Biomedicines

Research

27 pages, 4058 KiB

Open AccessArticle

BDNF Spinal Overexpression after Spinal Cord Injury Partially Protects Soleus Neuromuscular Junction from Disintegration, Increasing VAChT and AChE Transcripts in Soleus but Not Tibialis Anterior Motoneurons

by Anna Głowacka, Benjun Ji, Andrzej Antoni Szczepankiewicz, Małgorzata Skup and Olga Gajewska-Woźniak

Biomedicines 2022, 10(11), 2851; https://doi.org/10.3390/biomedicines10112851 - 8 Nov 2022

Cited by 6 | Viewed by 3019

Abstract

After spinal cord transection (SCT) the interaction between motoneurons (MNs) and muscle is impaired, due to reorganization of the spinal network after a loss of supraspinal inputs. Rats subjected to SCT, treated with intraspinal injection of a AAV-BDNF (brain-derived neurotrophic factor) construct, partially [...] Read more.

After spinal cord transection (SCT) the interaction between motoneurons (MNs) and muscle is impaired, due to reorganization of the spinal network after a loss of supraspinal inputs. Rats subjected to SCT, treated with intraspinal injection of a AAV-BDNF (brain-derived neurotrophic factor) construct, partially regained the ability to walk. The central effects of this treatment have been identified, but its impact at the neuromuscular junction (NMJ) has not been characterized. Here, we compared the ability of NMJ pre- and postsynaptic machinery in the ankle extensor (Sol) and flexor (TA) muscles to respond to intraspinal AAV-BDNF after SCT. The gene expression of cholinergic molecules (VAChT, ChAT, AChE, nAChR, mAChR) was investigated in tracer-identified, microdissected MN perikarya, and in muscle fibers with the use of qPCR. In the NMJs, a distribution of VAChT, nAChR and Schwann cells was studied by immunofluorescence, and of synaptic vesicles and membrane active zones by electron microscopy. We showed partial protection of the Sol NMJs from disintegration, and upregulation of the VAChT and AChE transcripts in the Sol, but not the TA MNs after spinal enrichment with BDNF. We propose that the observed discrepancy in response to BDNF treatment is an effect of difference in the TrkB expression setting BDNF responsiveness, and of BDNF demands in Sol and TA muscles. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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14 pages, 2202 KiB

Open AccessArticle

The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury

by Maria E. Hammarlund, C. Joakim Ek, Sukaina Akar, Alma Karlsson, Bagmi Pattanaik, Filip Mjörnstedt, Pernilla Svedin, Maryam Ardalan, Eridan Rocha-Ferreira, Carina Mallard and Maria E. Johansson

Biomedicines 2022, 10(8), 2023; https://doi.org/10.3390/biomedicines10082023 - 19 Aug 2022

Cited by 1 | Viewed by 2741

Abstract

Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (α7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about [...] Read more.

Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (α7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about the role of the α7nAChR in neonatal brain injury. Hypoxic-ischemic (HI) brain injury was induced in male and female C57BL/6 mice, α7nAChR knock-out (KO) mice and their littermate controls on postnatal day (PND) 9–10. C57BL/6 pups received i.p. injections of α7nAChR agonist PHA 568487 (8 mg/kg) or saline once daily, with the first dose given directly after HI. Caspase-3 activity and cytokine mRNA expression in the brain was analyzed 24 h after HI. Motor function was assessed 24 and 48 h after HI, and immunohistochemistry was used to assess tissue loss at 24 h and 7 days after HI and microglial activation 7 days after HI. Activation of α7nAChR with the agonist PHA 568487 significantly decreased CCL2/MCP-1, CCL5/RANTES and IL-6 gene expression in the injured brain hemisphere 24 h after HI compared with saline controls in male, but not female, pups. However, α7nAChR activation did not alter caspase-3 activity and TNFα, IL-1β and CD68 mRNA expression. Furthermore, agonist treatment did not affect motor function (24 or 48 h), neuronal tissue loss (24 h or 7 days) or microglia activation (7 days) after HI in either sex. Knock-out of α7nAChR did not influence neuronal tissue loss 7 days after HI. In conclusion, targeting the α7nAChR in neonatal brain injury shows some effect on dampening acute inflammatory responses in male pups. However, this does not lead to an effect on overall injury outcome. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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16 pages, 1753 KiB

Open AccessArticle

Acetylcholine Reduces I_Kr and Prolongs Action Potentials in Human Ventricular Cardiomyocytes

by István Koncz, Arie O. Verkerk, Michele Nicastro, Ronald Wilders, Tamás Árpádffy-Lovas, Tibor Magyar, Noémi Tóth, Norbert Nagy, Micah Madrid, Zexu Lin and Igor R. Efimov

Biomedicines 2022, 10(2), 244; https://doi.org/10.3390/biomedicines10020244 - 24 Jan 2022

Cited by 3 | Viewed by 4503

Abstract

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) [...] Read more.

