Novel insight into astrocyte-mediated gliotransmission modulates the synaptic plasticity in major depressive disorder

Life Sciences, Journal Year: 2024, Volume and Issue: 355, P. 122988 - 122988

Published: Aug. 15, 2024

Language: Английский

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Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(6), P. 708 - 708

Published: May 24, 2024

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable characterized by the gradual loss neurons, culminating in decline cognitive and/or motor functions. Alzheimer’s disease (AD) Parkinson’s (PD) most common NDs represent an enormous burden both terms human suffering economic cost. The available therapies for AD PD only provide symptomatic palliative relief limited period unable to modify diseases’ progression. Over last decades, research efforts have been focused on developing new pharmacological treatments these NDs. However, date, no breakthrough treatment has discovered. Hence, development disease-modifying drugs able halt or reverse progression remains unmet clinical need. This review summarizes major hallmarks treatment. It also sheds light potential directions that can be pursued develop new, treat PD, describing as representative examples some advances drug candidates targeting oxidative stress adenosine A2A receptors.

Language: Английский

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Theobromine improves hyperactivity, inattention, and working memory via modulation of dopaminergic neural function in the frontal cortex of spontaneously hypertensive rats

Food & Function, Journal Year: 2024, Volume and Issue: 15(10), P. 5579 - 5595

Published: Jan. 1, 2024

Attention-deficit/hyperactivity disorder (ADHD) is a developmental and dopaminergic dysfunction in the prefrontal cortex (PFC) may play role. Our previous research indicated that theobromine (TB), methylxanthine, enhances cognitive function rodents via PFC. This study investigates TB's effects on hyperactivity stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received diet containing 0.05% TB for 40 days, while control normal diets. Age-matched male Wistar-Kyoto (WKY) served as genetic controls. During administration period, we conducted open-field tests Y-maze tasks to evaluate function, then assessed dopamine concentrations tyrosine hydroxylase (TH), receptor D1-5 (DRD1-5), transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), brain-derived neurotrophic factor (BDNF) expressions Additionally, binding affinity of adenosine receptors (ARs) was evaluated. Compared WKY, SHR exhibited hyperactivity, inattention working memory deficits. However, chronic significantly improved these ADHD-like behaviors SHR. also normalized expression levels TH, DRD2, DRD4, SNAP-25, BDNF PFC No changes were observed DRD1, DRD3, DRD5, DAT, VMAT-2 between WKY rats, intake had minimal effects. found have ARs. These results indicate long-term supplementation mitigates deficits by modulating nervous PFC, representing potential adjunctive treatment ADHD.

Language: Английский

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Understanding electrical and chemical transmission in the brain

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: June 26, 2024

The histochemical Falck-Hillarp method for the localization of dopamine (DA), noradrenaline (NA) and serotonin in central nervous system (CNS) rodents was introduced 1960s. It supported existence chemical neurotransmission CNS. monoamine neurons lower brain stem formed monosynaptic ascending systems to telencephalon diencephalon descending entire spinal cord. monoamines were early on suggested operate via synaptic transmission This reduced impact electrical transmission. In 1969 1970s indications obtained that important modes communication CNS also took place through extra-synaptic fluid, extracellular long-distance cerebrospinal fluid involving diffusion flow transmitters like DA, NA serotonin. 1986, this type named volume (VT) by Agnati Fuxe their colleagues, characterized transmitter varicosity receptor mismatches. short VT pathways fraction, tortuosity clearance. Electrical exists mammalian CNS, but is dominance. One mode represented synapses gap junctions which represent low resistant passages between nerve cells. allows a more rapid passage action potentials cells compared second based ability currents generate fields modulate aim understand how can be integrated with putative (aquaporin water channel, D2R adenosine A2AR) complexes astrocytes significancy participate clearance waste products from glymphatic system. may help accomplish operation acupuncture meridians essential Chinese medicine view indicated pathways.

Language: Английский

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Comparing adenosine A_2A receptor modulation of cannabinoid CB₁ receptor‐mediated inhibition of GABA and glutamate release in rodent striatal nerve terminals

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(1)

Published: Jan. 1, 2025

Abstract In corticostriatal nerve terminals, glutamate release is stimulated by adenosine via A 2A receptors (A Rs) and simultaneously inhibited endocannabinoids CB 1 (CB Rs). We previously identified presynaptic R–CB R heterotetrameric complexes in terminals. now explored the possible functional interaction between Rs purified striatal GABAergic terminals (synaptosomes) compared these findings with those on of glutamate. synaptosomes rats wild‐type mice, synthetic cannabinoid receptor agonist WIN55212‐2 (10–1000 nM) attenuated Ca 2+ ‐dependent, high‐K + ‐evoked γ‐[2,3‐ 3 H(N)]‐aminobutyric acid ([ H]GABA) [ H]glutamate. did not affect evoked either neurotransmitter under blockade AM251 or O‐2050 knockout (KO) mice. The R‐selective CGS21680 (30 antagonist SCH58261 (100 dampened inhibitory action rat synaptosomes. Another antagonist, ZM241385 nM), abolished inhibition both H]GABA Surprisingly, also failed to inhibit but H]glutamate KO mice CD‐1 C57BL/6 strains. synaptosomal membranes, binding H]ZM241385 was affected cannabinoids. However, reduced B max while increased K D H]SR141716A R, indicating an R‐ligand‐specific modulation function. were whereas smaller Altogether, our data reveal intricate interdependence neuromodulation.

