Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
4.7
4.6
Journals
Pharmaceuticals
Special Issues
Therapeutic Agents for Neurological Disorders
share announcement

Therapeutic Agents for Neurological Disorders

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 70744

Special Issue Editor

Dr. Damian Holsinger

E-Mail Website
Guest Editor
Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
Interests: neurodegenerative diseases; Alzheimer’s disease; dementia; cell biology; molecular biology; ageing; therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The World Health Organization defines neurological disorders as disabling conditions that encompass but are not limited to cerebrovascular diseases, epilepsy, dementias including Alzheimer’s, multiple sclerosis, movement disorders resulting from nervous system deficits, brain tumours, neuroinfections and neurological disorders as a result of malnutrition 1. Globally, in 2016, neurological disorders were the leading cause of disability-adjusted life years (DALYs) (276 million [95% UI 247–308]) and second leading cause of deaths (9.0 million [8.8–9.4]) 2. The absolute number of deaths and DALYs from all neurological disorders combined increased by 39% and 15% respectively2. These figures outline an impending epidemic that requires urgent attention.

Treatments for neurological disorders are challenging, but numerous advancements have been made in identifying mechanisms and delineating pathways underlying these diseases. Advances in technologies that garner information from the fields of bioinformatics and next generation and whole genome sequencing have added invaluable support in identifying ‘culprit’ genes and proteins. Using this information, scientists and clinicians have ventured into areas previously deemed ‘fiction.’ From brain-controlled, non-invasive muscle stimulators that help paraplegics walk to the editing of the CEP290 gene in individuals with Leber congenital amaurosis 10 (LCA10) and a plethora of therapies in between, biomedicine has made giant leaps in just over two decades.

In this Special Issue, we aim to draw together research from experts in the field that highlight therapeutic agents and strategies, and identify future directions that will lead to discoveries and therapies for neurological disorders.

Dr. Damian Holsinger
Guest Editor

  1. http://www.who.int/features/qa/55/en
  2. GBD 2016 Neurology Collaborators (2019) Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18: 459–80.

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

  • neurodegeneration
  • brain injury
  • spinal cord injury
  • neurodevelopmental disorders
  • nerve repair
  • brain tumors
  • neuromodulation
  • neuroinflammation

Related Special Issues

Published Papers (16 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

17 pages, 12546 KiB  
Article
N-3 PUFA Prevent Oxidative Stress in a Rat Model of Beta-Amyloid-Induced Toxicity
by Maria Grazia Morgese, Stefania Schiavone, Maria Bove, Anna Laura Colia, Stefania Dimonte, Paolo Tucci and Luigia Trabace
Pharmaceuticals 2021, 14(4), 339; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040339 - 08 Apr 2021
Cited by 11 | Viewed by 1795
Abstract
Polyunsaturated fatty acids (PUFA) are involved in brain disorders associated to amyloid beta (Aβ) toxicity for which oxidative stress, neurochemical dysfunctions, and neuroinflammation are underlying mechanisms. Here, mechanisms through which lifelong exposure to n-3 PUFA-enriched or n-6/n-3 balanced diets could elicit a protective [...] Read more.
Polyunsaturated fatty acids (PUFA) are involved in brain disorders associated to amyloid beta (Aβ) toxicity for which oxidative stress, neurochemical dysfunctions, and neuroinflammation are underlying mechanisms. Here, mechanisms through which lifelong exposure to n-3 PUFA-enriched or n-6/n-3 balanced diets could elicit a protective role in a rat model of Aβ-induced toxicity were investigated. To this aim, we quantified hippocampal reactive oxygen species (ROS) amount, 8-hydroxy-2′-deoxyguanosine and interleukin-10 levels, NADPH oxidase (NOX) 1, NOX2, superoxide dismutase 1, and glutathione contents, as well as plasmatic malondialdehyde. Moreover, in the same experimental groups, we assessed tryptophan, serotonin, and its turnover, kynurenine, and noradrenaline amounts. Results showed increased hippocampal ROS and NOX2 levels, serotonin turnover, kynurenine, and noradrenaline contents in Aβ-treated rats. Both n-6/n-3 balanced and n-3 PUFA enriched diets reduced ROS production, NOX1 and malondialdehyde levels, serotonin turnover, and kynurenine amount in Aβ-injected rats, while increasing NOX2, superoxide dismutase 1, and serotonin contents. No differences in plasmatic coenzyme Q10, reduced glutathione (GSH) and tryptophan levels were detected among different experimental groups, whereas GSH + oxidized glutathione (GSSG) levels were increased in sham animals fed with n-3 PUFA enriched diet and in Aβ-treated rats exposed to both n-6/n-3 balanced and n-3 enriched diets. In addition, Aβ-induced decrease of interleukin-10 levels was prevented by n-6/n-3 PUFA balanced diet. N-3 PUFA enriched diet further increased interleukin-10 and 8-hydroxy-2′-deoxyguanosine levels. In conclusion, our data highlight the possible neuroprotective role of n-3 PUFA in perturbation of oxidative equilibrium induced by Aβ-administration. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