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) on repolarization in human ventricular cardiomyocytes, as well as the effect of ACh on the rapid component of the delayed rectifier K⁺ current (I_Kr). Here, we investigated the effect of ACh on the action potential parameters in human ventricular preparations and on I_Kr in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Using standard microelectrode technique, we demonstrated that ACh (5 µM) significantly increased the action potential duration in human left ventricular myocardial slices. ACh (5 µM) also prolonged repolarization in a human Purkinje fiber and a papillary muscle. Optical mapping revealed that ACh increased the action potential duration in human left ventricular myocardial slices and that the effect was dose-dependent. Perforated patch clamp experiments demonstrated action potential prolongation and a significant decrease in I_Kr by ACh (5 µM) in hiPSC-CMs. Computer simulations of the electrical activity of a human ventricular cardiomyocyte showed an increase in action potential duration upon implementation of the experimentally observed ACh-induced changes in the fully activated conductance and steady-state activation of I_Kr. Our findings support the hypothesis that ACh can influence the repolarization in human ventricular cardiomyocytes by at least changes in I_Kr. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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Review

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15 pages, 1576 KiB

Open AccessReview

Emerging Roles of Cholinergic Receptors in Schwann Cell Development and Plasticity

by Roberta Piovesana, Adam J. Reid and Ada Maria Tata

Biomedicines 2023, 11(1), 41; https://doi.org/10.3390/biomedicines11010041 - 24 Dec 2022

Cited by 8 | Viewed by 2655

Abstract

The cross talk between neurons and glial cells during development, adulthood, and disease, has been extensively documented. Among the molecules mediating these interactions, neurotransmitters play a relevant role both in myelinating and non-myelinating glial cells, thus resulting as additional candidates regulating the development [...] Read more.

The cross talk between neurons and glial cells during development, adulthood, and disease, has been extensively documented. Among the molecules mediating these interactions, neurotransmitters play a relevant role both in myelinating and non-myelinating glial cells, thus resulting as additional candidates regulating the development and physiology of the glial cells. In this review, we summarise the contribution of the main neurotransmitter receptors in the regulation of the morphogenetic events of glial cells, with particular attention paid to the role of acetylcholine receptors in Schwann cell physiology. In particular, the M2 muscarinic receptor influences Schwann cell phenotype and the α7 nicotinic receptor is emerging as influential in the modulation of peripheral nerve regeneration and inflammation. This new evidence significantly improves our knowledge of Schwann cell development and function and may contribute to identifying interesting new targets to support the activity of these cells in pathological conditions. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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12 pages, 1313 KiB

Open AccessReview

Presynaptic Acetylcholine Receptors Modulate the Time Course of Action Potential-Evoked Acetylcholine Quanta Secretion at Neuromuscular Junctions

by Ellya A. Bukharaeva, Andrey I. Skorinkin, Dmitry V. Samigullin and Alexey M. Petrov

Biomedicines 2022, 10(8), 1771; https://doi.org/10.3390/biomedicines10081771 - 22 Jul 2022

Cited by 5 | Viewed by 3263

Abstract

For effective transmission of excitation in neuromuscular junctions, the postsynaptic response amplitude must exceed a critical level of depolarization to trigger action potential spreading along the muscle-fiber membrane. At the presynaptic level, the end-plate potential amplitude depends not only on the acetylcholine quanta [...] Read more.

For effective transmission of excitation in neuromuscular junctions, the postsynaptic response amplitude must exceed a critical level of depolarization to trigger action potential spreading along the muscle-fiber membrane. At the presynaptic level, the end-plate potential amplitude depends not only on the acetylcholine quanta number released from the nerve terminals in response to the nerve impulse but also on a degree of synchronicity of quanta releases. The time course of stimulus-phasic synchronous quanta secretion is modulated by many extra- and intracellular factors. One of the pathways to regulate the neurosecretion kinetics of acetylcholine quanta is an activation of presynaptic autoreceptors. This review discusses the contribution of acetylcholine presynaptic receptors to the control of the kinetics of evoked acetylcholine release from nerve terminals at the neuromuscular junctions. The timing characteristics of neurotransmitter release is nowadays considered an essential factor determining the plasticity and efficacy of synaptic transmission. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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12 pages, 464 KiB

Open AccessReview

Cholinergic Regulation of Hippocampal Theta Rhythm

by Zhenglin Gu and Jerrel L. Yakel

Biomedicines 2022, 10(4), 745; https://doi.org/10.3390/biomedicines10040745 - 23 Mar 2022

Cited by 20 | Viewed by 3231

Abstract

Cholinergic regulation of hippocampal theta rhythm has been proposed as one of the central mechanisms underlying hippocampal functions including spatial memory encoding. However, cholinergic transmission has been traditionally associated with atropine-sensitive type II hippocampal theta oscillations that occur during alert immobility or in [...] Read more.

Cholinergic regulation of hippocampal theta rhythm has been proposed as one of the central mechanisms underlying hippocampal functions including spatial memory encoding. However, cholinergic transmission has been traditionally associated with atropine-sensitive type II hippocampal theta oscillations that occur during alert immobility or in urethane-anesthetized animals. The role of cholinergic regulation of type I theta oscillations in behaving animals is much less clear. Recent studies strongly suggest that both cholinergic muscarinic and nicotinic receptors do actively regulate type I hippocampal theta oscillations and thus provide the cholinergic mechanism for theta-associated hippocampal learning. Septal cholinergic activation can regulate hippocampal circuit and theta expression either through direct septohippocampal cholinergic projections, or through septal glutamatergic and GABAergic neurons, that can precisely entrain hippocampal theta rhythmicity. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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36 pages, 6129 KiB

Open AccessReview

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

by Chad R. Johnson, Brian D. Kangas, Emily M. Jutkiewicz, Jack Bergman and Andrew Coop

Biomedicines 2022, 10(2), 398; https://doi.org/10.3390/biomedicines10020398 - 7 Feb 2022

Cited by 30 | Viewed by 11593

Abstract

There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, [...] Read more.

There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology of the orthosteric binding site, many drug candidates resulted in limited clinical success. Although several advances in treating peripheral pathologies have been achieved, targeting CNS pathologies remains challenging for researchers. Nevertheless, significant progress has been made in recent years to develop functionally selective orthosteric and allosteric ligands targeting the mAChRs with limited side effect profiles. This review highlights past efforts and focuses on recent advances in drug design targeting these receptors for Alzheimer’s disease (AD), schizophrenia (SZ), and depression. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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Other

Jump to: Research, Review

21 pages, 3866 KiB

Open AccessConcept Paper

Kinetic Processes in Enzymatic Nanoreactors for In Vivo Detoxification

by Zukhra Shajhutdinova, Tatiana Pashirova and Patrick Masson

Biomedicines 2022, 10(4), 784; https://doi.org/10.3390/biomedicines10040784 - 27 Mar 2022

Cited by 12 | Viewed by 3078

Abstract

Enzymatic nanoreactors are enzyme-encapsulated nanobodies that are capable of performing biosynthetic or catabolic reactions. For this paper, we focused on therapeutic enzyme nanoreactors for the neutralization of toxicants, paying special attention to the inactivation of organophosphorus compounds (OP). Therapeutic enzymes that are capable [...] Read more.

Enzymatic nanoreactors are enzyme-encapsulated nanobodies that are capable of performing biosynthetic or catabolic reactions. For this paper, we focused on therapeutic enzyme nanoreactors for the neutralization of toxicants, paying special attention to the inactivation of organophosphorus compounds (OP). Therapeutic enzymes that are capable of detoxifying OPs are known as bioscavengers. The encapsulation of injectable bioscavengers by nanoparticles was first used to prevent fast clearance and the immune response to heterologous enzymes. The aim of enzyme nanoreactors is also to provide a high concentration of the reactive enzyme in stable nanocontainers. Under these conditions, the detoxification reaction takes place inside the compartment, where the enzyme concentration is much higher than in the toxicant diffusing across the nanoreactor membrane. Thus, the determination of the concentration of the encapsulated enzyme is an important issue in nanoreactor biotechnology. The implications of second-order reaction conditions, the nanoreactor’s permeability in terms of substrates, and the reaction products and their possible osmotic, viscosity, and crowding effects are also examined. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors)

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