Language: Английский

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Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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GPCR oligomerization across classes: A2AR-mediated regulation of mGlu5R activation

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 299, P. 139880 - 139880

Published: Jan. 20, 2025

The adenosine A2A receptor (A2AR), a class A GPCR, is known player in neurological diseases, including Parkinson's disease and Alzheimer's disease, also implicated SARS-CoV-2 infection. Recent studies have revealed its oligomerization with metabotropic glutamate type 5 (mGlu5R), C G protein coupled (GPCR) that exists the homodimeric form. Simultaneous activation of both receptors synergistically enhances mGlu5R-mediated effects hippocampus. Despite their importance, molecular mechanisms governing these interactions remain unclear. In this study, we used modelling techniques, docking, extensive dynamics (MD) simulations, detailed analysis, to elucidate between mGlu5R A2AR inactive active states. Our findings provide molecular-level insights into permissive role activation, demonstrating interface within oligomer blocks transmembrane helix 6 (TM6), which crucial for activation. Upon undergoes conformational rearrangement, exposing mGlu5R-TM6 allowing Furthermore, identified pivotal mGlu5R-TM4:A2AR-TM4 facilitating These results highlight intricate architecture mGlu5R:A2AR oligomer, advancing our understanding GPCR regulatory on activity.

Language: Английский

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Role of dopamine receptor heteromerization in preclinical models of addiction and other psychiatric disorders

Exploration of Neuroprotective Therapy, Journal Year: 2025, Volume and Issue: 5

Published: April 1, 2025

Similar to other psychiatric disorders, drug addiction is linked changes in neuronal activity within the mesolimbic system, which consists of dopamine (DA) neurons ventral tegmental area projecting part striatum, nucleus accumbens (NAc). All drugs abuse indeed artificially increase DA concentration NAc, hijacks reward system and triggers lasting behavioral alterations, including compulsive drug-seeking drug-taking behavior despite negative consequences a high rate relapse after abstinence. chiefly signals through receptor (DAR) type 1 (D1R) 2 (D2R), are G protein-coupled (GPCR) that positively negatively coupled adenyl cyclase, respectively. Multiple evidence indicates potent modulatory roles on neurotransmitters neuromodulator systems implicate direct physical interactions (i.e., heteromerization) DAR with receptors. heteromerization, increased several preclinical models leads reciprocal fine-tuned modulation partner receptors, therefore suggesting targeting heteromerization may contribute development clinically relevant strategies. Herein, we provide an overview current methodologies used for detecting heteromers both heterologous situ brain discuss their respective advantages limitations. We also argue D1R D2R have been shown form multiple receptors but only few studies were able proof existence or establish biological roles. This review will emphasize describing functions particular focus addiction, field those processes most extensively studied.

Language: Английский

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Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?

Published: April 5, 2024

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable characterized by the gradual loss neurons, culminating in decline cognitive and/or motor functions. Alzheimer’s disease (AD) Parkinson’s (PD) most common NDs represent an enormous burden both terms human suffering economic cost. The available therapies for AD PD only provide symptomatic palliative relief limited period unable to modify diseases’ progression. Over last decades, research efforts have been focused on developing new pharmacological treatments these NDs. However, date, no breakthrough treatment has discovered. Hence, development disease-modifying drugs able halt or reverse progression remains unmet clinical need. This review summarizes major hallmarks treatment. It also sheds light potential directions that can be pursued develop new, treat PD, thereby decreasing social burdens linked

Language: Английский

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Modulation of Neuron and Astrocyte Dopamine Receptors via Receptor–Receptor Interactions

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(10), P. 1427 - 1427

Published: Oct. 8, 2023

Dopamine neurotransmission plays critical roles in regulating complex cognitive and behavioral processes including reward, motivation, reinforcement learning, movement. receptors are classified into five subtypes, widely distributed across the brain, regions responsible for motor functions specific areas related to emotional functions. also acts on astrocytes, which express dopamine as well. The discovery of direct receptor–receptor interactions, leading formation multimeric receptor complexes at cell membrane providing decoding apparatus with flexible dynamics terms recognition signal transduction, has expanded knowledge G-protein-coupled receptor-mediated signaling processes. purpose this review article is provide an overview currently identified containing their modulatory action dopamine-mediated between neurons astrocytes. Pharmacological possibilities offered by targeting addressing neuropsychiatric disorders associated altered will be briefly discussed.

Language: Английский

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