18 pages, 62202 KiB  
Article
Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis
by Suliman Y. Alomar, Rehab E. Abo El Gheit, Eman T. Enan, Khaled S. El-Bayoumi, Mohamed Z. Shoaeir, Amany Y. Elkazaz, Sultan S. Al Thagfan, Sawsan A. Zaitone and Rehab M. El-Sayed
Pharmaceuticals 2021, 14(4), 307; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040307 - 01 Apr 2021
Cited by 22 | Viewed by 3620
Abstract
Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on [...] Read more.
Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

11 pages, 796 KiB  
Article
Α Multicenter Retrospective Study Evaluating Brivaracetam in the Treatment of Epilepsies in Clinical Practice
by Maria Stefanatou, Eirini Vasileiadou Kapetanou, Vasilios K. Kimiskidis, Vasileios Papaliagkas, Panagiotis Polychronopoulos, Sofia Markoula, Kleoniki Charisiou, Dimitrios Kazis, Anastasia Verentzioti, Panayiotis Patrikelis, Athanasia Alexoudi and Stylianos Gatzonis
Pharmaceuticals 2021, 14(2), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020165 - 19 Feb 2021
Cited by 3 | Viewed by 2763
Abstract
Brivaracetam (BRV) is the latest approved antiepileptic drug. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. In this retrospective, observational, multicenter study, data from epilepsy patients receiving BRV from January 2018 to July [...] Read more.
Brivaracetam (BRV) is the latest approved antiepileptic drug. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. In this retrospective, observational, multicenter study, data from epilepsy patients receiving BRV from January 2018 to July 2019 were analyzed. Patients with age ≥16 suffering from any type of epilepsy and having at least one follow up encounter after dose titration were included. 156 consecutive patients were included in the study. The mean age was 40 (16–84 years) and the mean duration of epilepsy was 21 years. Of the 156 patients, 81% were diagnosed with focal-onset seizures, 16% with generalized seizures, while 3% suffered from unclassified seizures. Nine patients received BRV as monotherapy as a switching therapy. At the first follow up visit, seizure cessation was achieved in 56 (36%) patients and the rate of ≥50% responders was 36%. Twenty four patients (15%) remained unchanged; six patients (4%) were recorded with increased seizure frequency, while the remaining 9% had a response of less than 50%. Twenty-six patients (17%) showed clinically significant adverse events, but none were life threatening. Brivaracetam seems to be an effective, easy to use and safe antiepileptic drug in the clinical setting. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

15 pages, 53318 KiB  
Article
Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease
by Anishchal A. Pratap and R. M. Damian Holsinger
Pharmaceuticals 2020, 13(11), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110401 - 18 Nov 2020
Cited by 11 | Viewed by 2871
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates [...] Read more.
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

20 pages, 3522 KiB  
Article
Brain-Targeted Delivery of Pre-miR-29b Using Lactoferrin-Stearic Acid-Modified-Chitosan/Polyethyleneimine Polyplexes
by Patrícia Pereira, Maria Barreira, Carla Cruz, Joana Tomás, Ângelo Luís, Augusto Q. Pedro, João A. Queiroz and Fani Sousa
Pharmaceuticals 2020, 13(10), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100314 - 15 Oct 2020
Cited by 15 | Viewed by 3248
Abstract
The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), [...] Read more.
The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), foreseeing a decrease in the expression of the BACE1 protein, with potential implications in Alzheimer’s disease (AD) treatment. Stearic acid (SA) and lactoferrin (Lf) were successfully exploited as brain-targeting ligands to modify cationic polymers (chitosan (CS) or polyethyleneimine (PEI)), and its BBB penetration behavior was evaluated. The intracellular uptake of the dual-targeting drug delivery systems by neuronal cell models, as well as the gene silencing efficiency of recombinant pre-miR-29b, was analyzed in vitro. Labeled pre-miR-29b-CS/PEI-SA-Lf systems showed very strong fluorescence in the cytoplasm and nucleus of RBE4 cells, being verified the delivery of pre-miR-29b to neuronal cells after 1 h transfection. The experiment of transport across the BBB showed that CS-SA-Lf delivered 65% of recombinant pre-miR-29b in a period of 4 h, a significantly higher transport ratio than the 42% found for PEI-SA-Lf in the same time frame. Overall, a novel procedure for the dual targeting of DDS is disclosed, opening new perspectives in nanomedicines delivery, whereby a novel drug delivery system harvests the merits and properties of the different immobilized ligands. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

