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International Journal of Molecular... May 2024Alzheimer's disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the... (Review)
Review
Alzheimer's disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep-wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CBR-OXR complex expression, while OXR antagonism potentiates the neuroprotective effects of CBR. Specifically, pretreatment with the OXR antagonist has been shown to strongly potentiate CBR signaling in the cAMP pathway. Furthermore, the blockade of OXR can also abolish the detrimental effects of OXR overactivation in AD. In this sense, CBR-OXR becomes a new potential therapeutic target to combat AD.
Topics: Alzheimer Disease; Animals; Humans; Cannabinoids; Orexins; Orexin Receptors; Receptors, Cannabinoid; Signal Transduction; Amyloid beta-Peptides
PubMed: 38791416
DOI: 10.3390/ijms25105378 -
Brain Sciences May 2024Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy...
Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE.
PubMed: 38790443
DOI: 10.3390/brainsci14050464 -
The Journal of Neuroscience : the... May 2024We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by...
We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin releasing hormone (CRH) neurons. We hypothesized that in male rats orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, ) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867;1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine-hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R. Previously we showed that orexin contributes to the peripheral chemoreflex (PCR), but the mechanisms underlying this effect remain unknown. Here we show that: 1) orexin receptor blockade reduces the activation of the PVN and nTS; 2) hypoxia activates orexin neurons that project to the PVN, but not those projecting to nTS; 3) orexin receptor blockade reduces the activation of nTS-projecting corticotrophin releasing hormone (CRH) neurons in the PVN; 4) orexin 1 receptor (Ox1R) blockade and specific Ox1R knockdown in the PVN reduce the strength of the PCR, and 5) Ox1R knockdown reduces the number of activated PVN neurons and tyrosine-hydroxylase neurons in the nTS. These findings suggest that PVN-projecting orexin neurons facilitate the PCR via Ox1R on nTS-projecting CRH neurons.
PubMed: 38789262
DOI: 10.1523/JNEUROSCI.2383-23.2024 -
Neuropeptides Aug 2024Heat stress (HS) is a global serious issue in the poultry industry with numerous adverse effects, including increased stress, depressed feed intake (FI), poor growth...
Heat stress (HS) is a global serious issue in the poultry industry with numerous adverse effects, including increased stress, depressed feed intake (FI), poor growth performance and higher mortality. Herbal adaptogens, plant extracts considered as stress response modifiers, are metabolic regulators that improve an organism's ability to adapt to and minimize damage from environmental stresses. Previously, we showed that herbal adaptogen supplementation increased FI and body weight (BW) of broiler (meat-type) chickens reared under HS conditions. Therefore, we hypothesized that these effects may be mediated through modulation of hypothalamic feeding-related neuropeptides. Male Cobb 500 chicks were reared in 12 environmental chambers with three diets: a corn-soybean-based diet (C) and two herbal adaptogen-supplemented diets at 500 g/1000 kg (NR-PHY-500) and 1 kg/1000 kg (NR-PHY-1000). Broilers in 9 chambers were exposed to chronic cyclic HS (35 °C for 8 h/day) from d29 to d42, while 3 chambers were maintained at 24 °C (thermoneutral, TN) for all 42 days. Hypothalamic samples were collected on d42 from each group, both before the onset of HS (Pre-HS) that day and after 3 h of HS (post-HS). Hypothalamic expressions of neuropeptide Y (NPY) receptors Y4 and Y7, Corticotropin-releasing hormone (CRH), orexin receptor 1 (ORXR1), melanocortin receptors (MC1R, MC4R, and MC5R), visfatin and neurosecretory protein GL (NPGL) genes were significantly upregulated by adaptogen supplementation. The hypothalamic expression of MC2R was affect by period, with a significant upregulation during post-HS phase. There was a significant period by treatment interaction for hypothalamic orexin and adiponectin expression. The hypothalamic expression of NPY, Y1, Y2, Y5, Y6, proopiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), agouti-related peptide (AgRP), ORXR2, AdipR1/2, MC3R, and ghrelin was not affected by diet supplementation nor by HS exposure. In conclusion, these findings suggest that in-feed supplementation of adaptogen might improve FI and growth via modulation of hypothalamic feeding-related neuropeptides in heat-stressed broilers.
Topics: Animals; Chickens; Hypothalamus; Neuropeptides; Male; Dietary Supplements; Animal Feed; Heat-Shock Response; Eating
PubMed: 38788297
DOI: 10.1016/j.npep.2024.102439 -
Molecular Biology Reports May 2024The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been...
Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.
BACKGROUND
The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear.
METHODS
An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK).
RESULTS
OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells.
CONCLUSIONS
This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.
Topics: Dopaminergic Neurons; Animals; Mice; Phosphorylation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Extracellular Signal-Regulated MAP Kinases; Orexins; Humans; Male; Cell Line, Tumor; Disease Models, Animal; Neuroprotective Agents; Mice, Inbred C57BL; Parkinson Disease; 1-Methyl-4-phenylpyridinium; MAP Kinase Signaling System
PubMed: 38787465
DOI: 10.1007/s11033-024-09587-2 -
Clinical Neurology and Neurosurgery Jul 2024Parkinson's disease (PD) is a progressive neurological condition that affects movement and coordination. Orexin-A (OXA) is an excitatory neuropeptide that is found... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Parkinson's disease (PD) is a progressive neurological condition that affects movement and coordination. Orexin-A (OXA) is an excitatory neuropeptide that is found throughout the central nervous system. There is growing interest in investigating the potential diagnostic and therapeutic utility of OXA in PD. To date, studies have reported a wide range of OXA concentrations in patients with PD. In this review, we discuss the current understanding of the dysregulation of OXA in PD and analyze its levels in the CSF.
