pathways will be induced that transmit from ER to cytosol and nucleus to compensate damage and to restore the normal cellular homeostasis, collectively known as unfolded protein response (UPR). However, failure of UPR due to severe or prolonged stress leads to cell death. Following acute CNS injuries, chronic disturbances in protein folding and oxidative stress prolong ER stress leading to sustained ER dysfunction and neuronal cell death. While ER stress responses have been well studied after stroke, there is an emerging need to study the association of ER stress with other cell pathways that exacerbate neuronal death after an injury. In this review, we summarize the current understanding of the role for ER stress in acute brain injuries, highlighting the diverse molecular mechanisms associated with ER stress and its relation to oxidative stress and autophagy. We also discussed the existing and developing therapeutic options aimed to reduce ER stress to protect the CNS after acute injuries.
185 citations
TL;DR: The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5 -HT1B), and serotonin 2A ( 5-HT2A) receptors.
Abstract: Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. Its diagnosis mainly relies on the characterization of a wide range of symptoms including changes in mood and behavior. Despite the availability of antidepressant drugs, 10 to 30 % of patients fail to respond after a single or multiple treatments, and the recurrence of depression among responsive patients is very high. Evidence from the past decades suggests that the brain neurotransmitter serotonin (5-HT) is incriminated in MDD, and that a dysfunction of 5-HT receptors may play a role in the genesis of this disease. The 5-HT membrane transporter protein (SERT), which helps regulate the serotonergic transmission, is also implicated in MDD and is one of the main targets of antidepressant therapy. Although a number of behavioral tests and animal models have been developed to study depression, little is known about the neurobiological bases of MDD. Understanding the role of the serotonergic pathway will significantly help improve our knowledge of the pathophysiology of depression and may open up avenues for the development of new antidepressant drugs. The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5-HT1B), and serotonin 2A (5-HT2A) receptors. This paper also describes some of the main molecules involved in the internalization of 5-HT receptors and illustrates the changes in 5-HT neurotransmission in knockout mice and animal model of depression.
179 citations
TL;DR: An inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies.
Abstract: Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.
175 citations
TL;DR: The bioenergetic properties of mitochondria, such as those found in the ETC that may be altered in Alzheimer’s disease (AD), are described.
Abstract: Mitochondria are the primary source for energy generation in the cell, which manifests itself in the form of the adenosine triphosphate (ATP). Nicotinamide dinucleotide (NADH) molecules are the first to enter the so-called electron transport chain or ETC of the mitochondria. The ETC represents a chain of reducing agents organized into four major protein-metal complexes (I-IV) that utilize the flow of electrons to drive the production of ATP. An additional integral protein that is related to oxidative phosphorylation is ATP synthase, referred to as complex V. Complex V carries out ATP synthesis as a result of the electron flow through the ETC. The coupling of electron flow from NADH to molecular oxygen to the production of ATP represents a process known as oxidative phosphorylation. In this review, we describe mainly the bioenergetic properties of mitochondria, such as those found in the ETC that may be altered in Alzheimer's disease (AD). Increasing evidence points to several mitochondrial functions that are affected in AD. Furthermore, it is becoming apparent that mitochondria are a potential target for treatment in early-stage AD. With growing interest in the mitochondria as a target for AD, it has been hypothesized that deficit in this organelle may be at the heart of the progression of AD itself. The role of mitochondria in AD may be significant and is emerging as a main area of AD research.
161 citations
TL;DR: The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT- QuIC as an innovative and robust diagnostic method.
Abstract: Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP Sc ). Recent studies applied the RT-QuIC methodol- ogy to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi- centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establish- ment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluo- rescence units (rfu), we obtained a sensitivity of 85 % and a specificity of 99 %. The multi-centre inter-laboratory reproduc- ibility of RT-QuIC revealed a Fleiss'kappa value of 0.83 (95 % CI: 0.40-1.00) indicating an almost perfect agreement. More- over, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP Sc seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/ μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days)can be rescued by remov- al of erythrocytes. The present study underlines the reproduc- ibility and high stability of RT-QuIC across various CSF stor- age conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method.
