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- Volume 20, Issue 1, 2022
Current Neuropharmacology - Volume 20, Issue 1, 2022
Volume 20, Issue 1, 2022
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Putative Roles of Astrocytes in General Anesthesia
Authors: Daniel K. Mulkey, Michelle L. Olsen, Mengchan Ou, Colin M. Cleary and Guizhi DuGeneral anesthetics are a mainstay of modern medicine, and although much progress has been made towards identifying molecular targets of anesthetics and neural networks contributing to endpoints of general anesthesia, our understanding of how anesthetics work remains unclear. Reducing this knowledge gap is of fundamental importance to prevent unwanted and life-threatening side-effects associated with general anesthesia. General anesthetics are chemically diverse, yet they all have similar behavioral endpoints, and so for decades, research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the ‘multiple target hypothesis’ as it has become clear that anesthetics target many cellular proteins, including GABAA receptors, glutamate receptors, voltage-independent K+ channels, and voltagedependent K+, Ca2+ and Na+ channels, to name a few. Yet, despite evidence that astrocytes are capable of modulating multiple aspects of neural function and express many anesthetic target proteins, they have been largely ignored as potential targets of anesthesia. The purpose of this brief review is to highlight the effects of anesthetic on astrocyte processes and identify potential roles of astrocytes in behavioral endpoints of anesthesia (hypnosis, amnesia, analgesia, and immobilization).
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Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels
Authors: Lu Huang, Guangyin Xu, Ruotian Jiang, Yuncheng Luo, Yunxia Zuo and Jin LiuTwo-pore domain potassium (K2P) channels are a diverse family of potassium channels. K2P channels generate background leak potassium currents to regulate cellular excitability and are thereby involved in a wide range of neurological disorders. K2P channels are modulated by a variety of physicochemical factors, such as mechanical stretch, temperature, and pH. In the peripheral nervous system, K2P channels are widely expressed in nociceptive neurons and play a critical role in pain perception. In this review, we summarize the recent advances in the pharmacological properties of K2P channels, with a focus on the exogenous small-molecule activators targeting K2P channels. We emphasize the subtype-selectivity, cellular and in vivo pharmacological properties of all the reported small-molecule activators. The key underlying analgesic mechanisms mediated by K2P are also summarized based on the data in the literature from studies using small-molecule activators and genetic knock-out animals. We discuss the advantages and limitations of the translational perspectives of K2P in pain medicine and provide outstanding questions for future studies in the end.
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Effects of General Anesthetics on Synaptic Transmission and Plasticity
Authors: Jimcy Platholi and Hugh C. HemmingsGeneral anesthetics depress excitatory and/or enhance inhibitory synaptic transmission principally by modulating the function of glutamatergic or GABAergic synapses, respectively, with relative anesthetic agent-specific mechanisms. Synaptic signaling proteins, including ligand- and voltage-gated ion channels, are targeted by general anesthetics to modulate various synaptic mechanisms, including presynaptic neurotransmitter release, postsynaptic receptor signaling, and dendritic spine dynamics to produce their characteristic acute neurophysiological effects. As synaptic structure and plasticity mediate higher-order functions such as learning and memory, long-term synaptic dysfunction following anesthesia may lead to undesirable neurocognitive consequences depending on the specific anesthetic agent and the vulnerability of the population. Here we review the cellular and molecular mechanisms of transient and persistent general anesthetic alterations of synaptic transmission and plasticity.
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Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System
Authors: Donghang Zhang, Jin Liu, Tao Zhu and Cheng ZhouAlthough general anesthetics have been used in the clinic for more than 170 years, the ways in which they induce amnesia, unconsciousness, analgesia, and immobility remain elusive. Modulations of various neural nuclei and circuits are involved in the actions of general anesthetics. The expression of the immediate-early gene c-fos and its nuclear product, c-fos protein, can be induced by neuronal depolarization; therefore, c-fos staining is commonly used to identify the activated neurons during sleep and/or wakefulness, as well as in various physiological conditions in the central nervous system. Identifying c-fos expression is also a direct and convenient method to explore the effects of general anesthetics on the activity of neural nuclei and circuits. Using c-fos staining, general anesthetics have been found to interact with sleep- and wakefulness-promoting systems throughout the brain, which may explain their ability to induce unconsciousness and emergence from general anesthesia. This review summarizes the actions of general anesthetics on neural nuclei and circuits based on a c-fos expression.
