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Pharmaceuticals
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Therapeutics Agents for Neural Repair
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Therapeutics Agents for Neural Repair

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 64881

Special Issue Editor

Dr. Nuno A. Silva

E-Mail Website
Guest Editor
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Interests: spinal cord injury; biomaterials; pharmacology; regeneration; immunomodulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

An insult on the Central Nervous System (CNS) usually leads to permanent and irreversible pathological conditions. Events, such as stroke, trauma or neurodegenerative diseases, have a strong impact on the physiological, psychological and social behavior of patients. For these reasons, it is urgent to develop therapeutic strategies that can specifically target these problems. Typically, the pathophysiology of these conditions entail several molecular and cellular events and, given its multifaceted nature, many conceptually different paths are under investigation to promote neural repair. This Special Issue is dedicated to “Therapeutics Agents for Neural Repair” and it is mainly focused on the use of pharmaceutical agents, administrated alone or in combination with other therapeutic approaches.

I sincerely hope that you will be able to contribute a research manuscript or review article dealing with your research in this area of investigation. The proposed topics include, but are not limited to:

  • Pathologies of the CNS (Parkinson, Alzheimer, Huntington, multiple sclerosis, depression, autism, Machado-Joseph, amyotrophic lateral sclerosis, stroke, traumatic brain injury, spinal cord injury).
  • Therapeutic Approaches (molecular therapy, cell therapy, gene therapy, deep brain/epidural stimulation, tissue engineering).
  • Personalized medicine
  • Biomarkers of disease
  • In vitro/ex vivo studies
  • In vivo preclinical studies
  • Clinical studies

I look forward to your participation.

Dr. Nuno A. Silva
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neural Repair
  • Neuroprotection
  • Neuroregeration
  • Trauma
  • Neurodegenerative Disease
  • Therapeutic Agents
  • Biomarkers

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Related Special Issues

Published Papers (10 papers)