TL;DR: The MeDi and higher consumption of unsaturated fatty acids, antioxidants, and B vitamins decrease the risk of dementia while smoking andHigher consumption of aluminum increase therisk of dementia.
Abstract: Dietary patterns and some dietary components have been linked with dementia. We therefore performed a meta-analysis of available studies to determine whether there is an association between diet and risk of dementia. We included eligible articles and estimated risk ratio (RR) with 95 % confidence intervals (95 % CIs). Finally, there were 43 trials that met the inclusion standard. Some food intake was related with decrease of dementia, such as unsaturated fatty acids (RR: 0.84, 95 % CI: [0.74–0.95], P = 0.006), antioxidants (RR: 0.87, 95 % CI: [0.77–0.98], P = 0.026), vitamin B (RR: 0.72, 95 % CI: [0.54–0.96], P = 0.026), and the Mediterranean diet (MeDi) (RR: 0.69, 95 % CI: [0.57–0.84], P < 0.001). Some material intakes were related with increase of dementia, such as aluminum (RR: 2.24, 95 % CI: [1.49–3.37], P < 0.001), smoking (RR: 1.43, 95 % CI: [1.15–1.77], P = 0.001), and low levels of vitamin D (RR: 1.52, 95 % CI: [1.17–1.98], P = 0.002). The effect of some materials needs further investigation, such as fish (RR: 0.79, 95 % CI: [0.59–1.06], P = 0.113), vegetables and fruits (RR: 0.46, 95 % CI: [0.16–1.32], P = 0.149), and alcohol (RR: 0.74, 95 % CI: [0.55- 1.01], P = 0.056). Thus, the MeDi and higher consumption of unsaturated fatty acids, antioxidants, and B vitamins decrease the risk of dementia while smoking and higher consumption of aluminum increase the risk of dementia. Low levels of vitamin D were associated with cognitive decline. The effect of fish, vegetables, fruits, and alcohol needs further investigation. The findings will be of great significance to guide people to prevent dementia.
TL;DR: This review summarizes the current progress on the biochemical identity and biological significance of NeuN and recommends caution when applying Neu N immunoreactivity as a definitive marker of mature neurons in certain diseases and specific physiological states.
Abstract: Neuronal nuclei (NeuN) is a well-recognized “marker” that is detected exclusively in post-mitotic neurons and was initially identified through an immunological screen to produce neuron-specific antibodies Immunostaining evidence indicates that NeuN is distributed in the nuclei of mature neurons in nearly all parts of the vertebrate nervous system NeuN is highly conserved among species and is stably expressed during specific stages of development Therefore, NeuN has been considered to be a reliable marker of mature neurons for the past two decades However, this role has been challenged by recent studies indicating that NeuN staining is variable and even absent during certain diseases and specific physiological states More importantly, despite the widespread use of the anti-NeuN antibody, the natural identity of the NeuN protein remained elusive for 17 years NeuN was recently eventually identified as an epitope of Rbfox3, which is a novel member of the Rbfox1 family of splicing factors This identification might provide a novel perspective on NeuN expression during both physiological and pathological conditions This review summarizes the current progress on the biochemical identity and biological significance of NeuN and recommends caution when applying NeuN immunoreactivity as a definitive marker of mature neurons in certain diseases and specific physiological states
TL;DR: In vitro studies showed that lipoxin A4, MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and thatMaR1 and RvD 1 down-regulated β-amyloid (Aβ)42-induced inflammation in human microglia, indicating that stimulating this pathway is a promising treatment strategy for AD.
Abstract: Inflammation in the brain is a prominent feature in Alzheimer's disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study, we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1), and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated β-amyloid (Aβ)42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aβ42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.
TL;DR: Both low and high education showed a trend of dose-response relation with risk of dementia and AD, and the dementia risk was reduced by 7 % for per year increase in education.
