-
Aging May 2024Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical...
BACKGROUND
Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical stimulation (TNS) is a promising therapeutic intervention for neurological impairment following TBI. However, the precise mechanisms underlying the neuroprotective effects of TNS in TBI are poorly understood. Thus, the objective of this study was to investigate the potential involvement of the orexin-A (OX-A)/orexin receptor 1 (OX1R) mediated TLR4/NF-κB/NLRP3 signaling pathway in the neuroprotective effects of TNS in rats with TBI.
METHODS
Sprague-Dawley rats were randomly assigned to four groups: sham, TBI, TBI+TNS+SB334867, and TBI+TNS. TBI was induced using a modified Feeney's method, and subsequent behavioral assessments were conducted to evaluate neurological function. The trigeminal nerve trunk was isolated, and TNS was administered following the establishment of the TBI model. The levels of neuroinflammation, brain tissue damage, and proteins associated with the OX1R/TLR4/NF-κB/NLRP3 signaling pathway were assessed using hematoxylin-eosin staining, Nissl staining, western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence techniques.
RESULTS
The findings of our study indicate that TNS effectively mitigated tissue damage, reduced brain edema, and alleviated neurological deficits in rats with TBI. Furthermore, TNS demonstrated the ability to attenuate neuroinflammation levels and inhibit the expression of proteins associated with the TLR4/NF-κB/NLRP3 signaling pathway. However, it is important to note that the aforementioned effects of TNS were reversible upon intracerebroventricular injection of an OX1R antagonist.
CONCLUSION
TNS may prevent brain damage and relieve neurological deficits after a TBI by inhibiting inflammation, possibly via the TLR4/NF-κB/NLRP3 signaling pathway mediated by OX-A/OX1R.
Topics: Animals; Brain Injuries, Traumatic; Toll-Like Receptor 4; Rats, Sprague-Dawley; Orexin Receptors; Signal Transduction; Rats; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Male; Trigeminal Nerve; Orexins; Electric Stimulation Therapy; Disease Models, Animal
PubMed: 38713160
DOI: 10.18632/aging.205795 -
Molecular and Cellular Neurosciences Jun 2024Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is...
Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is sex-based and presence of sleeping disorders in PD also shows sex bias with a stronger phenotype in males. In addition to loss of dopamine-containing neurons in the striatum, arousal-related, orexin-containing neurons in the lateral hypothalamus (LH) are lost in PD, which could contribute to state-related disorders. As orexin has been shown to be involved in sleeping disorders and to have neuroprotective effects, we asked whether orexin could protect sleep-related LH neurons from damage putatively from the protein α-synuclein (α-syn), which is found at high levels in the PD brain and that we have shown is associated with putatively excitotoxic rises in intracellular calcium in brainstem sleep-controlling nuclei, especially in males. Accordingly, we monitored intracellular calcium transients induced by α-syn and whether concurrent exposure to orexin affected those transients in LH cells of the mouse brain slice using calcium imaging. Further, we used an assay of cell death to determine whether LH cell viability was influenced when α-syn and orexin were co-applied when compared to exposure to α-syn alone. We found that excitatory calcium events induced by α-syn were reduced in amplitude and frequency when orexin was co-applied, and when data were evaluated by sex, this effect was found to be greater in females. In addition, α-syn exposure was associated with cell death that was higher in males, and interestingly, reduced cell death was noted when orexin was present, which did not show a sex bias. We interpret our findings to indicate that orexin is protective to α-syn-mediated damage to hypothalamic neurons, and the actions of orexin on α-syn-induced cellular effects differ between sexes, which could underlie sex-based differences in sleeping disorders in PD.
Topics: Animals; Orexins; Male; Mice; Neurons; Female; Hypothalamic Area, Lateral; alpha-Synuclein; Cell Death; Calcium; Mice, Inbred C57BL; Sex Characteristics
PubMed: 38701995
DOI: 10.1016/j.mcn.2024.103934 -
Frontiers in Cellular Neuroscience 2024The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small... (Review)
Review
The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.
PubMed: 38699177
DOI: 10.3389/fncel.2024.1336145 -
Clinical Case Reports May 2024This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal...
KEY CLINICAL MESSAGE
This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse.
ABSTRACT
Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.
PubMed: 38698873
DOI: 10.1002/ccr3.8740 -
Research (Washington, D.C.) 2024Proper timing of vigilance states serves fundamental brain functions. Although disturbance of sleep onset rapid eye movement (SOREM) sleep is frequently reported after...