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Neural Substrates for the Regulation of Sleep and General Anesthesia
Authors: Qianzi Yang, Fang Zhou, Ao Li and Hailong DongGeneral anesthesia has been successfully used in clinics for over 170 years, but its mechanisms of effect remain unclear. Behaviorally, general anesthesia is similar to sleep as it produces a reversible transition between wakefulness and the state of being unaware of one’s surroundings. A discussion regarding the common circuits of sleep and general anesthesia has been ongoing as an increasing number of sleep-arousal regulatory nuclei are reported to participate in the consciousness shift occurring during general anesthesia. Recently, with progress in research technology, both positive and negative evidence for overlapping neural circuits between sleep and general anesthesia has emerged. This article provides a review of the latest evidence on the neural substrates for sleep and general anesthesia regulation by comparing the roles of pivotal nuclei in sleep and anesthesia.
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From Inhibition of GABA-A Receptor-Mediated Synaptic Transmission by Conventional Antidepressants to Negative Allosteric Modulators of Alpha5- GABA-A Receptors as Putative Fast-Acting Antidepressant Drugs: Closing the Circle?
More LessThe present perspective paper shortly and specifically addresses the issues of whether inhibition of GABA-A receptor-mediated synaptic transmission may be involved in antidepressantlike actions and the therapeutic effects of conventional antidepressant (AD) drugs, and whether the recent development of negative allosteric modulators (NAMs) of the alpha5-GABA-A receptor may constitute significant progress in our knowledge on the neurobiology and the treatment of depression.
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Perspective on the Relationship between GABAA Receptor Activity and the Apparent Potency of an Inhibitor
Authors: Allison L. Germann, Spencer R. Pierce, Alex S. Evers, Joe H. Steinbach and Gustav AkkBackground: In electrophysiological experiments, inhibition of a receptor-channel, such as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response with an inhibitor to calculate the fraction of the control response remaining in the presence of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentration- response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve Objective: We sought to estimate sensitivity of the fitted IC50 to the level of activity of the control response Methods: The inhibition concentration-response relationships were calculated for models with distinct mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site. In Model III, the inhibitor stabilizes the desensitized state. Results: The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the probability of being in the active state (PA) of the control response increased. In Model III, the IC50 of inhibition was reduced at higher PA. Conclusion: We infer that the apparent potency of an inhibitor depends on the PA of the control response. While the calculations were carried out using the activation and inhibition properties that are representative of the GABAA receptor, the principles and conclusions apply to a wide variety of receptor- channels.
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Early Biomarkers and Intervention Programs for the Infant Exposed to Prenatal Stress
Functional development of affective and reward circuits, cognition and response inhibition later in life exhibits vulnerability periods during gestation and early childhood. Extensive evidence supports the model that exposure to stressors in the gestational period and early postnatal life increases an individual's susceptibility to future impairments of functional development. Recent versions of this model integrate epigenetic mechanisms of the developmental response. Their understanding will guide the future treatment of the associated neuropsychiatric disorders. A combination of non-invasively obtainable physiological signals and epigenetic biomarkers related to the principal systems of the stress response, the Hypothalamic-Pituitary axis (HPA) and the Autonomic Nervous System (ANS), are emerging as the key predictors of neurodevelopmental outcomes. Such electrophysiological and epigenetic biomarkers can prove to timely identify children benefiting most from early intervention programs. Such programs should ameliorate future disorders in otherwise healthy children. The recently developed Early Family-Centered Intervention Programs aim to influence the care and stimuli provided daily by the family and improving parent/child attachment, a key element for healthy socio-emotional adult life. Although frequently underestimated, such biomarker-guided early intervention strategy represents a crucial first step in the prevention of future neuropsychiatric problems and in reducing their personal and societal impact.
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Drugs Used in the Treatment of Multiple Sclerosis During COVID-19 Pandemic: A Critical Viewpoint
Since COVID-19 has emerged as a word public health problem, attention has been focused on how immune-suppressive drugs used for the treatment of autoimmune disorders influence the risk for SARS-CoV-2 infection and the development of acute respiratory distress syndrome (ARDS). Here, we discuss the disease-modifying agents approved for the treatment of multiple sclerosis (MS) within this context. Interferon (IFN)-β1a and -1b, which display antiviral activity, could be protective in the early stage of COVID-19 infection, although SARS-CoV-2 may have developed resistance to IFNs. However, in the hyperinflammation stage, IFNs may become detrimental by facilitating macrophage invasion in the lung and other organs. Glatiramer acetate and its analogues should not interfere with the development of COVID-19 and may be considered safe. Teriflunomide, a first-line oral drug used in the treatment of relapsing-remitting MS (RRMS), may display antiviral activity by depleting cellular nucleotides necessary for viral replication. The other first-line drug, dimethyl fumarate, may afford protection against SARS-CoV-2 by activating the Nrf-2 pathway and reinforcing the cellular defenses against oxidative stress. Concern has been raised regarding the use of second-line treatments for MS during the COVID-19 pandemic. However, this concern is not always justified. For example, fingolimod might be highly beneficial during the hyperinflammatory stage of COVID-19 for a number of mechanisms, including the reinforcement of the endothelial barrier. Caution is suggested for the use of natalizumab, cladribine, alemtuzumab, and ocrelizumab, although MS disease recurrence after discontinuation of these drugs may overcome a potential risk for COVID-19 infection.
