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The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 10908

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Dr. Jonathan Mapelli

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Dept Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Interests: synaptic plasticity; cerebellum; computational neuroscience; neural circuits; synaptic transmission; neuronal excitability; imaging; non-linear microscopy
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue “The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments”.

Brain functionality is inherently bound to the information transmitted among neural circuits, which, in turn, depends on a wide series of factors residing in synaptic connections. It is therefore evident that changes in synaptic functions are critically involved in the emergence of brain functionality as well as neural diseases and pharmacological treatments. In particular, despite their reduced dimensions, synaptic complexes display a huge number of molecular pathways both on the pre- and post-synaptic side, which can be potentially targeted by exogenous molecules, and although several drugs and molecules have been described to interfering with synaptic activity, we are very far from a definitive description.

This Special Issue will accept articles covering different aspects of the pharmacology of neurotransmission, paying particular attention to the effects on synaptic targets in terms of functionality. Manuscripts regarding new synaptic molecular targets, new drugs, treatments of neural disorders or neurodegenerative diseases, and computational effects of drug application will be more than welcome.

This Special Issue aims to focus on both basic science and translational research as well as clinical evidence to have a larger and more inclusive understanding of neurotransmission, allowing to shed light into this complicated and puzzling scenario.

Dr. Jonathan Mapelli
Guest Editor

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Keywords

synapses
ion channels
neuromodulation
neurons
information transmission
neurotransmitter
synaptic plasticity
mutual information
neurogenerative diseases
neural disorders
neural circuits
synaptic complex
GABA
glutamate
glycine
peptides
synaptic proteins
synaptic vesicles
vesicle release

Published Papers (5 papers)

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Research

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19 pages, 2863 KiB

Open AccessArticle

Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer’s Disease

by Xueqi Qu, Li Lin, Wanying Yi, Changyu Sun, Yuewen Chen and Yu Chen

Int. J. Mol. Sci. 2022, 23(16), 8888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168888 - 10 Aug 2022

Cited by 1 | Viewed by 1820

Abstract

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by the progressive decline of cognitive functions, and is closely associated with the dysfunction of synapses, which comprise the basic structure that mediates the communication between neurons. Although the protein architecture and machinery for protein translation at synapses are extensively studied, the impact that local changes in the mRNA reservoir have on AD progression is largely unknown. Here, we investigated the changes in transcriptomic profiles in the synaptodendrosomes purified from the cortices of AD mice at ages 3 and 6 months, a stage when early signatures of synaptic dysfunction are revealed. The transcriptomic profiles of synaptodendrosomes showed a greater number of localized differentially expressed genes (DEGs) in 6-month-old AD mice compared with mice 3 months of age. Gene Ontology (GO) analysis showed that these DEGs are majorly enriched in mitochondrial biogenesis and metabolic activity. More specifically, we further identified three representative DEGs in mitochondrial and metabolic pathways—Prnp, Cst3, and Cox6c—that regulate the dendritic spine density and morphology in neurons. Taken together, this study provides insights into the transcriptomic changes in synaptodendrosomes during AD progression, which may facilitate the development of intervention strategies targeting local translation to ameliorate the pathological progression of AD. Full article

(This article belongs to the Special Issue The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0)

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16 pages, 4411 KiB

Open AccessArticle

An Anthranilate Derivative Inhibits Glutamate Release and Glutamate Excitotoxicity in Rats

by Cheng-Wei Lu, Chen-Jung Lin, Pei-Wen Hsieh, Kuan-Ming Chiu, Ming-Yi Lee, Tzu-Yu Lin and Su-Jane Wang

Int. J. Mol. Sci. 2022, 23(5), 2641; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052641 - 27 Feb 2022

Cited by 2 | Viewed by 1814

Abstract

The neurotransmitter glutamate plays an essential role in excitatory neurotransmission; however, excessive amounts of glutamate lead to excitotoxicity, which is the most common pathogenic feature of numerous brain disorders. This study aimed to investigate the role of butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034), a synthesized anthranilate derivative, in the central glutamatergic system. We used rat cerebro-cortical synaptosomes to examine the effect of HFP034 on glutamate release. In addition, we used a rat model of kainic acid (KA)-induced glutamate excitotoxicity to evaluate the neuroprotective potential of HFP034. We showed that HFP034 inhibits 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes, and this inhibition was absent in the absence of extracellular calcium. HFP034-mediated inhibition of glutamate release was associated with decreased 4-AP-evoked Ca²⁺ level elevation and had no effect on synaptosomal membrane potential. The inhibitory effect of HFP034 on evoked glutamate release was suppressed by blocking P/Q-type Ca²⁺ channels and protein kinase C (PKC). Furthermore, HFP034 inhibited the phosphorylation of PKC and its substrate, myristoylated alanine-rich C kinase substrate (MARCKS) in synaptosomes. We also observed that HFP034 pretreatment reduced neuronal death, glutamate concentration, glial activation, and the levels of endoplasmic reticulum stress-related proteins, calpains, glucose-regulated protein 78 (GRP 78), C/EBP homologous protein (CHOP), and caspase-12 in the hippocampus of KA-injected rats. We conclude that HFP034 is a neuroprotective agent that prevents glutamate excitotoxicity, and we suggest that this effect involves inhibition of presynaptic glutamate release through the suppression of P/Q-type Ca²⁺ channels and PKC/MARCKS pathways. Full article

