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International Journal of Molecular... Jan 2024Amyloid beta 1-42 (Aβ42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17β-estradiol is crucial for hippocampal LTP....
Amyloid beta 1-42 (Aβ42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17β-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17β-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aβ42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aβ42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aβ42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aβ42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aβ42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.
Topics: Rats; Animals; Estradiol; Long-Term Potentiation; Amyloid beta-Peptides; Memantine; Hippocampus; Glutamates
PubMed: 38338656
DOI: 10.3390/ijms25031377 -
Epileptic Disorders : International... Apr 2024
Topics: Humans; Alzheimer Disease; Memantine; Receptors, N-Methyl-D-Aspartate; Epilepsy
PubMed: 38334219
DOI: 10.1002/epd2.20202 -
European Journal of Medicinal Chemistry Mar 2024Influenza outbreaks cause pandemics in millions of people. The treatment of influenza remains a challenge due to significant genetic polymorphism in the influenza virus.... (Review)
Review
Influenza outbreaks cause pandemics in millions of people. The treatment of influenza remains a challenge due to significant genetic polymorphism in the influenza virus. Also, developing vaccines to protect against seasonal and pandemic influenza infections is constantly impeded. Thus, antibiotics are the only first line of defense against antigenically distinct strains or new subtypes of influenza viruses. Among several anti-influenza targets, the M2 protein of the influenza virus performs several activities. M2 protein is an ion channel that permits proton conductance through the virion envelope and the deacidification of the Golgi apparatus. Both these functions are critical for viral replication. Thus, targeting the M2 protein of the influenza virus is an essential target. Rimantadine and amantadine are two well-known drugs that act on the M2 protein. However, these drugs acquired resistance to influenza and thus are not recommended to treat influenza infections. This review discusses an overview of anti-influenza therapy, M2 ion channel functions, and its working principle. It also discusses the M2 structure and its role, and the change in the structure leads to mutant variants of influenza A virus. We also shed light on the recently identified compounds acting against wild-type and mutated M2 proteins of influenza virus A. These scaffolds could be an alternative to M2 inhibitors and be developed as antibiotics for treating influenza infections.
Topics: Humans; Influenza A virus; Antiviral Agents; Influenza, Human; Amantadine; Orthomyxoviridae; Ion Channels; Anti-Bacterial Agents; Viral Matrix Proteins
PubMed: 38330869
DOI: 10.1016/j.ejmech.2024.116172 -
Clinical Neurology and Neurosurgery Feb 2024Severe disorders of consciousness (sDoC) are a common sequela of aneurysmal subarachnoid hemorrhages (aSAH), and amantadine has been used to improve cognitive recovery... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Severe disorders of consciousness (sDoC) are a common sequela of aneurysmal subarachnoid hemorrhages (aSAH), and amantadine has been used to improve cognitive recovery after traumatic brain injury.
OBJECTIVE
This study evaluated the effect of amantadine treatment on consciousness in patients with sDoC secondary to aSAH.
METHODS
This double-center, randomized, prospective, cohort study included patients ≥ 18 years old with sDoC after aSAH from February 2020 to September 2023. Individual patient data of patients were pooled to determine the effect of amantadine, in comparison to placebo. The primary outcomes at 3 and 6 months after the ictus were evaluated using the modified Rankin scale (mRS) and Glasgow outcome scale (GOS). In addition to all-cause mortality, secondary endpoints were assessed weekly during intervention by scores on Rappaport's Disability Rating Scale (RDRS) and Coma Recovery Scale-Revised (CRSR).
RESULTS
Overall, 37 patients with sDoC and initial Glasgow Coma Scale (GCS) varying between 3 and 11 were recruited and randomized to amantadine (test group, n = 20) or placebo (control group, n = 17). The average age was 59.5 years (28 to 81 year-old), 24 (65%) were women, and the mean GCS at the beginning of intervention was 7.1. Most patients evolved to vasospasm (81%), with ischemia in 73% of them. The intervention was started between 30 to 180 days after the ictus, and administered for 6 weeks, with progressively higher doses. Neither epidemiological characteristics nor considerations regarding the treatment of the aneurysm and its complications differed between both arms. Overall mortality was 10.8% (4 deaths). During the study, four patients had potential adverse drug effects: two presented seizures, one had paralytic ileus, and another evolved with tachycardia; the medication was not suspended, only the dose was not increased. At data opening, 2 were taking amantadine and 2 placebo.