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Research

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11 pages, 1360 KiB  
Article
Comparative Analysis of Urso- and Tauroursodeoxycholic Acid Neuroprotective Effects on Retinal Degeneration Models
by Alejandra Daruich, Emilie Picard, Justine Guégan, Thara Jaworski, Léa Parenti, Kimberley Delaunay, Marie-Christine Naud, Marianne Berdugo, Jeffrey H. Boatright and Francine Behar-Cohen
Pharmaceuticals 2022, 15(3), 334; https://doi.org/10.3390/ph15030334 - 9 Mar 2022
Cited by 7 | Viewed by 3327
Abstract
Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids have shown neuroprotective properties in neurodegenerative diseases, but differential effects of the two bile acids have been poorly explored. The aim of this study was to evaluate the neuroprotective effects of UDCA versus TUDCA in a neuroretinal [...] Read more.
Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids have shown neuroprotective properties in neurodegenerative diseases, but differential effects of the two bile acids have been poorly explored. The aim of this study was to evaluate the neuroprotective effects of UDCA versus TUDCA in a neuroretinal degeneration model and to compare transcriptionally regulated pathways. The WERI-Rb-1 human cone-like cell line and retinal explants were exposed to albumin and TUDCA or UDCA. Viability, cell death, and microglial activation were quantified. Transcriptionally regulated pathways were analyzed after RNA sequencing using the edgeR bioconductor package. Pre-treatment of cone-like cells with UDCA or TUDCA significantly protected cells from albumin toxicity. On retinal explants, either bile acid reduced apoptosis, necroptosis, and microglia activation at 6 h. TUDCA induced the regulation of 463 genes, whilst 31 genes were regulated by UDCA. Only nineteen common genes were regulated by both bile acids, mainly involved in iron control, cell death, oxidative stress, and cell metabolism. As compared to UDCA, TUDCA up-regulated genes involved in endoplasmic reticulum stress pathways and down-regulated genes involved in axonal and neuronal development. Either bile acid protected against albumin-induced cell loss. However, TUDCA regulated substantially more neuroprotective genes than UDCA. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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17 pages, 1979 KiB  
Article
Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer’s Disease
by Massimiliano Runfola, Michele Perni, Xiaoting Yang, Maria Marchese, Andrea Bacci, Serena Mero, Filippo M. Santorelli, Beatrice Polini, Grazia Chiellini, Daniela Giuliani, Antonietta Vilella, Martina Bodria, Eleonora Daini, Eleonora Vandini, Simon Rudge, Sheraz Gul, Michale O. J. Wakelam, Michele Vendruscolo and Simona Rapposelli
Pharmaceuticals 2021, 14(12), 1330; https://doi.org/10.3390/ph14121330 - 19 Dec 2021
Cited by 8 | Viewed by 3988
Abstract
The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that [...] Read more.
The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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19 pages, 5736 KiB  
Article
Fatty Acid Amides Synthesized from Andiroba Oil (Carapa guianensis Aublet.) Exhibit Anticonvulsant Action with Modulation on GABA-A Receptor in Mice: A Putative Therapeutic Option
by Fábio Rodrigues de Oliveira, Keuri Eleuterio Rodrigues, Moisés Hamoy, Ícaro Rodrigues Sarquis, Akira Otake Hamoy, Maria Elena Crespo Lopez, Irlon Maciel Ferreira, Barbarella de Matos Macchi and José Luiz Martins do Nascimento
Pharmaceuticals 2020, 13(3), 43; https://doi.org/10.3390/ph13030043 - 10 Mar 2020
Cited by 12 | Viewed by 4270
Abstract
Epilepsy is a chronic neurological disease characterized by excessive neuronal activity leading to seizure; about 30% of affected patients suffer from the refractory and pharmacoresistant form of the disease. The anticonvulsant drugs currently used for seizure control are associated with adverse reactions, making [...] Read more.
Epilepsy is a chronic neurological disease characterized by excessive neuronal activity leading to seizure; about 30% of affected patients suffer from the refractory and pharmacoresistant form of the disease. The anticonvulsant drugs currently used for seizure control are associated with adverse reactions, making it important to search for more effective drugs with fewer adverse reactions. There is increasing evidence that endocannabinoids can pharmacologically modulate action against seizure and antiepileptic disorders. Therefore, the objective of this study is to investigate the anticonvulsant effects of fatty acid amides (FAAs) in a pentylenetetrazole (PTZ)-induced seizure model in mice. FAAs (FAA1 and FAA2) are obtained from Carapa guianensis oil by biocatalysis and are characterized by Fourier Transform Infrared Analysis (FT-IR) and Gas Chromatography-Mass Spectrometry (GC-MS). Only FAA1 is effective in controlling the increased latency time of the first myoclonic jerk and in significantly decreasing the total duration of tonic-clonic seizures relative to the pentylenetetrazol model. Also, electrocortical alterations produced by pentylenetetrazol are reduced when treated by FAA1 that subsequently decreased wave amplitude and energy in Beta rhythm. The anticonvulsant effects of FAA1 are reversed by flumazenil, a benzodiazepine antagonist on Gamma-Aminobutyric Acid-A (GABA-A) receptors, indicating a mode of action via the benzodiazepine site of these receptors. To conclude, the FAA obtained from C. guianensis oil is promising against PTZ-induced seizures. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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20 pages, 4396 KiB  
Article
Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation
by Carla Montecinos-Oliva, Macarena S. Arrázola, Claudia Jara, Cheril Tapia-Rojas and Nibaldo C. Inestrosa
Pharmaceuticals 2020, 13(2), 24; https://doi.org/10.3390/ph13020024 - 2 Feb 2020
Cited by 12 | Viewed by 3598
Abstract
Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in [...] Read more.
Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aβ40. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30–100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aβ40, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ42 over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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Review