Abstract: Educational level has been regarded as one of the most widely accepted risk factors in the epidemiological studies for dementia, despite with discordant qualitative results. However, the dose-response relation between education and incident dementia was still unknown. To quantitatively evaluate the association between exposure level to high and low education and risk of dementia, we searched PubMed, EMBASE, and the Cochrane Library up to November 2014 and references of retrieved literatures. Specific prospective cohort studies, in which educational attainment was categorized into at least three levels, were included. Newcastle-Ottawa scale was used to assess the quality of included studies. Fifteen prospective cohort studies with 55655 for low education and eight prospective cohort studies with 20172 for high education were included. In the qualitative analysis, both low and high education showed a dose-response trend with risk of dementia and Alzheimer's disease (AD). In the quantitative analysis, the dementia risk was reduced by 7 % for per year increase in education (RR, 0.93; 95 % CI, 0.92-0.94; p for overall trend = 0.000; p for nonlinearity = 0.0643). Nonetheless, we did not find statistically significant association between per year decrease in education and dementia (RR, 1.03; 95 % CI, 0.96-1.10; p for overall trend = 0.283; p for nonlinearity = 0.0041) or AD (RR, 1.03; 95 % CI, 0.97-1.10; p for overall trend = 0.357; p for nonlinearity = 0.0022). Both low and high education showed a trend of dose-response relation with risk of dementia and AD. The dementia risk was reduced by 7 % for per year increase in education.
TL;DR: Evidence for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system is presented and COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer’s disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products.
Abstract: Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2α, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2α, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2α, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Δ(12,14)-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.
TL;DR: Improved functional long-term recovery is found which is paralleled by a reduction of apoptosis after intrathecal treatment with SDF-1a, and Immunofluorescence double-labeling demonstrated that microglia and neurons are major sources of the ASC and NLRP3 respectivley.
Abstract: Stromal cell-derived factor-1 alpha (SDF-1a) or CXCL12 is an important cytokine with multiple functions in the brain during development and in adulthood. The inflammatory response initiated by spinal cord injury (SCI) involves the processing of interleukin-1beta (IL-1s) and IL-18 mediated by caspase-1 which is under the control of an intracellular multiprotein complex termed inflammasome. Using an SCI rat model, we found improved functional long-term recovery which is paralleled by a reduction of apoptosis after intrathecal treatment with SDF-1a. An intriguing aspect is that SDF-1a changed the number of neuroinflammatory cells in the damaged area. We further examined the cellular localization and sequential expression of several inflammasomes during SCI at 6 h, 24 h, 3 days, and 7 days as well as the role of SDF-1a as a regulatory factor for inflammasomes. Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1s (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. Immunofluorescence double-labeling demonstrated that microglia and neurons are major sources of the ASC and NLRP3 respectivley. Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.
TL;DR: HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome.
Abstract: Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH, involved to anti-oxidative and anti-apoptotic effect. We have previously reported that HS could attenuate neuronal apoptosis as well as vasospasm. However, the underlying mechanism of HS on inflammation in SAH-induced EBI remains unclear. In this study, we explored the influence of HS on nuclear factor-κB (NF-κB) pathway and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome at early stage after SAH, by injecting HS intraperitoneally to SAH rats. One hundred and twenty-nine SD rats were randomly divided into four groups: sham group, SAH group, SAH+vehicle group, and SAH+HS group. SAH model was conducted using endovascular perforation method; all rats were sacrificed at 24 h after SAH. Protein level of pIκBα, cytosolic and nuclear p65, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-1β (IL-1β), and cleaved caspase-3 were measured by western blot. mRNA level of IL-1β, interleukin-6 (IL-6), tumor necrosis factor-c (TNF-α) were evaluated by RT-PCR. Cellular injury and death was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining, respectively. Our results showed that pIκBα, nuclear p65, NLRP3, ASC, caspase-1, IL-1β, cleaved caspase-3 proteins, as well as the mRNA of IL-1β, IL-6, and TNF-ɑ increased at 24 h after SAH, while cytosolic p65 decreased. TUNEL and Nissl staining presented severe cellular injury at 24 h post-SAH. However, after HS administration, the changes mentioned above were reversed. In conclusion, HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome.
