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Pharmaceuticals
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New Drugs and Biologics For Treatment of Central Nervous Dysfunction
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New Drugs and Biologics For Treatment of Central Nervous Dysfunction

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

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 62198

Special Issue Editors

Dr. Lusine Danielyan

E-Mail Website
Guest Editor
Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany
Interests: astrocytes; neuroprotection; Alzheimer's disease; brain diseases; neurobiology; stem cells; central nervous system; neurodegenerative diseases; neurology
Dr. Huu Phuc Nguyen

E-Mail Website1 Website2
Guest Editor
Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
Interests: neurodegenerative diseases; Huntington disease; polyglutamine diseases; neuroscience
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Experimental neuroscience in recent years has brought to light numerous exciting technologies, discoveries of new therapeutic interventions, and molecular targets of CNS disorders. However, many theoretical and practical challenges in establishing novel drugs and biologicals remain when tested in in vivo studies or translated into the clinical use; for example, a number of novel or repurposed compounds have beneficial effects within the central nervous system (CNS), but exert some unwanted side effects, when distributed systemically. Emerging technologies, such as intranasal delivery can be employed as a non-invasive option for delivering drugs and therapeutic cells to the CNS with minimal peripheral exposure. This Special Issue will gather discoveries of novel molecular targets, drugs, and biologics, as well as new delivery routes for the treatment of CNS disorders, including but not limited to Alzheimer’s disease, Parkinson’s disease, Huntington disease, depression, anxiety, autism spectrum disorders, seizures, and stroke. Short and comprehensive research papers including in vitro and in vivo studies, as well as case reports and reviews are welcome.

Dr. Lusine Danielyan
Dr. Huu Phuc Nguyen
Guest Editors

Manuscript Submission Information

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Keywords

  • Neurodegeneration
  • Neurotransmission
  • Intranasal administration
  • Neuroinflammation
  • Stem cells
  • New drug

Published Papers (15 papers)