Proper timing of vigilance states serves fundamental brain functions. Although disturbance of sleep onset rapid eye movement (SOREM) sleep is frequently reported after orexin deficiency, their causal relationship still remains elusive. Here, we further study a specific subgroup of orexin neurons with convergent projection to the REM sleep promoting sublaterodorsal tegmental nucleus (OX neurons). Intriguingly, although OX and other projection-labeled orexin neurons exhibit similar activity dynamics during REM sleep, only the activation level of OX neurons exhibits a significant positive correlation with the post-inter-REM sleep interval duration, revealing an essential role for the orexin-sublaterodorsal tegmental nucleus (SLD) neural pathway in relieving REM sleep pressure. Monosynaptic tracing reveals that multiple inputs may help shape this REM sleep-related dynamics of OX neurons. Genetic ablation further shows that the homeostatic architecture of sleep/wakefulness cycles, especially avoidance of SOREM sleep-like transition, is dependent on this activity. A positive correlation between the SOREM sleep occurrence probability and depression states of narcoleptic patients further demonstrates the possible significance of the orexin-SLD pathway on REM sleep homeostasis.
PubMed: 38694202
DOI: 10.34133/research.0355 -
Endocrine Connections Jun 2024This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying...
OBJECTIVE
This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism.
METHODS
A total of 156 adult men were included, comprising active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, as well as the trace elements iron and zinc in CSF, were assessed.
RESULTS
Compared to nonsmokers, active smokers showed higher BMI, and elevated CSF levels of FGF21, Zn, and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers.
CONCLUSION
These data relate smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize metabolic hormones such as adiponectin, ghrelin, leptin, or orexin A in the brain, by disrupting mitochondrial function and causing oxidative stress in the neurons.
PubMed: 38688314
DOI: 10.1530/EC-24-0016 -
[Research Progress in the Correlation Between Dopamine and Clinical Characterization of Narcolepsy].Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Apr 2024Dopamine,a neurotransmitter ubiquitous in the body fluids,blood,and urine of mammals and humans,is responsible for regulating their functions and metabolism.The dopamine... (Review)
Review
Dopamine,a neurotransmitter ubiquitous in the body fluids,blood,and urine of mammals and humans,is responsible for regulating their functions and metabolism.The dopamine system is involved in the neurobiological mechanisms of narcolepsy in animals and humans.However,researchers have drawn different or even opposite conclusions when measuring the dopamine level in the cerebrospinal fluid of narcolepsy patients.Studies have confirmed that the occurrence of narcolepsy is related to the irreversible loss of orexins.The autoimmune reaction caused by the interactions of environmental factors with genetic factors destroys the hypothalamic orexin neurons and reduces orexin secretion,thereby lowering the level of arousal.We introduce the research progress and current status of dopamine and clinical characterization of narcolepsy by reviewing more than 40 articles published from 1982 to 2023,aiming to provide a reference for studying the relationship between the dopamine level and clinical characterization of narcolepsy and searching for the biomarkers of type 2 narcolepsy.
Topics: Animals; Humans; Dopamine; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins
PubMed: 38686723
DOI: 10.3881/j.issn.1000-503X.15593 -
Journal of Cellular and Molecular... May 2024Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited....
Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi-omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin-A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin-A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin-A-induced ferroptosis.
Topics: Animals; Humans; Mice; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Ferroptosis; Gene Expression Regulation, Neoplastic; Glioblastoma; Iron; NF-E2-Related Factor 2; Orexins; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38685674
DOI: 10.1111/jcmm.18318 -
Biological Psychiatry Global Open... May 2024Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of...
BACKGROUND
Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO reactivity predicts fear memory after extinction. We also examined whether CO reactivity predicts fear memory after retrieval-extinction.
METHODS
Male rats first underwent a CO challenge and fear conditioning and were assigned to receive either standard extinction ( = 28) or retrieval-extinction ( = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test.
RESULTS
We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree.
CONCLUSIONS
CO reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.
PubMed: 38680941
DOI: 10.1016/j.bpsgos.2024.100310 -
Respirology Case Reports May 2024We report the first case of drug-induced interstitial lung disease attributed to lemborexant. A 66-year-old man reported to our hospital with the acute onset of cough...
We report the first case of drug-induced interstitial lung disease attributed to lemborexant. A 66-year-old man reported to our hospital with the acute onset of cough and breathlessness with ground-glass opacity on radiological examination. Symptoms were identified after taking lemborexant for 2 consecutive days. The patient had undergone lemborexant treatment 2 years prior and had exhibited no symptoms at that time. The drug-induced lymphocyte stimulation test for lemborexant was positive. He showed rapid improvement upon treatment with steroid. With the rise in prescriptions of lemborexant for insomnia, lemborexant should be considered as a possible cause of drug-induced interstitial lung disease.
PubMed: 38680666
DOI: 10.1002/rcr2.1334