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Science Advances Dec 2023Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor...
Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals ( = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.
Topics: Rats; Animals; Memantine; Brain Injuries, Traumatic; Brain; Electrocorticography; Receptors, N-Methyl-D-Aspartate
PubMed: 38091390
DOI: 10.1126/sciadv.adj2417 -
World Journal of Clinical Cases Nov 2023Tardive dyskinesia (TD) is a serious and disabling movement disorder; it impairs social function and quality of life and increases the mortality rate. TD is usually...
BACKGROUND
Tardive dyskinesia (TD) is a serious and disabling movement disorder; it impairs social function and quality of life and increases the mortality rate. TD is usually induced by the use of antipsychotic drugs; however, the underlying mechanism remains unclear. Pharmacotherapy of TD includes cholinergic drugs, benzodiazepines, ginkgo biloba extract (GBE), antioxidants, amantadine, propanolol, botulinum toxin, valbenazine, and deutetrabenazine, whereas the non-pharmacotherapy approach includes modified electroconvulsive therapy (MECT) and deep brain stimulation. We successfully treated a chronic schizophrenia patient with comorbid long-term severe TD using deutetrabenazine, clozapine, and MECT.
CASE SUMMARY
A 69-year-old woman who was diagnosed as having schizophrenia 16 years ago developed severe TD after 6-mo prescription of risperidone oral solution. Her TD symptoms did not resolve despite various treatments, such as GBE, vitamin E, trihexyphenidyl, promethazine, benzodiazepines, and switching to quetiapine and olanzapine. After admission, she was given deutetrabenazine 6 mg bid. Her buccal tremor was slightly resolved 3 d later; however, her tongue remained protruded and could not be retracted. Quetiapine was switched to clozapine on day 4, and the buccal tremor remarkably resolved, and the tongue could be retracted into the mouth from day 6 onward. After three sessions of MECT, the buccal tremor resolved further. Since then, she has been able to take a semifluid diet, and her quality of life improved remarkably during 6 mo of follow-up.
CONCLUSION
TD is a serious condition which could be caused by antipsychotic medications; however, the best strategy against TD is prevention and monitoring during using antipsychotics. For patients with TD caused by antipsychotic medication use, multiple measures should be considered like switching to clozapine, adjunction with deutetrabenazine, or even MECT.
PubMed: 38073685
DOI: 10.12998/wjcc.v11.i32.7895 -
Cancers Nov 2023A common feature of Parkinson's disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce... (Review)
Review
A common feature of Parkinson's disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce two types of melanin: eumelanin and pheomelanin. These dyes are designed to protect epidermal cells from the harmful effects of UV radiation. Neurones of the substantia nigra, which degenerate during PD, produce neuromelanin, the physiological role of which is not fully explained. This article discusses the potential role of melanins in the pathogenesis of both diseases. Melanins, due to their ability to accumulate toxic substances, may become their sources over time. The use of glutathione for the synthesis of pheomelanins and neuromelanins may reduce the antioxidant capacity of cells, leading to an excessive synthesis of free radicals. This study also tested the hypothesis that certain drugs used in the treatment of PD (L-DOPA, MAO-B and COMT inhibitors, and amantadine), aimed at increasing dopamine concentration, could potentially contribute to the development of melanoma. The role and properties of melanins should continue to be researched. Whether excessive melanin synthesis or its accumulation in the extracellular space may be factors initiating the development of diseases remains an open question.
PubMed: 38067245
DOI: 10.3390/cancers15235541 -
Cells Nov 2023A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications... (Review)
Review
A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.
Topics: Humans; Levodopa; Phosphoric Diester Hydrolases; Glutamic Acid; Dyskinesia, Drug-Induced; Nucleotides, Cyclic
PubMed: 38067182
DOI: 10.3390/cells12232754 -
New anti-SARS-CoV-2 aminoadamantane compounds as antiviral candidates for the treatment of COVID-19.Virus Research Feb 2024Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells...
Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells up to a concentration of 1,000 µM. The inhibitory concentration (IC) of aminoadamantane was 39.71 µM in Vero CCL-81 cells and the derivatives showed significantly lower IC values, especially for compounds 3F4 (0.32 µM), 3F5 (0.44 µM) and 3E10 (1.28 µM). Additionally, derivatives 3F5 and 3E10 statistically reduced the fluorescence intensity of SARS-CoV-2 protein S from Vero cells at 10 µM. Transmission microscopy confirmed the antiviral activity of the compounds, which reduced cytopathic effects induced by the virus, such as vacuolization, cytoplasmic projections, and the presence of myelin figures derived from cellular activation in the face of infection. Additionally, it was possible to observe a reduction of viral particles adhered to the cell membrane and inside several viral factories, especially after treatment with 3F4. Moreover, although docking analysis showed favorable interactions in the catalytic site of Cathepsin L, the enzymatic activity of this enzyme was not inhibited significantly in vitro. The new derivatives displayed lower predicted toxicities than aminoadamantane, which was observed for either rat or mouse models. Lastly, in vivo antiviral assays of aminoadamantane derivatives in BALB/cJ mice after challenge with the mouse-adapted strain of SARS-CoV-2, corroborated the robust antiviral activity of 3F4 derivative, which was higher than aminoadamantane and its other derivatives. Therefore, aminoadamantane derivatives show potential broad-spectrum antiviral activity, which may contribute to COVID-19 treatment in the face of emerging and re-emerging SARS-CoV-2 variants of concern.