(This article belongs to the Special Issue The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0)

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13 pages, 3209 KiB

Open AccessArticle

Effect of NSAIDs Supplementation on the PACAP-, SP- and GAL-Immunoreactive Neurons in the Porcine Jejunum

by Marta Brzozowska, Barbara Jana and Jarosław Całka

Int. J. Mol. Sci. 2021, 22(21), 11689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111689 - 28 Oct 2021

Cited by 4 | Viewed by 1550

Abstract

Side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment are a serious limitation of their use in anti-inflammatory therapy. The negative effects of taking NSAIDs include abdominal pain, indigestion nausea as well as serious complications such as bleeding and perforation. The enteric nervous system is involved in regulation of gastrointestinal functions through the release of neurotransmitters. The present study was designed to determine, for the first time, the changes in pituitary adenylate cyclase-activating polypeptide (PACAP), substance P (SP) and galanin (GAL) expression in porcine jejunum after long-term treatment with aspirin, indomethacin and naproxen. The study was performed on 16 immature pigs. The animals were randomly divided into four experimental groups: control, aspirin, indomethacin and naproxen. Control animals were given empty gelatin capsules, while animals in the test groups received selected NSAIDs for 28 days. Next, animals from each group were euthanized. Frozen sections were prepared from collected jejunum and subjected to double immunofluorescence staining. NSAIDs supplementation caused a significant increase in the population of PACAP-, SP- and GAL-containing enteric neurons in the porcine jejunum. Our results suggest the participation of the selected neurotransmitters in regulatory processes of the gastrointestinal function and may indicate the direct toxic effect of NSAIDs on the ENS neurons. Full article

(This article belongs to the Special Issue The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0)

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14 pages, 3635 KiB

Open AccessArticle

Chlorogenic Acid Decreases Glutamate Release from Rat Cortical Nerve Terminals by P/Q-Type Ca²⁺ Channel Suppression: A Possible Neuroprotective Mechanism

by Yi-Chieh Hung, Yi-Hsiu Kuo, Pei-Wen Hsieh, Ting-Yang Hsieh, Jinn-Rung Kuo and Su-Jane Wang

Int. J. Mol. Sci. 2021, 22(21), 11447; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111447 - 23 Oct 2021

Cited by 14 | Viewed by 2698

Abstract

The glutamatergic neurotransmitter system has received substantial attention in research on the pathophysiology and treatment of neurological disorders. The study investigated the effect of the polyphenolic compound chlorogenic acid (CGA) on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). CGA inhibited 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes. This inhibition was prevented in the absence of extracellular Ca²⁺ and was associated with the inhibition of 4-AP-induced elevation of Ca²⁺ but was not attributed to changes in synaptosomal membrane potential. In line with evidence observed through molecular docking, CGA did not inhibit glutamate release in the presence of P/Q-type Ca²⁺ channel inhibitors; therefore, CGA-induced inhibition of glutamate release may be mediated by P/Q-type Ca²⁺ channels. CGA-induced inhibition of glutamate release was also diminished by the calmodulin and Ca²⁺/calmodilin-dependent kinase II (CaMKII) inhibitors, and CGA reduced the phosphorylation of CaMKII and its substrate, synapsin I. Furthermore, pretreatment with intraperitoneal CGA injection attenuated the glutamate increment and neuronal damage in the rat cortex that were induced by kainic acid administration. These results indicate that CGA inhibits glutamate release from cortical synaptosomes by suppressing P/Q-type Ca²⁺ channels and CaMKII/synapsin I pathways, thereby preventing excitotoxic damage to cortical neurons. Full article

(This article belongs to the Special Issue The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0)

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Review

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11 pages, 273 KiB

Open AccessReview

Stem Cell Homing in Intrathecal Applications and Inspirations for Improvement Paths

by Dusan M. Maric, Gordana Velikic, Dusica L. Maric, Gordana Supic, Danilo Vojvodic, Vedrana Petric and Dzihan Abazovic

Int. J. Mol. Sci. 2022, 23(8), 4290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084290 - 13 Apr 2022

Cited by 7 | Viewed by 2352

Abstract

A transplanted stem cell homing is a directed migration from the application site to the targeted tissue. Intrathecal application of stem cells is their direct delivery to cerebrospinal fluid, which defines the homing path from the point of injection to the brain. In the case of neurodegenerative diseases, this application method has the advantage of no blood–brain barrier restriction. However, the homing efficiency still needs improvement and homing mechanisms elucidation. Analysis of current research results on homing mechanisms in the light of intrathecal administration revealed a discrepancy between in vivo and in vitro results and a gap between preclinical and clinical research. Combining the existing research with novel insights from cutting-edge biochips, nano, and other technologies and computational models may bridge this gap faster. Full article

(This article belongs to the Special Issue The Pharmacology of Neurotransmission: Focus on Synaptic Alterations during Neurodegeneration and Treatments 2.0)

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