13 pages, 3747 KiB  
Article
Altered Brain Adiponectin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease
by Anishchal A. Pratap and R. M. Damian Holsinger
Pharmaceuticals 2020, 13(7), 150; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13070150 - 12 Jul 2020
Cited by 6 | Viewed by 3495
Abstract
Metabolic syndromes share common pathologies with Alzheimer’s disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer’s, we examined their expression in the aged 5XFAD mouse model of [...] Read more.
Metabolic syndromes share common pathologies with Alzheimer’s disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer’s, we examined their expression in the aged 5XFAD mouse model of AD. In age-matched wild-type mice, we observed neuronal expression of both ARs throughout the brain as well as endothelial expression of AdipoR1. The pattern of receptor expression in the aged 5XFAD brain was significantly perturbed. Here, we observed decreased neuronal expression of both ARs and decreased endothelial expression of AdipoR1, but robust expression of AdipoR2 in activated astrocytes. We also observed AdipoR2-expressing astrocytes in the dorsomedial hypothalamic and thalamic mediodorsal nuclei, suggesting the possibility that astrocytes utilise AdipoR2 signalling to fuel their activated state in the AD brain. These findings provide further evidence of a metabolic disturbance and demonstrate a potential shift in energy utilisation in the AD brain, supporting imaging studies performed in AD patients. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

22 pages, 3957 KiB  
Article
Effects of Carbamazepine, Lacosamide and Zonisamide on Gliotransmitter Release Associated with Activated Astroglial Hemichannels
by Kouji Fukuyama, Yuto Ueda and Motohiro Okada
Pharmaceuticals 2020, 13(6), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13060117 - 05 Jun 2020
Cited by 27 | Viewed by 3049
Abstract
Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na+ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), [...] Read more.
Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na+ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), lacosamide (LCM), and zonisamide (ZNS) on the astroglial release of l-glutamate and adenosine triphosphate (ATP). The effects of subchronic administration of therapeutic-relevant dose of three anticonvulsants on the release of l-glutamate and ATP in the orbitofrontal cortex (OFC) were determined using microdialysis. The concentration-dependent effects of acute and subchronic administrations of anticonvulsants on astroglial gliotransmitter release were determined using primary cultured astrocytes. The concentration-dependent effects of subchronic administrations of anticonvulsants on connexin43 (Cx43) expression in the plasma membrane of primary cultured astrocytes were determined using the Simple Western system. An increase in the levels of extracellular K+ resulted in a concentration-dependent increase in the astroglial release of l-glutamate and ATP. The depleted levels of extracellular Ca2+ alone did not affect astroglial gliotransmitter release but did accelerate K+-evoked gliotransmitter release via activation of astroglial hemichannels. Both non-selective hemichannel inhibitor carbenoxolone (CBX) and selective Cx43 inhibitor GAP19 prevented both gliotransmitter release through activated astroglial hemichannels and the hemichannel-activating process induced by elevation of the levels of extracellular K+ with depletion of the levels of extracellular Ca2+. ZNS subchronically decreased Cx43 expression and acutely/subchronically inhibited Cx43 hemichannel activity. LCM acutely inhibited hemichannel activity but did not subchronically affect Cx43 expression. Therapeutic-relevant concentration of CBZ did not affect hemichannel activity or Cx43 expression, but supratherapeutic concentration of CBZ decreased Cx43 expression and hemichannel activity. Therefore, the present study demonstrated the distinct effects of CBZ, LCM, and ZNS on gliotransmitter release via modulation of astroglial hemichannel function. The different features of the effects of three VDSC-inhibiting anticonvulsants on astroglial transmission associated with hemichannels, at least partially, possibly contributing to the formation of the properties of these three anticonvulsants, including the antiepileptic spectrum and adverse effects regarding mood and cognitive disturbance. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

