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Neurochemical Research Jun 2024There is some evidence that the serotonin receptor subtype 7 (5-HT) could be new therapeutic target for neuroprotection. The aim of this study was to compare the...
There is some evidence that the serotonin receptor subtype 7 (5-HT) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 μM), whereas at higher concentrations (above 10 μM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of HO-evoked cell damage by all tested 5-HT agonists. However, 5-HT-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to HO. Furthermore, none of the tested 5-HT agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT agonists.
PubMed: 38834845
DOI: 10.1007/s11064-024-04159-z -
Neurochemical Research Jun 2024The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic... (Review)
Review
The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.
PubMed: 38833089
DOI: 10.1007/s11064-024-04172-2 -
Neurobiology of Disease Aug 2024Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and...
BACKGROUND
Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates.
METHODS
A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity.
RESULTS
MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits.
CONCLUSIONS
Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.
Topics: Humans; Multiple System Atrophy; Parkinson Disease; Male; Female; Middle Aged; Aged; Brain; Magnetic Resonance Imaging; Iron; Neurotransmitter Agents; Brain Mapping
PubMed: 38830476
DOI: 10.1016/j.nbd.2024.106549 -
European Journal of Pharmacology Aug 2024The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents...
The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.
Topics: Animals; Lycopene; Indoleamine-Pyrrole 2,3,-Dioxygenase; Mice; Depression; Male; Brain; Receptors, Serotonin, 5-HT3; Phenotype; Molecular Docking Simulation; Serotonin; BCG Vaccine; Ondansetron; Behavior, Animal; Serotonin 5-HT3 Receptor Antagonists; Antidepressive Agents; Minocycline
PubMed: 38830456
DOI: 10.1016/j.ejphar.2024.176707 -
BioRxiv : the Preprint Server For... May 2024Serotonin 2A receptors (5-HT Rs) mediate the effects of psychedelic drugs. 5-HT R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that...
Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner.
Serotonin 2A receptors (5-HT Rs) mediate the effects of psychedelic drugs. 5-HT R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT Rs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT R expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed -Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT R-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT R expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed -Cre compared with control mice, indicating that optogenetic activation of 5-HT R+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT R expressing neurons augmented the HTR produced by DOI. However, this result was not seen in mice. In contrast, inhibition of 5-HT R expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT Rs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT R agonist but is necessary for induction of HTRs by a 5-HT R agonist in a sex-dependent manner.
PubMed: 38826361
DOI: 10.1101/2024.05.21.595211 -
[Zhonghua Yan Ke Za Zhi] Chinese... Jun 2024With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression... (Review)
Review
With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression of various hormone receptors in ocular tissues of both animals and humans. Additionally, changes in hormone levels accompany the development of myopia, although the exact relationships remain inconclusive. This article reviews the potential influences and mechanisms of action of endogenous hormones such as melatonin, serotonin, insulin, glucagon, sex hormones, vitamin D, and prostaglandins in ocular tissues including the retina, choroid, and sclera. It elaborates on the relationship between fluctuations in these hormone levels and the progression of myopia, aiming to provide guidance for exploring targets for myopia prevention and control.
Topics: Humans; Myopia; Melatonin; Vitamin D; Serotonin; Insulin; Glucagon; Animals; Gonadal Steroid Hormones; Prostaglandins; Hormones; Retina
PubMed: 38825955
DOI: 10.3760/cma.j.cn112142-20231106-00213 -
Journal of Psychopharmacology (Oxford,... Jun 2024The highly selective 5-HT serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD)...
The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, like ketamine, elicit rapid-acting antidepressant activity in the rat chronic mild stress model via cortical mechanisms.
BACKGROUND
The highly selective 5-HT serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM).
AIMS
Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT receptor activation in the RAAD activity of NLX compounds.
RESULTS/OUTCOMES
In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT receptors.
CONCLUSIONS/INTERPRETATION
These data indicate that 5-HT receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine's primary mechanism of action) but also by activating 5-HT receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine's troublesome side effects.
PubMed: 38825869
DOI: 10.1177/02698811241254832 -
Biochimica Et Biophysica Acta. General... Aug 2024The phosphoinositide 3-kinase (PI3K) is involved in regulation of multiple intracellular processes. Although the inhibitory analysis is generally employed for validating...