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Research

Jump to: Review

19 pages, 1649 KiB  
Article
The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains
by Eva Kudova, Pavel Mares, Martin Hill, Katerina Vondrakova, Grygoriy Tsenov, Hana Chodounska, Hana Kubova and Karel Vales
Pharmaceuticals 2022, 15(1), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010049 - 30 Dec 2021
Cited by 5 | Viewed by 2562
Abstract
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of [...] Read more.
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of γ-aminobutyric acid receptors (GABAARs). In this study, we addressed the hypothesis that combined GABAAR potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABAARs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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23 pages, 2085 KiB  
Article
Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats
by Romina Vargiu, Francesca Broccia, Carla Lobina, Daniele Lecca, Alessandro Capra, Pier Paolo Bassareo and Valentina Bassareo
Pharmaceuticals 2021, 14(7), 609; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070609 - 24 Jun 2021
Cited by 7 | Viewed by 3619
Abstract
Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the [...] Read more.
Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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27 pages, 3063 KiB  
Article
Nrf2/ARE Activators Improve Memory in Aged Mice via Maintaining of Mitochondrial Quality Control of Brain and the Modulation of Gut Microbiome
by Irina S. Sadovnikova, Artem P. Gureev, Daria A. Ignatyeva, Maria V. Gryaznova, Ekaterina V. Chernyshova, Ekaterina P. Krutskikh, Anastasia G. Novikova and Vasily N. Popov
Pharmaceuticals 2021, 14(7), 607; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070607 - 23 Jun 2021
Cited by 28 | Viewed by 3681
Abstract
Aging is one of the most serious factors for central nervous dysfunctions, which lead to cognitive impairment. New highly effective drugs are required to slow the development of cognitive dysfunction. This research studied the effect of dimethyl fumarate (DMF), methylene blue (MB), and [...] Read more.
Aging is one of the most serious factors for central nervous dysfunctions, which lead to cognitive impairment. New highly effective drugs are required to slow the development of cognitive dysfunction. This research studied the effect of dimethyl fumarate (DMF), methylene blue (MB), and resveratrol (RSV) on the cognitive functions of 15-month-old mice and their relationship to the maintenance of mitochondrial quality control in the brain and the bacterial composition of the gut microbiome. We have shown that studied compounds enhance mitochondrial biogenesis, mitophagy, and antioxidant defense in the hippocampus of 15-month-old mice via Nrf2/ARE pathway activation, which reduces the degree of oxidative damage to mtDNA. It is manifested in the improvement of short-term and long-term memory. We have also shown that memory improvement correlates with levels of Roseburia, Oscillibacter, ChristensenellaceaeR-7, Negativibacillus, and Faecalibaculum genera of bacteria. At the same time, long-term treatment by MB induced a decrease in gut microbiome diversity, but the other markers of dysbiosis were not observed. Thus, Nrf2/ARE activators have an impact on mitochondrial quality control and are associated with a positive change in the composition of the gut microbiome, which together lead to an improvement in memory in aged mice. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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13 pages, 3959 KiB  
Article
Dextran Sodium Sulphate-Induced Gastrointestinal Injury Further Aggravates the Impact of Galantamine on the Gastric Myoelectric Activity in Experimental Pigs
by Jan Bures, Ilja Tacheci, Jaroslav Kvetina, Vera Radochova, Darina Kohoutova, Martin Valis, Stanislav Rejchrt, Veronika Knoblochova and Jana Zdarova Karasova
Pharmaceuticals 2021, 14(6), 590; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060590 - 18 Jun 2021
Cited by 3 | Viewed by 1879
Abstract
Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5–7%) are the most common side effects. [...] Read more.
Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5–7%) are the most common side effects. The aim of this study was to assess the effect of galantamine on porcine gastric myoelectric activity without (Group A) and with (Group B) dextran sodium sulphate (DSS)-induced gastrointestinal injury. Galantamine hydrobromide was administrated to twelve pigs as a single intragastric dose (24 mg). Gastric myoelectric activity was investigated by electrogastrography (EGG). Basal (15 min before galantamine administration) and study recordings after galantamine administration (300 min) were evaluated using a running spectral analysis. Results were expressed as dominant frequency of gastric slow waves and power analysis (areas of amplitudes). Altogether, 3780 one-minute EGG recordings were evaluated. In Group A, power was steady from basal values for 180 min, then gradually decreased till 270 min (p = 0.007). In Group B, there was a rapid gradual fall from basal values to those after 120 min (p = 0.007) till 300 min (p ˂ 0.001). In conclusion, galantamine alone revealed an unfavourable effect on porcine myoelectric activity assessed by gastric power. It can be a plausible explanation of galantamine-associated dyspepsia in humans. DSS caused further profound decrease of EGG power. That may indicate that underlying inflammatory, ischaemic or NSAIDs-induced condition of the intestine in humans can have aggravated the effect of galantamine on gastric myoelectric activity. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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16 pages, 24263 KiB  
Article
The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease
by Elisabeth Singer, Lilit Hunanyan, Magda M. Melkonyan, Jonasz J. Weber, Lusine Danielyan and Huu Phuc Nguyen
Pharmaceuticals 2021, 14(3), 257; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030257 - 12 Mar 2021
Viewed by 2636
Abstract
Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 [...] Read more.
Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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17 pages, 3684 KiB  
Article
Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice
by Henning Johannes Drews, Roman Klein, Ali Lourhmati, Marine Buadze, Elke Schaeffeler, Thomas Lang, Torgom Seferyan, Leah R. Hanson, William H. Frey II, Tom C.G.M. de Vries, Inge A.E.W. Thijssen-van Loosdregt, Christoph H. Gleiter, Matthias Schwab and Lusine Danielyan