Topics: Chlorocebus aethiops; Humans; Animals; Mice; Rats; SARS-CoV-2; COVID-19; COVID-19 Drug Treatment; HEK293 Cells; Vero Cells; Amantadine; Antiviral Agents
PubMed: 38065303
DOI: 10.1016/j.virusres.2023.199291 -
Turkish Journal of Medical Sciences Aug 2023Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant,...
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model.
METHODS
Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg for 2 weeks. Group 2 (sham group): In addition to ICV STZ, 9% NaCl, 1 mL/day i.p. for 2 weeks of injection, was applied. Group 3 (TQ group): In addition to ICV STZ, rats received TQ 10 mg/kg i.p. for 2 weeks. Group 4 (MEM group): In addition to ICV STZ, rats were given MEM at a dose of 5 mg/kg for two weeks. Group 5 (TQ+MEM group): In addition to ICV STZ, this group was given TQ (10 mg/kg/day, i.p.) and MEM (5 mg/kg/day, i.p.) for 2 weeks. On the 15th day, passive avoidance learning (PAL) was applied to all groups. Then, rats were sacrificed, neurons in the hippocampal CA1, CA2, CA3 regions were evaluated.
RESULTS
Groups 3, 4, 5 had longer latency periods than groups 1 and 2. The neuron density in the CA1, CA2, CA3 regions had decreased in groups 1 and 2 compared to groups 3, 4, 5. There were significantly more neurons in groups 3, 4, 5 than in groups 1 and 2.
DISCUSSION
We found that TQ alone and in combination with MEM showed ameliorative effects on memory and hippocampal morphology. TQ may offer a promising treatment strategy for AD.
Topics: Rats; Male; Animals; Alzheimer Disease; Memantine; Streptozocin; Neurodegenerative Diseases; Hippocampus; Disease Models, Animal; Maze Learning
PubMed: 38031940
DOI: 10.55730/1300-0144.5653 -
Neuropsychiatric Disease and Treatment 2023Fatigue is a common, debilitating and often underestimated symptom in patients with multiple sclerosis (MS). The exact pathophysiological mechanism of fatigue in MS is... (Review)
Review
Fatigue is a common, debilitating and often underestimated symptom in patients with multiple sclerosis (MS). The exact pathophysiological mechanism of fatigue in MS is still unknown. However, there are many theories involving different immunological, metabolic and inflammatory mechanisms of fatigue. Owing to the subjective nature of this symptom, its diagnosis is still very limited and is still based only on diagnostic questionnaires. Although several therapeutic agents have been used in the past to try to influence fatigue in MS patients, no single effective approach for the treatment of fatigue has yet been found. This review article aims to provide the reader with information on the current theories on the origin and mechanism of fatigue in MS, as well as diagnostic procedures and, finally, current therapeutic strategies for the management of fatigue in MS patients.
PubMed: 38029042
DOI: 10.2147/NDT.S429862 -
Maturitas Feb 2024History of cancer has been associated with decreased risk of dementia, but it is unclear if this is due to the use of antineoplastic medications. Participants were...
History of cancer has been associated with decreased risk of dementia, but it is unclear if this is due to the use of antineoplastic medications. Participants were 442,795 adults aged ≥60 years, of whom 235,841 (53.26 %) were women. Those dispensed antineoplastic medications during 2012-2013 had lower odds of being dispensed an anti-dementia drug between 2015 and 2021 (age/sex-adjusted OR = 0.60, 95%CI = 0.55-0.66). The dispensing of antineoplastic medications was associated with an adjusted hazard ratio of 0.72 (95%CI = 0.65-0.80) of subsequent dispensing of an anti-dementia drug. Understanding the mechanisms that support this association may contribute to the introduction of novel approaches to dementia prevention.
Topics: Humans; Female; Male; Cohort Studies; Memantine; Cholinesterase Inhibitors; Dementia; Antineoplastic Agents; Alzheimer Disease
PubMed: 38006816
DOI: 10.1016/j.maturitas.2023.107888 -
Molecules (Basel, Switzerland) Nov 2023Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have...
Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.
Topics: Humans; Edaravone; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Adamantane; Riluzole; Amantadine
PubMed: 38005288
DOI: 10.3390/molecules28227567 -
Brain Sciences Nov 2023Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We...
Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.
Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs ( = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline ( = 25) and amantadine ( = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.
PubMed: 38002511
DOI: 10.3390/brainsci13111551