CONCLUSION
Despite some good results associated with amantadine in the literature, this study did not find statistically significant positive effects in cognitive recovery in patients with delayed post-aSAH sDoC. Further large randomized clinical trials in patients' subgroups are needed to better define its effectiveness and clarify any therapeutic window where it can be advantageous.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Amantadine; Cohort Studies; Consciousness; Consciousness Disorders; Prospective Studies; Subarachnoid Hemorrhage
PubMed: 38330801
DOI: 10.1016/j.clineuro.2024.108135 -
Acta Pharmaceutica Sinica. B Feb 2024A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8 T cells is subject to the regulatory T lymphocytes...
A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8 T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated -cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile -carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and lung metastasis suppression with the aid of PD-1 antibody.
PubMed: 38322349
DOI: 10.1016/j.apsb.2023.10.006 -
BMJ Case Reports Feb 2024An incarcerated male patient with a psychiatric history of schizoaffective disorder presented to the emergency department with muscle rigidity and mutism after receiving...
An incarcerated male patient with a psychiatric history of schizoaffective disorder presented to the emergency department with muscle rigidity and mutism after receiving a 150 mg haloperidol decanoate injection. At the peak of his illness, symptoms included muscular rigidity, mutism, excessive drooling, an altered level of consciousness, tachycardia, diaphoresis and tremors. Atypical neuroleptic malignant syndrome (NMS) was diagnosed after discrediting similar illnesses through clinical reasoning, laboratory and imaging studies. He was successfully treated during a 40-day hospitalisation with lorazepam, amantadine, methocarbamol and supportive care. This case represents an atypical presentation of NMS due to the patient's lack of fever development. Nonetheless, he satisfied many other criteria, most notably rapid symptom onset after receiving a first-generation antipsychotic medication. The case also provides an opportunity to discuss the prevalence of psychiatric illness among the US incarcerated population and incarceration as a risk factor for developing NMS.
Topics: Male; Humans; Neuroleptic Malignant Syndrome; Mutism; Antipsychotic Agents; Demography; Prisoners
PubMed: 38320820
DOI: 10.1136/bcr-2023-257563 -
American Journal of Physical Medicine &... Jun 2024
Topics: Humans; Memantine; Aphasia; Stroke; Male; Chronic Disease; Female; Aged; Middle Aged; Excitatory Amino Acid Antagonists
PubMed: 38320236
DOI: 10.1097/PHM.0000000000002438 -
BMC Geriatrics Feb 2024Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored... (Review)
Review
BACKGROUND
Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023.
CASE PRESENTATION
Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation.
CONCLUSIONS
Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.
Topics: Male; Humans; Aged; Aged, 80 and over; Memantine; Autism Spectrum Disorder; Echolalia; Alzheimer Disease; Dementia; Drug-Related Side Effects and Adverse Reactions; Hypertension
PubMed: 38302876
DOI: 10.1186/s12877-024-04658-2 -
Expert Opinion on Emerging Drugs Mar 2024Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million.... (Review)
Review
INTRODUCTION
Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.
AREAS COVERED
After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.
EXPERT OPINION
Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.
Topics: Child; Humans; Risperidone; Antipsychotic Agents; Autism Spectrum Disorder; Aripiprazole; Riluzole
PubMed: 38296815
DOI: 10.1080/14728214.2024.2313650 -
Radiation Oncology (London, England) Jan 2024Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation,...
BACKGROUND
Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB.
METHODS
We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine.
RESULTS
The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy.
CONCLUSION
The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.
Topics: Humans; Xenon; Excitatory Amino Acid Antagonists; Glioblastoma; Memantine; HeLa Cells; Receptors, N-Methyl-D-Aspartate; Radiation-Sensitizing Agents
PubMed: 38291439
DOI: 10.1186/s13014-023-02395-1