Pharmaceuticals 2021, 14(2), 166; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020166 - 20 Feb 2021
Cited by 20 | Viewed by 3505
Abstract
Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also [...] Read more.
Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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10 pages, 1302 KiB  
Communication
Possibility of a New Indication for Amantadine in the Treatment of Bipolar Depression—Case Series Study
by Marek Krzystanek and Artur Pałasz
Pharmaceuticals 2020, 13(10), 326; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100326 - 21 Oct 2020
Cited by 10 | Viewed by 5402
Abstract
Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as [...] Read more.
Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as the repurposing of drugs used in other indications. In an open and naturalistic serious case study, 4 patients diagnosed with bipolar I disorder, chronically treated with a mood stabilizer, in whom at least two antidepressants were ineffective in the depressive phase, were treated with amantadine. The woman received 100 mg/day and 3 men received the target dose of 200 mg/day. All patients treated with amantadine improved their depressive symptoms after 1 week of treatment. None of them experienced side effects or manic switch. To reduce the risk of a manic switch, the treatment with amantadine was discontinued 2 weeks after the improvement of depressive symptoms, and no recurrence of depressive symptoms was observed. Amantadine may be a further therapeutic option for the treatment of acute bipolar depression. The drug in this indication may act quickly and be well tolerated. Confirmation of the antidepressant efficacy of amantadine in this indication requires replication of the results and conducting clinical trials. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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12 pages, 2416 KiB  
Article
Disruption of Cholinergic Circuits as an Area for Targeted Drug Treatment of Alzheimer’s Disease: In Vivo Assessment of Short-Term Plasticity in Rat Brain
by Vergine Chavushyan, Ani Soghomonyan, Gohar Karapetyan, Karen Simonyan and Konstantin Yenkoyan
Pharmaceuticals 2020, 13(10), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100297 - 09 Oct 2020
Cited by 6 | Viewed by 3456
Abstract
The search for new therapeutics for the treatment of Alzheimer’s disease (AD) is still in progress. Aberrant pathways of synaptic transmission in basal forebrain cholinergic neural circuits are thought to be associated with the progression of AD. However, the effect of amyloid-beta (Aβ) [...] Read more.
The search for new therapeutics for the treatment of Alzheimer’s disease (AD) is still in progress. Aberrant pathways of synaptic transmission in basal forebrain cholinergic neural circuits are thought to be associated with the progression of AD. However, the effect of amyloid-beta (Aβ) on short-term plasticity (STP) of cholinergic circuits in the nucleus basalis magnocellularis (NBM) is largely unknown. STP assessment in rat brain cholinergic circuitry may indicate a new target for AD cholinergic therapeutics. Thus, we aimed to study in vivo electrophysiological patterns of synaptic activity in NBM-hippocampus and NBM-basolateral amygdala circuits associated with AD-like neurodegeneration. The extracellular single-unit recordings of responses from the hippocampal and basolateral amygdala neurons to high-frequency stimulation (HFS) of the NBM were performed after intracerebroventricular injection of Aβ 25–35. We found that after Aβ 25–35 exposure the number of hippocampal neurons exhibiting inhibitory responses to HFS of NBM is decreased. The reverse tendency was seen in the basolateral amygdala inhibitory neural populations, whereas the number of amygdala neurons with excitatory responses decreased. The low intensity of inhibitory and excitatory responses during HFS and post-stimulus period is probably due to the anomalous basal synaptic transmission and excitability of hippocampal and amygdala neurons. These functional changes were accompanied by structural alteration of hippocampal, amygdala, and NBM neurons. We have thus demonstrated that Aβ 25–35 induces STP disruption in NBM-hippocampus and NBM-basolateral amygdala circuits as manifested by unbalanced excitatory/inhibitory responses and their frequency. The results of this study may contribute to a better understanding of synaptic integrity. We believe that advancing our understanding of in vivo mechanisms of synaptic plasticity disruption in specific neural circuits could lead to effective drug searches for AD treatment. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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14 pages, 5383 KiB  
Article
Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer’s Disease
by Miles Frost, Abby Keable, Dan Baseley, Amber Sealy, Diana Andreea Zbarcea, Maureen Gatherer, Ho Ming Yuen, Matt MacGregor Sharp, Roy O. Weller, Johannes Attems, Colin Smith, Paul R. Chiarot and Roxana O. Carare
Pharmaceuticals 2020, 13(9), 261; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090261 - 22 Sep 2020
Cited by 9 | Viewed by 2830
Abstract
Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force [...] Read more.
Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function may explain the deposition of amyloid-beta as cerebral amyloid angiopathy (CAA), a key feature of Alzheimer’s disease. The α-adrenoceptor subtype α1A is abundant in the brain, but its distribution in the cerebral vessels is unclear. We analysed cultured human cerebrovascular SMCs and young, old and CAA human brains for (a) the presence of α1A receptor and (b) the distribution of the α1A receptor within the cerebral vessels. The α1A receptor was present on the wall of cerebrovascular SMCs. No significant changes were observed in the vascular expression of the α1A-adrenergic receptor in young, old and CAA cases. The pattern of vascular staining appeared less punctate and more diffuse with ageing and CAA. Our results show that the α1A-adrenergic receptor is preserved in cerebral vessels with ageing and in CAA and is expressed on cerebrovascular smooth muscle cells, suggesting that vascular adrenergic receptors may hold potential for therapeutic targeting of IPAD. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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Review