TL;DR: It is shown that in the absence of a NLRP3 inflammasome, prolonged stress does not provoke depressive behaviors or microglial activation in mice or dampen hippocampal neurogenesis, and the inflammaome could be a target for new therapeutic interventions to prevent depression in patients.
Abstract: Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study shows the implication of NLRP3 inflammasome in animal model of stress-induced depression. Accordingly, we show here that in the absence of a NLRP3 inflammasome, prolonged stress does not provoke depressive behaviors or microglial activation in mice or dampen hippocampal neurogenesis. Indeed, NLRP3 deletion or inhibition of microglial activation impairs the stress-induced alterations associated with depression. According to these findings in animal model, the inflammasome could be a target for new therapeutic interventions to prevent depression in patients.
TL;DR: The inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation, and demonstrates a neuro-protective effect of H1N1 over HCy-induced cerebrovascular pathology through the NMDA receptor.
Abstract: Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease. Graphical Abstract ᅟ.
TL;DR: In this paper, the authors examined the influence of blood contamination on CSF miRNA levels as a potential confounding factor and concluded that miR-29a may be a candidate biomarker for AD, but only when used in cell-free CSF.
Abstract: The identification of reliable biomarkers for Alzheimer's disease (AD) remains challenging. Recently, abnormal levels of microRNAs (miRNAs) miR-27a, miR-29a, miR-29b, and miR-125b in cerebrospinal fluid (CSF) of AD patients were reported. We aimed to confirm the biomarker potential of these miRNAs for AD diagnosis. Additionally, we examined the influence of blood contamination on CSF miRNA levels as potential confounding factor. We studied expression levels of the four miRNAs by quantitative PCR in CSF samples of AD patients and non-demented controls, and in blood-spiked CSF. Levels of miR-29a, but not of the other three miRNAs, were increased by a factor of 2.2 in CSF of AD patients. Spiking of small amounts of blood into CSF revealed that miR-27a and miR-29a, but not miR-125b levels were strongly influenced by the number of blood cells in the sample. In conclusion, miR-29a may be a candidate biomarker for AD, but only when used in cell-free CSF.
TL;DR: The possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals is suggested and similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances.
Abstract: Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances.
TL;DR: Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury following SAH and its anti-inflammatory and anti-apoptotic effect may involve the reduction of ROS.
Abstract: Minocycline has beneficial effects in early brain injury (EBI) following subarachnoid hemorrhage (SAH); however, the molecular mechanisms underlying these effects have not been clearly identified. This study was undertaken to determine the influence of minocycline on inflammation and neural apoptosis and the possible mechanisms of these effects in early brain injury following subarachnoid hemorrhage. SAH was induced by the filament perforation model of SAH in male Sprague-Dawley rats. Minocycline or vehicle was given via an intraperitoneal injection 1 h after SAH induction. Minocycline treatment markedly attenuated brain edema secondary to blood-brain barrier (BBB) dysfunction by inhibiting NLRP3 inflammasome activation, which controls the maturation and release of pro-inflammatory cytokines, especially interleukin-1β (IL-1β). Minocycline treatment also markedly reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells. To further identify the potential mechanisms, we demonstrated that minocycline increased Bcl2 expression and reduced the protein expression of P53, Bax, and cleaved caspase-3. In addition, minocycline reduced the cortical levels of reactive oxygen species (ROS), which are closely related to both NLRP3 inflammasome and P53 expression. Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury following SAH. Minocycline's anti-inflammatory and anti-apoptotic effect may involve the reduction of ROS. Minocycline treatment may exhibit important clinical potentials in the management of SAH.