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17 pages, 3729 KiB  
Review
Regenerative Injections Including 5% Dextrose and Platelet-Rich Plasma for the Treatment of Carpal Tunnel Syndrome: A Systematic Review and Network Meta-Analysis
by Chih-Peng Lin, Ke-Vin Chang, Yi-Kai Huang, Wei-Ting Wu and Levent Özçakar
Pharmaceuticals 2020, 13(3), 49; https://doi.org/10.3390/ph13030049 - 18 Mar 2020
Cited by 43 | Viewed by 5893
Abstract
This network meta-analysis aimed to integrate the available direct and indirect evidence on regenerative injections—including 5% dextrose (D5W) and platelet-rich plasma (PRP)—for the treatment of carpal tunnel syndrome (CTS). Literature reports comparing D5W and PRP injections with non-surgical managements of CTS were systematically [...] Read more.
This network meta-analysis aimed to integrate the available direct and indirect evidence on regenerative injections—including 5% dextrose (D5W) and platelet-rich plasma (PRP)—for the treatment of carpal tunnel syndrome (CTS). Literature reports comparing D5W and PRP injections with non-surgical managements of CTS were systematically reviewed. The main outcome was the standardized mean difference (SMD) of the symptom severity and functional status scales of the Boston Carpal Tunnel Syndrome Questionnaire at three months after injections. Ranking probabilities of the SMD of each treatment were acquired by using simulation. Ten studies with 497 patients and comparing five treatments (D5W, PRP, splinting, corticosteroid, and normal saline) were included. The results of the simulation of rank probabilities showed that D5W injection was likely to be the best treatment, followed by PRP injection, in terms of clinical effectiveness in providing symptom relief. With respect to functional improvement, splinting ranked higher than PRP and D5W injections. Lastly, corticosteroid and saline injections were consistently ranked fourth and fifth in terms of therapeutic effects on symptom severity and functional status. D5W and PRP injections are more effective than splinting and corticosteroid or saline injection for relieving the symptoms of CTS. Compared with splinting, D5W and PRP injections do not provide better functional recovery. More studies investigating the long-term effectiveness of regenerative injections in CTS are needed in the future. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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18 pages, 703 KiB  
Review
Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders
by Andreia G. Pinho, Jorge R. Cibrão, Nuno A. Silva, Susana Monteiro and António J. Salgado
Pharmaceuticals 2020, 13(2), 31; https://doi.org/10.3390/ph13020031 - 20 Feb 2020
Cited by 57 | Viewed by 7355
Abstract
Transplantation of stem cells, in particular mesenchymal stem cells (MSCs), stands as a promising therapy for trauma, stroke or neurodegenerative conditions such as spinal cord or traumatic brain injuries (SCI or TBI), ischemic stroke (IS), or Parkinson’s disease (PD). Over the last few [...] Read more.
Transplantation of stem cells, in particular mesenchymal stem cells (MSCs), stands as a promising therapy for trauma, stroke or neurodegenerative conditions such as spinal cord or traumatic brain injuries (SCI or TBI), ischemic stroke (IS), or Parkinson’s disease (PD). Over the last few years, cell transplantation-based approaches have started to focus on the use of cell byproducts, with a strong emphasis on cell secretome. Having this in mind, the present review discusses the current state of the art of secretome-based therapy applications in different central nervous system (CNS) pathologies. For this purpose, the following topics are discussed: (1) What are the main cell secretome sources, composition, and associated collection techniques; (2) Possible differences of the therapeutic potential of the protein and vesicular fraction of the secretome; and (3) Impact of the cell secretome on CNS-related problems such as SCI, TBI, IS, and PD. With this, we aim to clarify some of the main questions that currently exist in the field of secretome-based therapies and consequently gain new knowledge that may help in the clinical application of secretome in CNS disorders. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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11 pages, 254 KiB  
Review
Therapeutic Plasmapheresis with Albumin Replacement in Alzheimer’s Disease and Chronic Progressive Multiple Sclerosis: A Review
by Rut Navarro-Martínez and Omar Cauli
Pharmaceuticals 2020, 13(2), 28; https://doi.org/10.3390/ph13020028 - 12 Feb 2020
Cited by 10 | Viewed by 3810
Abstract
Background: Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in [...] Read more.