Jump to: Research

12 pages, 639 KiB  
Review
Brain Glucose Hypometabolism and Iron Accumulation in Different Brain Regions in Alzheimer’s and Parkinson’s Diseases
by Indira Y. Rao, Leah R. Hanson, Julia C. Johnson, Michael H. Rosenbloom and William H. Frey II
Pharmaceuticals 2022, 15(5), 551; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050551 - 29 Apr 2022
Cited by 6 | Viewed by 4657
Abstract
The aim of this study was to examine the relationship between the presence of glucose hypometabolism (GHM) and brain iron accumulation (BIA), two potential pathological mechanisms in neurodegenerative disease, in different regions of the brain in people with late-onset Alzheimer’s disease (AD) or [...] Read more.
The aim of this study was to examine the relationship between the presence of glucose hypometabolism (GHM) and brain iron accumulation (BIA), two potential pathological mechanisms in neurodegenerative disease, in different regions of the brain in people with late-onset Alzheimer’s disease (AD) or Parkinson’s disease (PD). Studies that conducted fluorodeoxyglucose positron emission tomography (FDG-PET) to map GHM or quantitative susceptibility mapping—magnetic resonance imaging (QSM–MRI) to map BIA in the brains of patients with AD or PD were reviewed. Regions of the brain where GHM or BIA were reported in each disease were compared. In AD, both GHM and BIA were reported in the hippocampus, temporal, and parietal lobes. GHM alone was reported in the cingulate gyrus, precuneus and occipital lobe. BIA alone was reported in the caudate nucleus, putamen and globus pallidus. In PD, both GHM and BIA were reported in thalamus, globus pallidus, putamen, hippocampus, and temporal and frontal lobes. GHM alone was reported in cingulate gyrus, caudate nucleus, cerebellum, and parietal and occipital lobes. BIA alone was reported in the substantia nigra and red nucleus. GHM and BIA are observed independent of one another in various brain regions in both AD and PD. This suggests that GHM is not always necessary or sufficient to cause BIA and vice versa. Hypothesis-driven FDG-PET and QSM–MRI imaging studies, where both are conducted on individuals with AD or PD, are needed to confirm or disprove the observations presented here about the potential relationship or lack thereof between GHM and BIA in AD and PD. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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27 pages, 2131 KiB  
Review
Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update
by E. Maruthi Prasad and Shih-Ya Hung
Pharmaceuticals 2021, 14(8), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080717 - 25 Jul 2021
Cited by 50 | Viewed by 10365
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial’s status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT1A receptor agonist (sarizotan), and adenosine A2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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11 pages, 839 KiB  
Review
Whole Body Cryotherapy and Hyperbaric Oxygen Treatment: New Biological Treatment of Depression? A Systematic Review
by Marek Krzystanek, Monika Romańczyk, Stanisław Surma and Agnieszka Koźmin-Burzyńska
Pharmaceuticals 2021, 14(6), 595; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060595 - 21 Jun 2021
Cited by 2 | Viewed by 4751
Abstract
Treatment with antidepressants is often insufficiently effective, especially in treatment-resistant depression. In such a situation, it is possible to change the drug, add a second antidepressant, or use pharmacological and non-pharmacological methods of augmenting the effect of pharmacotherapy. New methods that may fall [...] Read more.
Treatment with antidepressants is often insufficiently effective, especially in treatment-resistant depression. In such a situation, it is possible to change the drug, add a second antidepressant, or use pharmacological and non-pharmacological methods of augmenting the effect of pharmacotherapy. New methods that may fall into the scope of multi-module depression treatment as an augmentation of depression treatment are whole body cryotherapy (WBC) and hyperbaric oxygen treatment (HBOT). 545 records were selected and analyzed for these two treatments and finally three clinical trials were selected for analysis. The review also includes data on the possibility of using WBC and HBOT in somatic indications and in organic mental syndromes. Despite the small number of studies on the effectiveness of WBC or HBOT in depression, the current data show that both methods may be effective in the treatment of depression. WBC may be effective in the augmentation of antidepressants, and additionally, it is a method in which a quick antidepressant effect is obtained. HBOT may be effective in endogenous depression, just as it is effective in the treatment of somatic depression symptoms. The results are very preliminary, but if confirmed in subsequent studies, both WBC and HBOT may become new treatment options in treating depression. The authors point to the need and directions for further research into these treatment methods as an augmentation strategy for pharmacological treatment of depression. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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15 pages, 1047 KiB  