21 pages, 5131 KiB  
Article
Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor
by Kouji Fukuyama, Masashi Fukuzawa and Motohiro Okada
Pharmaceuticals 2020, 13(5), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050099 - 18 May 2020
Cited by 25 | Viewed by 3462
Abstract
To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), [...] Read more.
To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), and connexin43 (Cx43) hemichannel of transgenic rats bearing rat S286L-mutant Chrna4 gene (S286L-TG), corresponding to the human S284L-mutant CHRNA4 gene using simple Western analysis and multiprobe microdialysis. Cx43 expression in the thalamic plasma membrane fraction of S286L-TG was upregulated compared with that of wild-type. Subchronic administrations of therapeutic-relevant doses of zonisamide (ZNS) and carbamazepine (CBZ) decreased and did not affect Cx43 expression of S286L-TG, respectively. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of GABAergic transmission RTN–MDTN pathway conversely enhanced, but not inhibited, l-glutamate release in the MDTN via upregulated/activated Cx43. Local administration of therapeutic-relevant concentration of ZNS and CBZ acutely supressed and did not affect glutamatergic transmission in the thalamocortical pathway, respectively. These results suggest that pathomechanisms of ADSHE seizure and its cognitive deficit comorbidity, as well as pathophysiology of CBZ-resistant/ZNS-sensitive ADSHE seizures of patients with S284L-mutation. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

23 pages, 3509 KiB  
Article
Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy
by Kouji Fukuyama, Masashi Fukuzawa, Ruri Okubo and Motohiro Okada
Pharmaceuticals 2020, 13(4), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13040058 - 29 Mar 2020
Cited by 25 | Viewed by 3437
Abstract
To study the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities of glutamatergic transmission in the thalamocortical motor pathway, from the reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN) tosecondary motor cortex (M2C) associated with the [...] Read more.
To study the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities of glutamatergic transmission in the thalamocortical motor pathway, from the reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN) tosecondary motor cortex (M2C) associated with the S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR) and the connexin43 (Cx43) hemichannel of transgenic rats bearing the rat S286L-mutant Chrna4 gene (S286L-TG), which corresponds to the human S284L-mutant CHRNA4 gene using multiprobe microdialysis, primary cultured astrocytes and a Simple Western system. Expression of Cx43 in the M2C plasma membrane fraction of S286L-TG was upregulated compared with wild-type rats. Subchronic nicotine administration decreased Cx43 expression of wild-type, but did not affect that of S286L-TG; however, zonisamide (ZNS) decreased Cx43 in both wild-type and S286L-TG. Primary cultured astrocytes of wild-type were not affected by subchronic administration of nicotine but was decreased by ZNS. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of glutamatergic transmission associated with upregulated Cx43 reinforced the prolonged Cx43 hemichannel activation. Subchronic administration of therapeutic-relevant doses of ZNS compensated the upregulation of Cx43 and prolonged reinforced activation of Cx43 hemichannel induced by physiological hyperexcitability during the non-rapid eye movement phase of sleep. The present results support the primary pathomechanisms and secondary pathophysiology of ADSHE seizures of patients with S284L-mutation. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

Review

Jump to: Research

13 pages, 814 KiB  
Review
Behavioral and Psychological Symptoms in Dementia (BPSD) and the Use of Antipsychotics
by Valeria Calsolaro, Grazia Daniela Femminella, Sara Rogani, Salvatore Esposito, Riccardo Franchi, Chukwuma Okoye, Giuseppe Rengo and Fabio Monzani
Pharmaceuticals 2021, 14(3), 246; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030246 - 09 Mar 2021
Cited by 26 | Viewed by 8652
Abstract
Dementia affects about 47 million people worldwide, number expected to exponentially increase within 30 years. Alzheimer’s disease (AD) is the most common dementia type, accounting on its own for almost 70% of all dementia cases. Behavioral and psychological symptoms (BPSD) frequently occur during [...] Read more.
Dementia affects about 47 million people worldwide, number expected to exponentially increase within 30 years. Alzheimer’s disease (AD) is the most common dementia type, accounting on its own for almost 70% of all dementia cases. Behavioral and psychological symptoms (BPSD) frequently occur during the disease progression; to treat agitation, aggressiveness, delusions and hallucinations, the use of antipsychotic drugs should be limited, due to their safety issues. In this literature review regarding the use of antipsychotics for treating BPSD in dementia, the advantages and limitation of antipsychotic drugs have been evaluated. The available medications for the management of behavioral and psychological symptoms are the antipsychotics, classed into typical and atypical, depending on their action on dopamine and serotonin receptors. First generation, or typical, antipsychotics exhibit lack of tolerability and display a broad range of side effects such as sedation, anticholinergic effects and extrapyramidal symptoms. Atypical, or second generation, antipsychotics bind more selectively to dopamine receptors and simultaneously block serotonin receptors, resulting in higher tolerability. High attention should be paid to the management of therapy interruption or switch between antipsychotics, to limit the possible rebound effect. Several switching strategies may be adopted, and clinicians should “tailor” therapies, accounting for patients’ symptoms, comorbidities, polytherapies and frailty. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

