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Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

Neuroscience Bulletin 2016年第4期32卷 311-322页

作者： Meng Zhang Jia Liu Meng-Meng Zhou Honghai Wu Yanning Hou Yun-Feng Li Yuxin Yin Lemin Zheng Feng-Yu Liu Ming Yi You Wan Neuroscience Research Institute Peking UniversityBeiiing 100191 China Institute of Systems Biomedicine Peking UniversityBeijing 100191 China Department of Pharmacy Bethune International PeaceHospital Shijiazhuang Shijiazhuang 050082 China Department of New Drug Evaluation Beijing Institute ofPharmacology and Toxicology Beijing 100007 China Institute of Cardiovascular Sciences and Institute of SystemsBiomedicine and Key Laboratory of MolecularCardiovascular Sciences of the Ministry of Education PekingUniversity Beijing 100191 China Key Laboratory for Neuroscience Ministry of Education/National Health and Family Planning Commission School ofBasic Medical Sciences Peking University Beijing 100191China Department of Neurobiology School of Basic MedicalSciences Peking University Beijing 100191 China

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （GABAARs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of Neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of Neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and Neurosteroids were sig- nificantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated Neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

关键词： Neurosteroids Translocator protein Sparednerve injury Thalamus GABAA receptors

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Impact of ovariectomy and estradiol-17β(E_(2))replacement on the brain steroid levels of the Indian stinging catfish Heteropneustes fossilis

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Aquaculture and Fisheries 2022年第5期7卷 474-483页

作者： Surabhi Mishra Radha Chaube Zoology and Fisheries Department Dolphin(PG)College of Science and AgricultureChunni KalanFatehgarh SahibPunjab140406India Department of Zoology Institute of ScienceBanaras Hindu UniversityVaranasi221005India

In the present study,effects of ovariectomy(Ovx)and estradiol-17β(E2)replacement on the brain steroid levels were investigated in the resting and prespawning phases of the female catfish Heteropneustes fossilis.The study showed that Ovx resulted in significant decreases in plasma levels of estradiol-17β(E2)and its precursors,and the effect varied with the reproductive stage and duration.Our study showed that E2 supplementation reversed the effect of Ovx in 3-week Ovx fish group,either restored or increased according to the dose.In contrast,E2 levels increased in the brain after Ovx in the resting stage and produced a biphasic effect of significant decreases on week 1 and 2,and significant increases on week 3,4 and 5 in the pre-spawning stage.The brain E2 levels significantly inhibited in E2 supplementation groups.The testosterone(T)levels showed biphasic effects,an initial decrease(up to 3 weeks Ovx)and an increase later(week 4,5)in the resting stage.In the pre-spawning stage,the T levels increased significantly after Ovx.The E2 supplementation significantly inhibited the T levels,more severely in the low dose group in the resting and pre-spawning stages.Brain 17-hydroxyprogesterone(17-OHP4)levels increased(week 1,2,3)but decreased on week 4 and 5 of Ovx in the resting stage and increased throughout Ovx in the pre-spawning stage except in the 5th week(though compared to other steroids,level was very low;almost negligible).The E2 replacement significantly decreased the steroid levels further down compared to the Ovx control group.Brain progesterone(P4)and pregnenolone(P5)levels decreased initially(week 1 and 2 Ovx)and recovered later.The E2 replacement significantly decreased P4 levels in the Ovx fish in the pre-spawning stage and in the lower dose group in the resting stage.The P5 levels remained inhibited after the E2 supplementation in the resting stage but unchanged or increased it in the pre-spawning stage.Brain cortisol(F)levels were inhibited initially(1 and 2 weeks and later increased after OVX in the rest

关键词： Catfish Neurosteroids Ovariectomy Estrogen replacement Seasonal variations

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Endoplasmic reticulum stress,autophagy,neuroinflammation,and sigma 1 receptors as contributors to depression and its treatment

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Neural Regeneration Research 2024年第10期19卷 2202-2211页

作者： Chika Fujii Charles F.Zorumski Yukitoshi Izumi Department of Psychiatry Washington University School of MedicineSt.LouisMOUSA Taylor Family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA

The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses. Initial inflammatory triggers induce endoplasmic reticulum stress, leading to neuroinflammatory responses. Subsequently, induction of autophagy by Neurosteroids and other signaling pathways that converge on autophagy induction are thought to participate in resolving neuroinflammation. The aim of this review is to summarize our current understanding of the molecular mechanisms governing the induction of endoplasmic reticulum stress, autophagy, and neuroinflammation in the central nervous system. Studies focused on innate immune factors, including Neurosteroids with anti-inflammatory roles will be reviewed. In the context of depression, animal models that led to our current understanding of molecular mechanisms underlying depression will be highlighted, including the roles of sigma 1 receptors and pharmacological agents that dampen endoplasmic reticulum stress and associated neuroinflammation.