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Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can, in turn, induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.
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The Comprehensive Neural Mechanism of Oxytocin in Analgesia
Authors: Liu-Nan Yang, Kai Chen, Xiao-Ping Yin, Dan Liu and Ling-Qiang ZhuOxytocin (OXT) is a nine amino acid neuropeptide hormone that has become one of the most intensively studied molecules in the past few decades. The vast majority of OXT is synthesized in the periventricular nucleus and supraoptic nucleus of the hypothalamus, and a few are synthesized in some peripheral organs (such as the uterus, ovaries, adrenal glands, thymus, pancreas, etc.) OXT modulates a series of physiological processes, including lactation, parturition, as well as some social behaviors. In addition, more and more attention has recently been focused on the analgesic effects of oxytocin. It has been reported that OXT can relieve tension and pain without other adverse effects. However, the critical role and detailed mechanism of OXT in analgesia remain unclear. This review aims to summarize the mechanism of OXT in analgesia and some ideas about the mechanism.
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Understanding the Role of Histone Deacetylase and their Inhibitors in Neurodegenerative Disorders: Current Targets and Future Perspective
Authors: Vishal Kumar, Satyabrata Kundu, Arti Singh and Shamsher SinghNeurodegenerative diseases are a group of pathological conditions that cause motor incordination (jerking movements), cognitive and memory impairments result from degeneration of neurons in a specific area of the brain. Oxidative stress, mitochondrial dysfunction, excitotoxicity, neuroinflammation, neurochemical imbalance and histone deacetylase enzymes (HDAC) are known to play a crucial role in neurodegeneration. HDAC is classified into four categories (class I, II, III and class IV) depending upon their location and functions. HDAC1 and 2 are involved in neurodegeneration, while HDAC3-11 and class III HDACs are beneficial as neuroprotective. HDACs are localized in different parts of the brain- HDAC1 (hippocampus and cortex), HDAC2 (nucleus), HDAC3, 4, 5, 7 and 9 (nucleus and cytoplasm), HDAC6 & HDAC7 (cytoplasm) and HDAC11 (Nucleus, cornus ammonis 1 and spinal cord). In pathological conditions, HDAC up-regulates glutamate, phosphorylation of tau, and glial fibrillary acidic proteins while down-regulating BDNF, Heat shock protein 70 and Gelsolin. Class III HDACs are divided into seven sub-classes (SIRT1-SIRT7). Sirtuins are localized in the different parts of the brain and neuron -Sirt1 (nucleus), Sirt2 (cortex, striatum, hippocampus and spinal cord), Sirt3 (mitochondria and cytoplasm), Sirt4, Sirt5 & Sirt6 (mitochondria), Sirt7 (nucleus) and Sirt8 (nucleolus). SIRTs (1, 3, 4, and 6) are involved in neuronal survival, proliferation and modulating stress response, and SIRT2 is associated with Parkinsonism, Huntington’s disease and Alzheimer’s disease, whereas SIRT6 is only associated with Alzheimer’s disease. In this critical review, we have discussed the mechanisms and therapeutic targets of HDACs that would be beneficial for the management of neurodegenerative disorders
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Plant-Derived Natural Compounds for the Treatment of Amyotrophic Lateral Sclerosis: An Update
Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. Objective/Aim: The current study aims to thoroughly review plant-derived compounds with welldefined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Results: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms Conclusion: These plant-derived compounds may be considered as supplements for conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structureactivity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.
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Dapsone, More than an Effective Neuro and Cytoprotective Drug
Background:Dapsone (4,4'-diamino-diphenyl sulfone) is a synthetic derivative of sulfones, with the antimicrobial activity described since 1937. It is also a drug traditionally used in dermatological therapies due to its anti-inflammatory effect. In recent years its antioxidant, antiexcitotoxic, and antiapoptotic effects have been described in different ischemic damage models, traumatic damage, and models of neurodegenerative diseases, such as Parkinson's (PD) and Alzheimer's diseases (AD). Finally, dapsone has proven to be a safe and effective drug as a protector against heart, renal and pulmonary cells damage; that is why it is now employed in clinical trials with patients as a neuroprotective therapy by regulating the main mechanisms of damage that lead to cell death ObjectiveThe objective of this study is to provide a descriptive review of the evidence demonstrating the safety and therapeutic benefit of dapsone treatment, evaluated in animal studies and various human clinical trials Methods: We conducted a review of PubMed databases looking for scientific research in animals and humans, oriented to demonstrate the effect of dapsone on regulating and reducing the main mechanisms of damage that lead to cell death ConclusionThe evidence presented in this review shows that dapsone is a safe and effective neuro and cytoprotective treatment that should be considered for translational therapy.