17 pages, 1225 KiB  
Review
The Angiotensin II Type 2 Receptor, a Target for Protection and Regeneration of the Peripheral Nervous System?
by Aurore Danigo, Amandine Rovini, Flavien Bessaguet, Hichem Bouchenaki, Amandine Bernard, Franck Sturtz, Sylvie Bourthoumieu, Alexis Desmoulière, Laurent Magy and Claire Demiot
Pharmaceuticals 2021, 14(3), 175; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030175 - 24 Feb 2021
Cited by 9 | Viewed by 2625
Abstract
Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of [...] Read more.
Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of AT2R and its related signaling are still under investigation, pharmacological studies have shown that stimulation of AT2R leads to neuritogenesis in vitro and in vivo. In this review, we focus on the potential neuroprotective and neuroregenerative roles of AT2R specifically in the peripheral nervous system (PNS). The first section describes the evidence for AT2R expression in the PNS and highlights current controversies concerning the cellular distribution of the receptor. The second section focuses on AT2R signaling implicated in neuronal survival and in neurite outgrowth. The following sections review the relatively few preclinical studies highlighting the putative neuroprotective and neuroregenerative effects of AT2R stimulation in the context of peripheral neuropathy. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

24 pages, 953 KiB  
Review
B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders
by Jan Traub, Leila Husseini and Martin S. Weber
Pharmaceuticals 2021, 14(1), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010037 - 06 Jan 2021
Cited by 7 | Viewed by 3854
Abstract
The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica [...] Read more.
The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

12 pages, 445 KiB  
Review
Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury
by Michał Wiciński, Eryk Wódkiewicz, Karol Górski, Maciej Walczak and Bartosz Malinowski
Pharmaceuticals 2020, 13(11), 379; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110379 - 11 Nov 2020
Cited by 54 | Viewed by 5567
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in [...] Read more.
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

25 pages, 503 KiB  
Review
Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics
by Maria Gavriilaki, Vasilios K. Kimiskidis and Eleni Gavriilaki
Pharmaceuticals 2020, 13(11), 341; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110341 - 26 Oct 2020
Cited by 16 | Viewed by 5667
Abstract
Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the [...] Read more.
Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)” complement system proteins” and “neurologic disease”. Complement’s role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

15 pages, 980 KiB  
Review
Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?
by Stephanie Kourakis, Cara A. Timpani, Judy B. de Haan, Nuri Gueven, Dirk Fischer and Emma Rybalka
Pharmaceuticals 2020, 13(10), 306; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100306 - 13 Oct 2020
Cited by 55 | Viewed by 8987
Abstract
Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, [...] Read more.
Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Figure 1

36 pages, 7924 KiB  
Review
Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer’s Disease
by Márcia Martins, Renata Silva, Madalena M. M. Pinto and Emília Sousa
Pharmaceuticals 2020, 13(9), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090242 - 11 Sep 2020
Cited by 30 | Viewed by 6036
Abstract
Alzheimer’s disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be [...] Read more.
Alzheimer’s disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine natural products (MNP) are a source of unique chemical structures with useful biological activities for AD treatment. One of the most promising compounds, a marine-derived acidic oligosaccharide (GV-971) just passed phase III clinical trials with a unique mechanism of action. Combination therapy and multitargeted-directed ligand therapy (MTDL) are also two important strategies, with several examples in clinical trials, based on the belief that the best approach for AD is a therapy capable of modulating multiple target pathways. Drug repurposing, a strategy that requires a smaller investment and is less time consuming, is emerging as a strong contender with a variety of pharmacological agents resurfacing in an attempt to identify a therapeutic candidate capable of modifying the course of this disease. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-16
Back to TopTop