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

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.

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

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.

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

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） and 3[B-hydroxysteroid dehydrogenase （313-HSD）, were determined in rat brain regions using reverse transcription-polymerase chain reaction. The distribution and expression of P450scc protein were visualized in brain regions associated with addiction by immunohistochemistry. RESULTS： In brain tissue from the morphine dependence group, the levels of pregnenolone and progesterone were decreased by 62% （P 〈 0.01） and 92% （P 〈 0.01 ） respectively, compared with the control group. In the morphine dependence group, the key steroidogenic enzyme P450scc mRNA was decreased in striatum （P 〈 0.05）, while 3-HSD mRNA was decreased in amygdala （P 〈 0.05）, striatum （P 〈 0.05） and frontal cortex （P 〈 0.05） compared with the control group. Morphine withdrawal induced a significant increase in the neurosteroid levels compared with the control group （P 〈 0.01）. However, there was no significant difference in the expressions of P450scc and 36-HSD mRNAs between the morphine withdrawal and control groups （P 〉 0.05）. CONCLUSION： The neurosteroid levels and expressions of steroidogenic enzymes changed similarly in morphine dependent rats, suggesting that the morphine dependence-induced decrease in neurosteroids might depend on local expression of steroidogenic enzymes in the central nervous system. However, the changes in neurosteroids in morphine withdrawal rats were not in accordance with the changes in the expression of steroidogenic enzymes, suggesting that the effects of morphine withdrawal on brain neurosteroid levels may not depend primarily on the local expression of steroidogenic enzymes in the central nervous system.

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

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 responsive proteins, matrix and structural proteins such as reelin and the Jmjd3 gene/enzyme. Calcitriol, the vitamin D receptor and vitamin D Responsive Elements collectively determine regulatory effects of this secosteroid hormone. Agents of homeostasis and plasticity include various D-system specific cytochrome enzymes (CYP 24, CYP 27 A1, B1), as well as more widely active enzymes and protein cell signalers (Jmjd3, Calbindin, BMP), many of which play a role in the nociceptive system. While the highlighted information represents an understanding of complex systems that is currently in its infancy, there are clear results from reliable research at a foundational level. These results are beginning to tell a compelling tale of the homeostasis and plasticity inherent in vitamin D and nociception systems.

Beyond boundaries:Neuroprotective effects of steroids and ecdysteroids in SH-SY5Y cells-A systematic review

Steroids and ecdysteroids have been shown to exhibit a range of biological effects,including anti-inflammatory,anticancer,and neuroprotective.This systematic review aims to highlight the evidence-based neuroprotective and antioxidant effects of steroids and ecdysteroids in SH-SY5Y neuroblastoma cells.A comprehensive literature search was conducted on May 11,2023,without publication source restrictions,using various electronic databases,including PubMed,Web of Science(WoS),Scopus,and Cumulative Index toNursing and Allied Health Literature.Of 103articles,only20 studies were included for investigating the neuroprotective effects of steroids and ecdysteroids in SH-SY5Y cells exposed to oxidative stress or neurotoxic agents.The risk of bias and quality assessment of the included studies were evaluated in accordance with the Nature Publication Quality Improvement Project specific criteria.The selected studies reported the antioxidant effects of the tested compounds on SH-SY5Y cells and demonstrated their ability to scavenge free radicals and prevent lipid peroxidation.These findings suggest that neurosteroids have potential therapeutic applications for the prevention and treatment of neurodegenerative diseases characterized by oxidative stress and neuronal damage.Some studies have investigated the molecular mechanisms underlying the neuroprotective and antioxidant effects of steroids and ecdysteroids in SH-SY5Y cells.These mechanisms include the activation of antioxidant enzymes,such as superoxide dismutase and glutathione peroxidase,and the modulation of various signaling pathways,including the phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways.This review provides evidence that the tested compounds have remarkable neuroprotective and antioxidant effects in human neuroblastoma SH-SY5Y cells.

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

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 resting stage.In the pre-spawning stage,the F levels increased in the week 1,2 and 3 of Ovx and decreased in the 4th and 5th weeks.The E2 supplementation inhibited the cortisol(F)levels in both phases.The results show that ovarian steroids influence neurosteroidogenesis in a reproductive stage-dependent manner.