The phosphoinositide 3-kinase (PI3K) is involved in regulation of multiple intracellular processes. Although the inhibitory analysis is generally employed for validating a physiological role of PI3K, increasing body of evidence suggests that PI3K inhibitors can exhibit PI3K-unrelated activity as well. Here we studied Ca signaling initiated by aminergic agonists in a variety of different cells and analyzed effects of the PI3K inhibitor PI828 on cell responsiveness. It turned out that PI828 inhibited Ca transients elicited by acetylcholine (ACh), histamine, and serotonin, but did not affect Ca responses to norepinephrine and ATP. Another PI3K inhibitor wortmannin negligibly affected Ca signaling initiated by any one of the tested agonists. Using the genetically encoded PIP sensor PH(Akt)-Venus, we confirmed that both PI828 and wortmannin effectively inhibited PI3K and ascertained that this kinase negligibly contributed to ACh transduction. These findings suggested that PI828 inhibited Ca responses to aminergic agonists tested, involving an unknown cellular mechanism unrelated to the PI3K inhibition. Complementary physiological experiments provided evidence that PI828 could inhibit Ca signals induced by certain agonists, by acting extracellularly, presumably, through their surface receptors. For the muscarinic M3 receptor, this possibility was verified with molecular docking and molecular dynamics. As demonstrated with these tools, wortmannin could be bound in the extracellular vestibule at the muscarinic M3 receptor but this did not preclude binding of ACh to the M3 receptor followed by its activation. In contrast, PI828 could sterically block the passage of ACh into the allosteric site, preventing activation of the muscarinic M3 receptor.
Topics: Humans; Phosphoinositide-3 Kinase Inhibitors; Calcium; Calcium Signaling; Phosphatidylinositol 3-Kinases; Animals; Wortmannin; Receptors, G-Protein-Coupled; Acetylcholine; HEK293 Cells
PubMed: 38823731
DOI: 10.1016/j.bbagen.2024.130649 -
FASEB Journal : Official Publication of... Jun 2024Previous studies on germ-free (GF) animals have described altered anxiety-like and social behaviors together with dysregulations in brain serotonin (5-HT) metabolism....
Previous studies on germ-free (GF) animals have described altered anxiety-like and social behaviors together with dysregulations in brain serotonin (5-HT) metabolism. Alterations in circulating 5-HT levels and gut 5-HT metabolism have also been reported in GF mice. In this study, we conducted an integrative analysis of various behaviors as well as markers of 5-HT metabolism in the brain and along the GI tract of GF male mice compared with conventional (CV) ones. We found a strong decrease in locomotor activity, accompanied by some signs of increased anxiety-like behavior in GF mice compared with CV mice. Brain gene expression analysis showed no differences in HTR1A and TPH2 genes. In the gut, we found decreased TPH1 expression in the colon of GF mice, while it was increased in the cecum. HTR1A expression was dramatically decreased in the colon, while HTR4 expression was increased both in the cecum and colon of GF mice compared with CV mice. Finally, SLC6A4 expression was increased in the ileum and colon of GF mice compared with CV mice. Our results add to the evidence that the microbiota is involved in regulation of behavior, although heterogeneity among studies suggests a strong impact of genetic and environmental factors on this microbiota-mediated regulation. While no impact of GF status on brain 5-HT was observed, substantial differences in gut 5-HT metabolism were noted, with tissue-dependent results indicating a varying role of microbiota along the GI tract.
Topics: Animals; Serotonin; Mice; Male; Germ-Free Life; Behavior, Animal; Gastrointestinal Microbiome; Brain; Tryptophan Hydroxylase; Anxiety; Serotonin Plasma Membrane Transport Proteins; Mice, Inbred C57BL; Receptor, Serotonin, 5-HT1A; Colon
PubMed: 38822661
DOI: 10.1096/fj.202400334R -
CNS Drugs Jul 2024Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology... (Review)
Review
Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorous than modern day treatment studies, of small sample size, and have not since been replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.
Topics: Migraine Disorders; Humans; Tryptamines; Serotonin Receptor Agonists
PubMed: 38822165
DOI: 10.1007/s40263-024-01091-2