TL;DR: A wide array of immune, inflammatory, oxidative and nitrosative stress (ON ON ON activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated molecular patterns, including heat shock proteins, altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump were delineated in this article.
Abstract: Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (ON ON activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.
TL;DR: This review focuses on the alpha-synucleinopathy multiple system atrophy, a prototypical disorder with a well-defined oligodendroglial pathology.
Abstract: Oligodendrocytes, the myelinating cells of the central nervous system, mediate rapid action potential conduction and provide trophic support for axonal as well as neuronal maintenance. Their progenitor cell population is widely distributed in the adult brain and represents a permanent cellular reservoir for oligodendrocyte replacement and myelin plasticity. The recognition of oligodendrocytes, their progeny, and myelin as contributing factors for the pathogenesis and the progression of neurodegenerative disease has recently evolved shaping our understanding of these disorders. In the present review, we aim to highlight studies on oligodendrocytes and their progenitors in neurodegenerative diseases. We dissect oligodendroglial biology and illustrate evolutionary aspects in regard to their importance for neuronal functionality and maintenance of neuronal circuitries. After covering recent studies on oligodendroglia in different neurodegenerative diseases mainly in view of their function as myelinating cells, we focus on the alpha-synucleinopathy multiple system atrophy, a prototypical disorder with a well-defined oligodendroglial pathology.
TL;DR: Results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders.
Abstract: Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.
TL;DR: Pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions and its pharmacologic characteristics are summarized and its mechanisms of action are discussed.
Abstract: Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications.
TL;DR: It is demonstrated that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that mi R-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.
Abstract: Emerging evidence indicates that certain microRNAs (miRNAs) play important roles in epileptogenesis. MiR-219 is a brain-specific miRNA and has been shown to negatively regulate the function of N-methyl-D-aspartate (NMDA) receptors by targeting Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)γ. Herein, we found that the level of miR-219 was decreased in both the kainic acid (KA)-induced epilepsy model and in cerebrospinal fluid specimens of epilepsy patients. Importantly, silencing of miR-219 by its antagomir in vivo resulted in seizure behaviors, abnormal cortical electroencephalogram (EEG) recordings in the form of high-amplitude and high-frequency discharges, and increased levels of CaMKIIγ and an NMDA receptor component, NR1, in a pattern similar to that found in KA-treated mice. Moreover, treatments with the miR-219 agomir in vivo alleviated seizures, abnormal EEG recordings, and decreased levels of CaMKIIγ and NR1 in KA-treated mice. Furthermore, treatment with MK-801, an antagonist of NMDA receptors, significantly alleviated abnormal EEG recordings induced by miR-219 antagomir. Together, these results demonstrate that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that miR-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.
TL;DR: Gangliosides (sialic acid-containing glycosphingolipids) are abundant in neurons of all animal species and play important roles in many cell physiological processes, including differentiation, memory control, cell signaling, neuronal protection, neuronal recovery, and apoptosis.
Abstract: Gangliosides (sialic acid-containing glycosphingolipids) are abundant in neurons of all animal species and play important roles in many cell physiological processes, including differentiation, memory control, cell signaling, neuronal protection, neuronal recovery, and apoptosis Gangliosides also function as anchors or entry points for various toxins, bacteria, viruses, and autoantibodies GM1, a ganglioside component of mammalian brains, is present mainly in neurons GM1 is one of the best studied gangliosides, and our understanding of its properties is extensive Simple and rapid procedures are available for preparation of GM1 as a natural compound on a large scale, or as a derivative containing an isotopic radionuclide or a specific probe Great research interest in the properties of GM1 arose from the discovery in the early 1970s of its role as receptor for the bacterial toxin responsible for cholera pathogenesis
TL;DR: The concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of Parkinson’s disease is supported.
Abstract: The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson’s disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2 % in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2 % trehalose at the same time as delivery of AAV. Trehalose (0.5 %) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.