Review
Prospects of Therapeutic Target and Directions for Ischemic Stroke
by Jung Hak Kim, So Young Kim, Bokyung Kim, Sang Rae Lee, Sang Hoon Cha, Dong Seok Lee and Hong Jun Lee
Pharmaceuticals 2021, 14(4), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040321 - 01 Apr 2021
Cited by 11 | Viewed by 3223
Abstract
Stroke is a serious, adverse neurological event and the third leading cause of death and disability worldwide. Most strokes are caused by a block in cerebral blood flow, resulting in neurological deficits through the death of brain tissue. Recombinant tissue plasminogen activator (rt-PA) [...] Read more.
Stroke is a serious, adverse neurological event and the third leading cause of death and disability worldwide. Most strokes are caused by a block in cerebral blood flow, resulting in neurological deficits through the death of brain tissue. Recombinant tissue plasminogen activator (rt-PA) is currently the only immediate treatment medication for stroke. The goal of rt-PA administration is to reduce the thrombus and/or embolism via thrombolysis; however, the administration of rt-PA must occur within a very short therapeutic timeframe (3 h to 6 h) after symptom onset. Components of the pathological mechanisms involved in ischemic stroke can be used as potential biomarkers in current treatment. However, none are currently under investigation in clinical trials; thus, further studies investigating biomarkers are needed. After ischemic stroke, microglial cells can be activated and release inflammatory cytokines. These cytokines lead to severe neurotoxicity via the overactivation of microglia in prolonged and lasting insults such as stroke. Thus, the balanced regulation of microglial activation may be necessary for therapy. Stem cell therapy is a promising clinical treatment strategy for ischemic stroke. Stem cells can increase the functional recovery of damaged tissue after post-ischemic stroke through various mechanisms including the secretion of neurotrophic factors, immunomodulation, the stimulation of endogenous neurogenesis, and neovascularization. To investigate the use of stem cell therapy for neurological diseases in preclinical studies, however, it is important to develop imaging technologies that are able to evaluate disease progression and to “chase” (i.e., track or monitor) transplanted stem cells in recipients. Imaging technology development is rapidly advancing, and more sensitive techniques, such as the invasive and non-invasive multimodal techniques, are under development. Here, we summarize the potential risk factors and biomarker treatment strategies, stem cell-based therapy and emerging multimodal imaging techniques in the context of stroke. This current review provides a conceptual framework for considering the therapeutic targets and directions for the treatment of brain dysfunctions, with a particular focus on ischemic stroke. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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14 pages, 1338 KiB  
Review
Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease
by Jacob Kosyakovsky, Jared M. Fine, William H. Frey and Leah R. Hanson
Pharmaceuticals 2021, 14(2), 95; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020095 - 27 Jan 2021
Cited by 27 | Viewed by 3527
Abstract
Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on [...] Read more.
Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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19 pages, 404 KiB  
Review
Endogenous Retroviruses in Nervous System Disorders
by Victoria Gröger, Alexander Emmer, Martin S. Staege and Holger Cynis
Pharmaceuticals 2021, 14(1), 70; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070 - 16 Jan 2021
Cited by 22 | Viewed by 3887
Abstract
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of [...] Read more.
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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