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Heliyon May 2024In this study, two derivatives, namely the ester derivative cinnamoyl metronidazole and the amide derivative cinnamoyl memantine, were synthesized from cinnamic acid and...
In this study, two derivatives, namely the ester derivative cinnamoyl metronidazole and the amide derivative cinnamoyl memantine, were synthesized from cinnamic acid and respective drugs for the purpose of exploring their potential as novel and efficient antimicrobial agents in the quest of prevailing the global antimicrobial resistance challenge. The synthesis process involved two steps: first, the chlorination of cinnamic acid using thionyl chloride, and second, the esterification of metronidazole or the amidation of memantine. These steps resulted in the formation of cinnamoyl metronidazole/memantine. Optimal reaction conditions were established, and chromatographic techniques were used to separate the synthesized compounds. Confirmation of successful synthesis was achieved through FT-IR analysis, which readily distinguished the chlorinated product and derivatives based on distinctive bands, including mainly the one of carbonyl group. Additionally, molecular structures were validated using H NMR and C NMR, with all peaks further confirming the successful esterification/amidation of cinnamoyl and drug moieties. Upon evaluating the biological activity, the parent compounds exhibited negligible effects within the tested concentration range. However, the derivatives demonstrated significant activity. The ester derivative exhibited potent activity against the Gram-positive bacterium , as evidenced by a zone of inhibition measuring 12-15 mm in diameter. Conversely, the amide derivative displayed appreciable biological activity against fungi, with an inhibition zone measuring 11-14 mm.
PubMed: 38694036
DOI: 10.1016/j.heliyon.2024.e29851 -
Porto Biomedical Journal 2024Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs... (Review)
Review
Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs aim only at a symptomatic effect. The subject of prescribing these drugs in advanced stages is a matter of considerable debate, with different countries making distinct recommendations. In this review article, we analyzed the evidence regarding cognitive and functional outcomes, adverse events, health-related costs, and caregiver burden in patients with advanced Alzheimer disease (AD) and mixed dementia. We included 35 studies. Most studies are heterogeneous, focus exclusively on AD, and show small benefits in terms of cognitive and functional scales. The overall evidence seems to suggest a benefit in introducing or maintaining anti-dementia drugs in patients with advanced dementia, but clinical meaningfulness is difficult to ascertain. The issue of costs and caregiver burden is significantly underexplored in this field but also seems to favor treatment continuation, despite a reduced overall effect. The decision of introducing or withdrawing anti-dementia drugs in advanced stages of dementia should be individualized. Future studies with homogeneous designs and outcomes are warranted.
PubMed: 38690178
DOI: 10.1097/j.pbj.0000000000000251 -
Frontiers in Neurology 2024Birth asphyxia and its main sequel, hypoxic-ischemic encephalopathy, are one of the leading causes of children's deaths worldwide and can potentially worsen the quality... (Review)
Review
Birth asphyxia and its main sequel, hypoxic-ischemic encephalopathy, are one of the leading causes of children's deaths worldwide and can potentially worsen the quality of life in subsequent years. Despite extensive research efforts, efficient therapy against the consequences of hypoxia-ischemia occurring in the perinatal period of life is still lacking. The use of hyperbaric oxygen, improving such vital consequences of birth asphyxia as lowered partial oxygen pressure in tissue, apoptosis of neuronal cells, and impaired angiogenesis, is a promising approach. This review focused on the selected aspects of mainly experimental hyperbaric oxygen therapy. The therapeutic window for the treatment of perinatal asphyxia is very narrow, but administering hyperbaric oxygen within those days improves outcomes. Several miRNAs (e.g., mir-107) mediate the therapeutic effect of hyperbaric oxygen by modulating the Wnt pathway, inhibiting apoptosis, increasing angiogenesis, or inducing neural stem cells. Combining hyperbaric oxygen therapy with drugs, such as memantine or ephedrine, produced promising results. A separate aspect is the use of preconditioning with hyperbaric oxygen. Overall, preliminary clinical trials with hyperbaric oxygen therapy used in perinatal asphyxia give auspicious results.
PubMed: 38685945
DOI: 10.3389/fneur.2024.1386695 -
Nutrients Apr 2024The excessive activation of glutamate in the brain is a factor in the development of vascular dementia. γ-Oryzanol is a natural compound that has been shown to enhance...
The excessive activation of glutamate in the brain is a factor in the development of vascular dementia. γ-Oryzanol is a natural compound that has been shown to enhance brain function, but more research is needed to determine its potential as a treatment for vascular dementia. This study investigated if γ-oryzanol can delay or improve glutamate neurotoxicity in an in vitro model of differentiated HT-22 cells and explored its neuroprotective mechanisms. The differentiated HT-22 cells were treated with 0.1 mmol/L glutamate for 24 h then given γ-oryzanol at appropriate concentrations or memantine (10 µmol/L) for another 24 h. Glutamate produced reactive oxygen species and depleted glutathione in the cells, which reduced their viability. Mitochondrial dysfunction was also observed, including the inhibition of mitochondrial respiratory chain complex I activity, the collapse of mitochondrial transmembrane potential, and the reduction of intracellular ATP levels in the HT-22 cells. Calcium influx triggered by glutamate subsequently activated type II calcium/calmodulin-dependent protein kinase (CaMKII) in the HT-22 cells. The activation of CaMKII-ASK1-JNK MAP kinase cascade, decreased Bcl-2/Bax ratio, and increased Apaf-1-dependent caspase-9 activation were also observed due to glutamate induction, which were associated with increased DNA fragmentation. These events were attenuated when the cells were treated with γ-oryzanol (0.4 mmol/L) or the N-methyl-D-aspartate receptor antagonist memantine. The results suggest that γ-oryzanol has potent neuroprotective properties against glutamate excitotoxicity in differentiated HT-22 cells. Therefore, γ-oryzanol could be a promising candidate for the development of therapies for glutamate excitotoxicity-associated neurodegenerative diseases, including vascular dementia.
Topics: Glutamic Acid; Phenylpropionates; Animals; Neuroprotective Agents; Mice; Cell Line; Reactive Oxygen Species; Mitochondria; Oryza; Membrane Potential, Mitochondrial; Cell Differentiation; Cell Survival; