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Molecular Aspects of Degeneration and Regeneration in the Peripheral Nervous System

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 21856

Special Issue Editor

Special Issue Information

Dear Colleagues,

In the peripheral nervous system, the intrinsic regenerative capacity of neurons coupled with permissive environments due to the activation of Schwann cells and macrophages during Wallerian degeneration contributes to axonal regeneration and reinnervation after injury. However, there is much room for investigation to elucidate the molecules and mechanisms involved in the repair process (e.g., neurotrophic and chemotactic factors, growth inhibitory molecules, and extracellular matrix conctituents), and clinical approaches for accelerating axonal regeneration with functional restoration remain insufficient. In addition, peripheral neuropathies caused by various etiologic mechanisms (e.g., genetic abnormalities, immune system disorders, drugs, diabetes, and other life style-related diseases) are intractable, and pathogenesis-based therapies to treat them have been unsuccessful or incomplete thus far. This Special Issue focuses on recent topics pertinent to the molecular aspects of peripheral nerve degeneration and regeneration following axonal injury; the development and progression of neuropathies; and therapeutic strategies against these lesions, including cell and tissue transplantation and neural interface.

Dr. Kazunori Sango
Guest Editor

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Keywords

  • peripheral nerve injury
  • Wallerian degeneration
  • axonal regeneration
  • peripheral neuropathies
  • Schwann cells
  • demyelination
  • remyelination
  • neurotrophic and chemotactic factors
  • growth inhibitory molecules
  • transplantation
  • neural interface

Published Papers (7 papers)

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Research

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19 pages, 2728 KiB  
Article
Distinct Changes in Calpain and Calpastatin during PNS Myelination and Demyelination in Rodent Models
by John A. Miller, Domenica E. Drouet, Leonid M. Yermakov, Mahmoud S. Elbasiouny, Fatima Z. Bensabeur, Michael Bottomley and Keiichiro Susuki
Int. J. Mol. Sci. 2022, 23(23), 15443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315443 - 06 Dec 2022
Viewed by 1704
Abstract
Myelin forming around axons provides electrical insulation and ensures rapid and efficient transmission of electrical impulses. Disruptions to myelinated nerves often result in nerve conduction failure along with neurological symptoms and long-term disability. In the central nervous system, calpains, a family of calcium [...] Read more.
Myelin forming around axons provides electrical insulation and ensures rapid and efficient transmission of electrical impulses. Disruptions to myelinated nerves often result in nerve conduction failure along with neurological symptoms and long-term disability. In the central nervous system, calpains, a family of calcium dependent cysteine proteases, have been shown to have a role in developmental myelination and in demyelinating diseases. The roles of calpains in myelination and demyelination in the peripheral nervous system remain unclear. Here, we show a transient increase of activated CAPN1, a major calpain isoform, in postnatal rat sciatic nerves when myelin is actively formed. Expression of the endogenous calpain inhibitor, calpastatin, showed a steady decrease throughout the period of peripheral nerve development. In the sciatic nerves of Trembler-J mice characterized by dysmyelination, expression levels of CAPN1 and calpastatin and calpain activity were significantly increased. In lysolecithin-induced acute demyelination in adult rat sciatic nerves, we show an increase of CAPN1 and decrease of calpastatin expression. These changes in the calpain-calpastatin system are distinct from those during central nervous system development or in acute axonal degeneration in peripheral nerves. Our results suggest that the calpain-calpastatin system has putative roles in myelination and demyelinating diseases of peripheral nerves. Full article
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16 pages, 3079 KiB  
Article
Pretreatment with Zonisamide Mitigates Oxaliplatin-Induced Toxicity in Rat DRG Neurons and DRG Neuron–Schwann Cell Co-Cultures
by Shizuka Takaku and Kazunori Sango
Int. J. Mol. Sci. 2022, 23(17), 9983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179983 - 01 Sep 2022
Cited by 2 | Viewed by 1712
Abstract
Oxaliplatin (OHP) is a platinum-based agent that can cause peripheral neuropathy, an adverse effect in which the dorsal root ganglion (DRG) neurons are targeted. Zonisamide has exhibited neuroprotective activities toward adult rat DRG neurons in vitro and therefore, we aimed to assess its [...] Read more.
Oxaliplatin (OHP) is a platinum-based agent that can cause peripheral neuropathy, an adverse effect in which the dorsal root ganglion (DRG) neurons are targeted. Zonisamide has exhibited neuroprotective activities toward adult rat DRG neurons in vitro and therefore, we aimed to assess its potential efficacy against OHP-induced neurotoxicity. Pretreatment with zonisamide (100 μM) alleviated the DRG neuronal death caused by OHP (75 μM) and the protective effects were attenuated by a co-incubation with 25 μM of the mitogen-activated protein kinase (MAPK; MEK/ERK) inhibitor, U0126, or the phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor, LY294002. Pretreatment with zonisamide also suppressed the OHP-induced p38 MAPK phosphorylation in lined DRG neurons, ND7/23, while the OHP-induced DRG neuronal death was alleviated by pretreatment with the p38 MAPK inhibitor, SB239063 (25 μM). Although zonisamide failed to protect the immortalized rat Schwann cells IFRS1 from OHP-induced cell death, it prevented neurite degeneration and demyelination-like changes, as well as the reduction of the serine/threonine-specific protein kinase (AKT) phosphorylation in DRG neuron–IFRS1 co-cultures exposed to OHP. Zonisamide’s neuroprotection against the OHP-induced peripheral sensory neuropathy is possibly mediated by a stimulation of the MEK/ERK and PI3K/AKT signaling pathways and suppression of the p38 MAPK pathway in DRG neurons. Future studies will allow us to solidify zonisamide as a promising remedy against the neurotoxic adverse effects of OHP. Full article
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14 pages, 5411 KiB  
Article
Functional Reconstruction of Denervated Muscle by Xenotransplantation of Neural Cells from Porcine to Rat
by Sota Saeki, Katsuhiro Tokutake, Masaki Takasu, Shigeru Kurimoto, Yuta Asami, Keiko Onaka, Masaomi Saeki and Hitoshi Hirata
Int. J. Mol. Sci. 2022, 23(15), 8773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158773 - 07 Aug 2022
Cited by 1 | Viewed by 1610
Abstract
Neural cell transplantation targeting peripheral nerves is a potential treatment regime for denervated muscle atrophy. This study aimed to develop a new therapeutic technique for intractable muscle atrophy by the xenotransplantation of neural stem cells derived from pig fetuses into peripheral nerves. In [...] Read more.
Neural cell transplantation targeting peripheral nerves is a potential treatment regime for denervated muscle atrophy. This study aimed to develop a new therapeutic technique for intractable muscle atrophy by the xenotransplantation of neural stem cells derived from pig fetuses into peripheral nerves. In this study, we created a denervation model using neurotomy in nude rats and transplanted pig-fetus-derived neural stem cells into the cut nerve stump. Three months after transplantation, the survival of neural cells, the number and area of regenerated axons, and the degree of functional recovery by electrical stimulation of peripheral nerves were compared among the gestational ages (E 22, E 27, E 45) of the pigs. Transplanted neural cells were engrafted at all ages. Functional recovery by electric stimulation was observed at age E 22 and E 27. This study shows that the xenotransplantation of fetal porcine neural stem cells can restore denervated muscle function. When combined with medical engineering, this technology can help in developing a new therapy for paralysis. Full article
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17 pages, 11070 KiB  
Article
A Therapeutic Strategy for Lower Motor Neuron Disease and Injury Integrating Neural Stem Cell Transplantation and Functional Electrical Stimulation in a Rat Model
by Katsuhiro Tokutake, Masaru Takeuchi, Shigeru Kurimoto, Sota Saeki, Yuta Asami, Keiko Onaka, Masaomi Saeki, Tadayoshi Aoyama, Yasuhisa Hasegawa and Hitoshi Hirata
Int. J. Mol. Sci. 2022, 23(15), 8760; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158760 - 06 Aug 2022
Cited by 3 | Viewed by 3209
Abstract
Promising treatments for upper motor neuron disease are emerging in which motor function is restored by brain–computer interfaces and functional electrical stimulation. At present, such technologies and procedures are not applicable to lower motor neuron disease. We propose a novel therapeutic strategy for [...] Read more.
Promising treatments for upper motor neuron disease are emerging in which motor function is restored by brain–computer interfaces and functional electrical stimulation. At present, such technologies and procedures are not applicable to lower motor neuron disease. We propose a novel therapeutic strategy for lower motor neuron disease and injury integrating neural stem cell transplantation with our new functional electrical stimulation control system. In a rat sciatic nerve transection model, we transplanted embryonic spinal neural stem cells into the distal stump of the peripheral nerve to reinnervate denervated muscle, and subsequently demonstrated that highly responsive limb movement similar to that of a healthy limb could be attained with a wirelessly powered two-channel neurostimulator that we developed. This unique technology, which can reinnervate and precisely move previously denervated muscles that were unresponsive to electrical stimulation, contributes to improving the condition of patients suffering from intractable diseases of paralysis and traumatic injury. Full article
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13 pages, 1961 KiB  
Article
Adipose-Derived Stem Cells from Type 2 Diabetic Rats Retain Positive Effects in a Rat Model of Erectile Dysfunction
by Marlene Louise Quaade, Pratibha Dhumale, Simon Gabriel Comerma Steffensen, Hans Christian Beck, Eva Bang Harvald, Charlotte Harken Jensen, Lars Lund, Ditte Caroline Andersen and Søren Paludan Sheikh
Int. J. Mol. Sci. 2022, 23(3), 1692; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031692 - 01 Feb 2022
Cited by 6 | Viewed by 2580
Abstract
Erectile dysfunction is a common complication associated with type 2 diabetes mellitus (T2DM) and after prostatectomy in relation to cancer. The regenerative effect of cultured adipose-derived stem cells (ASCs) for ED therapy has been documented in multiple preclinical trials as well as in [...] Read more.
Erectile dysfunction is a common complication associated with type 2 diabetes mellitus (T2DM) and after prostatectomy in relation to cancer. The regenerative effect of cultured adipose-derived stem cells (ASCs) for ED therapy has been documented in multiple preclinical trials as well as in recent Pase 1 trials in humans. However, some studies indicate that diabetes negatively affects the mesenchymal stem cell pool, implying that ASCs from T2DM patients could have impaired regenerative capacity. Here, we directly compared ASCs from age-matched diabetic Goto–Kakizaki (ASCGK) and non-diabetic wild type rats (ASCWT) with regard to their phenotypes, proteomes and ability to rescue ED in normal rats. Despite ASCGK exhibiting a slightly lower proliferation rate, ASCGK and ASCWT proteomes were more or less identical, and after injections to corpus cavernosum they were equally efficient in restoring erectile function in a rat ED model entailing bilateral nerve crush injury. Moreover, molecular analysis of the corpus cavernosum tissue revealed that both ASCGK and ASCWT treated rats had increased induction of genes involved in recovering endothelial function. Thus, our finding argues that T2DM does not appear to be a limiting factor for autologous adipose stem cell therapy when correcting for ED. Full article
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Review