关键词： allopregnanolone fluvoxamine ketamine Neurosteroids postpartum depression quercetin

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Changes in neurosteroid levels and steroidogenic enzyme expression in the brain of morphine dependent and withdrawing rats

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Neural Regeneration Research 2010年第7期5卷 514-518页

作者： Caizhen Yan Xiuli Wang Ping Jiang Yanning Hou Department of Pharmacology Hebei Medical University Shijiazhuang 050017 Hebei Province China Department of Anesthesiology Third Hospital of Hebei Medical University Shijiazhuang 050051 Hebei Province China Department of Pharmacology Beathune International Peace Hospital Shijiazhuang 050082 Hebei Province China

BACKGROUND： Studies have demonstrated that exogenous neurosteroid treatment prevents the development of morphine tolerance and dependence, and attenuates abstinence behavior in mice. However, there are few studies on whether the levels of endogenous Neurosteroids can be changed by morphine dependence and withdrawal. OBJECTIVE： To investigate the levels of various Neurosteroids in rat brain following morphine dependence and withdrawal. To evaluate the expressions of steroidogenic enzyme mRNAs and proteins. To identify the relationship between Neurosteroids and morphine dependence at the whole animal behavior, neural biochemistry, and molecular levels. DESIGN, TIME AND SETTING： A randomized, controlled study. Experiments were performed at the Department of Pharmacology of Hebei Medical University and Department of Pharmacology of Beathune International Peace Hospital, China, from June 2004 to October 2007. MATERIALS： Morphine hydrochloride injection （Shenyang First Pharmaceutical Factory, China）, naloxone hydrochloride （Hunan Yiqiao Pharmaceutical Co., China） and a gas chromatography-mass spectrometry system （Agilent, CA, USA） were used in this study. METHODS： Healthy adult Sprague Dawley rats were randomly divided into three groups： a morphine dependence group, morphine withdrawal group and control group （n = 20）. The rats in the morphine dependence and morphine withdrawal groups were given increasing doses of morphine （5, 10, 15, 20, 30, 40 and 50 mg/kg, intraperitoneal） to create morphine dependence. The rats in the morphine withdrawal group were injected with 2 mg/kg naloxone to precipitate withdrawal 1 hour after the last morphine injection. Rats in the control group were treated with an equal volume of saline. MAIN OUTCOME MEASURES： Following morphine dependence and withdrawal, brain levels of the Neurosteroids pregnenolone, progesterone and allopregnanolone were analyzed using gas chromatography-mass spectrometry. The mRNA expression of two key steroidogenic enzymes, P450 side-chain cleavage enzyme （P450scc）

关键词： morphine dependence withdrawal Neurosteroids steroidogenic enzymes gas chromatography-mass spectrometry neural regeneration

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Vitamin D, Testosterone, Epigenetics and Pain an Evolving Concept of Neurosignaling, Neuroplasticity and Homeostasis

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World Journal of Neuroscience 2018年第2期8卷 203-253页

作者： Joseph Thomas Pierre Morris Eric Seigel Wayne State University/Ascension Crittenton Detroit USA

The thought of exploring a possible relationship between the broad systems of steroid hormone physiology (specifically vitamin D and testosterone) and nocioception was prompted by an unexpectedly frequent personal clinical observation. Patients with chronic pain syndromes or chronic musculoskeletal pain often have low serum levels of vitamin D and testos-terone. Mining for relevant information in Pub Med, Medline and Cochrane Systems Review, three concepts repeatedly emerge that provide a common context for understanding the mechanics of these diverse sys-tems—epigenetic, homeostasis and neuroplasticity. Viewing homeostasis within the framework of epigenetics allows reasoned speculation as to how various human systems interact to maintain integrity and function, while simultaneously responding in a plastic manner to external stimuli. Cell signaling supports normal function by regulating synaptic activity, but can also effect plastic change in the central and peripheral nervous system. This is most commonly achieved by post-translational remodeling of chromatin. There is thus persistent epigenetic change in protein synthesis with all the related downstream effects but without disruption of normal DNA se-quencing. In itself, this may be considered an example of genomic homeo-stasis. Epigenetic mechanisms in nociception and analgesia are active in the paleospinothalamic and neospinothalamic tracts at all levels. Physiologic response to a nociceptive insult, whether mechanical, inflammatory or ischemic, is provided by cell signaling that is significantly enhanced through epigenetic mechanisms at work in nociceptors, Gamma-Aminobutyric Acid (GABA) and glutamate receptors, voltage gated receptors, higher order neurons in the various dorsal horn laminae and proximal nociceptive pro-cessing centers in the brainstem and cortex. The mediators of these direct or epigenetic effects are various ligands also active in signaling, such as free radicals, substance P, a variety of cytokines, growth factors and G proteins, stress r

关键词： Gamma-Aminobutyric Acid (GABA) Jumonji (Jmjd3) Homer Gene Cholecalciferol Calcitriol Neurosteroids Glutamate 5-HT

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