Background: Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in the brain and thus reduce the progression of these disorders. The objective of this review was to evaluate the efficacy of plasmapheresis (PP) in AD and chronic progressive MS patients (in terms of improving clinical symptoms) and to analyze its safety and protocols. Methods: Articles related to this topic and published without time limitations in the Medline, and Cochrane databases were reviewed. Results: In AD patients, PP reduced amyloid beta (Aβ) levels in the brain, accompanied by a tendency towards cognitive stabilization, and improved language and verbal fluency. In regards to structural and functional brain changes, PP reduced brain volume and favored the stabilization, or absence, of the progression of perfusion. In chronic progressive form of MS patients, PP improved neurological deficits in 20–70% of patients with a chronic progressive form of MS, and restored interferon (IFN) responsiveness, which was not accompanied by any image change in brain plaques. Conclusions: Therapeutic plasmapheresis with albumin replacement is a promising strategy for reducing Aβ mediated toxicity and slowing the progression of the disorder. Some patients with chronic progressive forms of MS show improvement in neurological deficits. The features of AD and MS patients who benefit most from this approach need further research. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
32 pages, 2178 KiB  
Review
Filling the Gap: Neural Stem Cells as A Promising Therapy for Spinal Cord Injury
by Inês M. Pereira, Ana Marote, António J. Salgado and Nuno A. Silva
Pharmaceuticals 2019, 12(2), 65; https://doi.org/10.3390/ph12020065 - 29 Apr 2019
Cited by 58 | Viewed by 14051
Abstract
Spinal cord injury (SCI) can lead to severe motor, sensory and social impairments having a huge impact on patients’ lives. The complex and time-dependent SCI pathophysiology has been hampering the development of novel and effective therapies. Current treatment options include surgical interventions, to [...] Read more.
Spinal cord injury (SCI) can lead to severe motor, sensory and social impairments having a huge impact on patients’ lives. The complex and time-dependent SCI pathophysiology has been hampering the development of novel and effective therapies. Current treatment options include surgical interventions, to stabilize and decompress the spinal cord, and rehabilitative care, without providing a cure for these patients. Novel therapies have been developed targeting different stages during trauma. Among them, cell-based therapies hold great potential for tissue regeneration after injury. Neural stem cells (NSCs), which are multipotent cells with inherent differentiation capabilities committed to the neuronal lineage, are especially relevant to promote and reestablish the damaged neuronal spinal tracts. Several studies demonstrate the regenerative effects of NSCs in SCI after transplantation by providing neurotrophic support and restoring synaptic connectivity. Therefore, human clinical trials have already been launched to assess safety in SCI patients. Here, we review NSC-based experimental studies in a SCI context and how are they currently being translated into human clinical trials. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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31 pages, 9116 KiB  
Review
BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease
by Miguel A. Maia and Emília Sousa
Pharmaceuticals 2019, 12(1), 41; https://doi.org/10.3390/ph12010041 - 19 Mar 2019
Cited by 95 | Viewed by 10809
Abstract
Alzheimer’s disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. [...] Read more.
Alzheimer’s disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia. Hence, several research and development (R&D) programs have been led by the pharmaceutical industry in an effort to discover effective and safety anti-amyloid agents as disease modifying agents for AD. Among 19 drug candidates identified in the AD pipeline, nine have their mechanism of action centered in the activity of β or γ-secretase proteases, covering almost 50% of the identified agents. These drug candidates must fulfill the general rigid prerequisites for a drug aimed for central nervous system (CNS) penetration and selectivity toward different aspartyl proteases. This review presents the classes of γ-secretase and beta-site APP cleaving enzyme 1 (BACE-1) inhibitors under development, highlighting their structure-activity relationship, among other physical-chemistry aspects important for the successful development of new anti-AD pharmacological agents. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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Other

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11 pages, 2753 KiB  
Systematic Review
Safety of Cerebrolysin for Neurorecovery after Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Twelve Randomized-Controlled Trials
by Stefan Strilciuc, László Vécsei, Dana Boering, Aleš Pražnikar, Oliver Kaut, Peter Riederer and Leontino Battistin
Pharmaceuticals 2021, 14(12), 1297; https://doi.org/10.3390/ph14121297 - 13 Dec 2021
Cited by 15 | Viewed by 6348
Abstract
We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up [...] Read more.
We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo. Full article
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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