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10 pages, 1557 KiB  
Review
Brain Mechanisms of Exercise-Induced Hypoalgesia: To Find a Way Out from “Fear-Avoidance Belief”
by Katsuya Kami, Fumihiro Tajima and Emiko Senba
Int. J. Mol. Sci. 2022, 23(5), 2886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052886 - 07 Mar 2022
Cited by 12 | Viewed by 6191
Abstract
It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we [...] Read more.
It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain. Full article
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19 pages, 1959 KiB  
Review
A Brief Review of In Vitro Models for Injury and Regeneration in the Peripheral Nervous System
by Parvathi Varier, Gayathri Raju, Pallavi Madhusudanan, Chinnu Jerard and Sahadev A. Shankarappa
Int. J. Mol. Sci. 2022, 23(2), 816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020816 - 13 Jan 2022
Cited by 8 | Viewed by 3735
Abstract
Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the [...] Read more.
Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the identification of cellular responses, screening of novel therapeutic molecules, and design of neural regeneration strategies. In addition to in vivo and mathematical models, in vitro axonal injury models provide a simple, robust, and reductionist platform to partially understand nerve injury pathogenesis and regeneration. In recent years, there have been several advances related to in vitro techniques that focus on the utilization of custom-fabricated cell culture chambers, microfluidic chamber systems, and injury techniques such as laser ablation and axonal stretching. These developments seem to reflect a gradual and natural progression towards understanding molecular and signaling events at an individual axon and neuronal-soma level. In this review, we attempt to categorize and discuss various in vitro models of injury relevant to the peripheral nervous system and highlight their strengths, weaknesses, and opportunities. Such models will help to recreate the post-injury microenvironment and aid in the development of therapeutic strategies that can accelerate nerve repair. Full article
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