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Post-Translational Modifications of BACE1 in Alzheimer's Disease
Authors: Wen Wen, Ping Li, Panwang Liu, Shijun Xu, Fushun Wang and Jason H HuangBeta-Amyloid Cleaving Enzyme1 (BACE1) is a monospecific enzyme for the key ratelimiting step in the synthesis of beta-amyloid(Aβ) from cleavage of amyloid precursor protein (APP), to form senile plaques and causes cognitive dysfunction in Alzheimer's disease (AD). Post-translation modifications of BACE1, such as acetylation, glycosylation, palmitoylation, phosphorylation, play a crucial role in the trafficking and maturation process of BACE1. The study of BACE1 is of great importance not only for understanding the formation of toxic Aβ but also for the development of an effective therapeutic target for the treatment of AD. This paper review recent advances in the studies about BACE1, with focuses being paid to the relationship of Aβ, BACE1 with posttranslational regulation of BACE1. In addition, we specially reviewed studies about the compounds that can be used to affect post-translational regulation of BACE1 or regulate BACE1 in the literature, which can be used for subsequent research on whether BACE1 is a post-translationally modified drug.
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Central Neural Circuits Orchestrating Thermogenesis, Sleep-Wakefulness States and General Anesthesia States
Authors: Jiayi Wu, Daiqiang Liu, Jiayan Li, Jia Sun, Yujie Huang, Shuang Zhang, Shaojie Gao and Wei MeiGreat progress has been made in specifically identifying the central neural circuits (CNCs) of the core body temperature (Tcore), sleep-wakefulness states (SWs), and general anesthesia states (GAs), mainly utilizing optogenetic or chemogenetic manipulations. We summarize the neuronal populations and neural pathways of these three CNCs, which gives evidence for the orchestration within these three CNCs, and the integrative regulation of these three CNCs by different environmental light signals. We also outline some transient receptor potential (TRP) channels that function in the CNCs-Tcore and are modulated by some general anesthetics, which makes TRP channels possible targets for addressing the general-anestheticsinduced- hypothermia (GAIH). We suggest this review will provide new orientations for further consummating these CNCs and elucidating the central mechanisms of GAIH.
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Voxel-wise Functional Connectivity of the Default Mode Network in Epilepsies: A Systematic Review and Meta-Analysis
Authors: Sisi Jiang, Hechun Li, Linli Liu, Dezhong Yao and Cheng LuoBackground: Default Mode Network (DMN) is recognized to be involved in the generation and propagation of epileptic activities in various epilepsies. Converging evidence has suggested disturbed Functional Connectivity (FC) in epilepsies, which was inferred to be related to underlying pathological mechanisms. However, abnormal changes of FC in DMN revealed by different studies are controversial, which obscures the role of DMN in distinct epilepsies. Objective: The present work aims to investigate the voxel-wise FC in DMN across epilepsies Methods: A systematic review was conducted on 22 published articles before October 2020, indexed in PubMed and Web of Science. A meta-analysis with a random-effect model was performed using the effect-size signed differential mapping approach. Subgroup analyses were performed in three groups: Idiopathic Generalized Epilepsy (IGE), mixed Temporal Lobe Epilepsy (TLE), and mixed Focal Epilepsy (FE) with different foci. Results: The meta-analysis suggested commonly decreased FC in mesial prefrontal cortices across different epilepsies. Additionally decreased FC in posterior DMN was observed in IGE. The TLE showed decreased FC in temporal lobe regions and increased FC in the dorsal posterior cingulate cortex. Interestingly, an opposite finding in the ventral and dorsal middle frontal gyrus was observed in TLE. The FE demonstrated increased FC in the cuneus. Conclusion: The current findings revealed both common and specific alterations of FC in DMN across different epilepsies, highlighting the contribution of these dysfunctions to epileptic activities and cognitive behaviors in patients. Furthermore, the current study provided powerful evidence to support DMN as a potential candidate for effective intervention in epilepsy.
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Volumes & issues
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Volume 22 (2024)
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Volume 21 (2023)
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Volume 20 (2022)
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Volume 19 (2021)
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Volume 18 (2020)
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Volume 17 (2019)
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Volume 16 (2018)
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Volume 15 (2017)
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Volume 14 (2016)
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Volume 13 (2015)
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Volume 12 (2014)
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Volume 11 (2013)
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Volume 10 (2012)
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Volume 9 (2011)
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Volume 8 (2010)
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Volume 7 (2009)
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Volume 6 (2008)
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Volume 5 (2007)
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Volume 4 (2006)
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Volume 3 (2005)
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Volume 2 (2004)
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Volume 1 (2003)