METHODS
We searched six databases (PubMed, Scopus, Web of Science, EMBASE, ProQuest, and EBSCOHost) and preprint servers using a predetermined search strategy through 4th March 4, 2023. The search keywords included "Parkinson's disease", "Orexin-A", "Hypocretin-1", "cerebrospinal fluid", and "CSF". Studies that reported OXA/Hypocretin-1 levels in the CSF of patients with PD were included. Two researchers independently reviewed the records and extracted data.
FINDINGS
Eighteen studies involving 244 patients were analyzed. CSF Orexin-A concentrations were lower in patients with Parkinson's disease than in controls, with a mean difference of -59.21 (95 % CI: -89.10 to -29.32). The mean OXA levels were 281.52 (95 % CI: 226.65-336.40).
CONCLUSION
Our analysis reveals lower concentrations of orexin-A in the cerebrospinal fluid of Parkinson's disease patients compared to controls, but within the normal range. These findings suggest a potential, but not significant, disruption in the orexinergic system associated with the disease.
Topics: Orexins; Humans; Parkinson Disease
PubMed: 38781804
DOI: 10.1016/j.clineuro.2024.108320 -
Cellular and Molecular Life Sciences :... May 2024CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This...
CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This includes reducing M1-like macrophages, enhancing M2-like macrophages, inhibiting NK cell cytotoxicity, and downregulating CTL responses. Activation of CD200R has been found to modulate dendritic cells, leading to the induction or enhancement of Treg cells expressing Foxp3. However, the precise mechanisms behind this process are still unclear. Our previous study demonstrated that B cells in Peyer's patches can induce Treg cells, so-called Treg-of-B (P) cells, through STAT6 phosphorylation. This study aimed to investigate the role of CD200 in Treg-of-B (P) cell generation. To clarify the mechanisms, we used wild-type, STAT6 deficient, and IL-24 deficient T cells to generate Treg-of-B (P) cells, and antagonist antibodies (anti-CD200 and anti-IL-20RB), an agonist anti-CD200R antibody, CD39 inhibitors (ARL67156 and POM-1), a STAT6 inhibitor (AS1517499), and soluble IL-20RB were also applied. Our findings revealed that Peyer's patch B cells expressed CD200 to activate the CD200R on T cells and initiate the process of Treg-of-B (P) cells generation. CD200 and CD200R interaction triggers the phosphorylation of STAT6, which regulated the expression of CD200R, CD39, and IL-24 in T cells. CD39 regulated the expression of IL-24, which sustained the expression of CD223 and IL-10 and maintained the cell viability. In summary, the generation of Treg-of-B (P) cells by Peyer's patch B cells was through the CD200R-STAT6-CD39-IL-24 axis pathway.
Topics: Animals; T-Lymphocytes, Regulatory; Mice; B-Lymphocytes; STAT6 Transcription Factor; Mice, Inbred C57BL; Orexin Receptors; Antigens, CD; Signal Transduction; Phosphorylation; Peyer's Patches; Apyrase; Membrane Glycoproteins
PubMed: 38780647
DOI: 10.1007/s00018-024-05268-2 -
Current Protein & Peptide Science May 2024Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory...
Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory dysfunctions, male infertility, polycystic ovary syndrome, and tubule disease. The remaining 15% have infertility for unknown reasons, including lifestyle and environmental factors. The regulation of the hypothalamic- pituitary-adrenal axis (HPA) is crucial for the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are essential for female reproductive functions. GnRH is the primary reproductive axis regulator. The pattern of GnRH, FSH, and LH release is determined by its pulsatile secretion, which in turn controls endocrine function and gamete maturation in the gonads. Peptides called Kisspeptin (KP), Neurokinin-B (NKB), and Orexin influence both positive and negative feedback modulation of GnRH, FSH, and LH secretion in reproduction. This review article mainly focuses on the historical perspective, isoform, and signaling pathways of KP, NKB, and Orexin novel peptide-based targets including clinical and preclinical studies and having a promising effect in the management of infertility.
PubMed: 38778605
DOI: 10.2174/0113892037304433240430144106 -
Nature Neuroscience May 2024Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to...
Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of >900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain's arousal orchestrators.
PubMed: 38773350
DOI: 10.1038/s41593-024-01648-w -
Appetite May 2024The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A (DYN) in the...
The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A (DYN) in the paraventricular hypothalamic nucleus (PVN) increases palatable food intake, and this effect is blocked by co-administration of the orexin-A neuropeptide, which is co-released with DYN in PVN from neurons located in the lateral hypothalamus. While PVN administration of DYN increases palatable food intake, whether it increases food-seeking behaviors has yet to be examined. We tested the effects of DYN and norBNI (a KOR antagonist) on the seeking and consumption of sucrose using a progressive ratio (PR) and demand curve (DC) tasks. In PVN, DYN did not alter the sucrose breaking point (BP) in the PR task nor the elasticity or intensity of demand for sucrose in the DC task. Still, DYN reduced the delay in obtaining sucrose and increased licks during sucrose intake in the PR task, irrespective of the co-administration of orexin-A. In PVN, norBNI increased the delay in obtaining sucrose and reduced licks during sucrose intake in the PR task while increasing elasticity without altering intensity of demand in the DC task. However, subcutaneous norBNI reduced the BP for sucrose and increased the delay in obtaining sucrose in the PR task while reducing the elasticity of demand. Together, these data show different effects of systemic and PVN blockade of KOR on food-seeking, consummatory behaviors, and incentive motivation for sucrose and suggest that KOR activity in PVN is necessary but not sufficient to drive seeking behaviors for palatable food.
PubMed: 38768926
DOI: 10.1016/j.appet.2024.107504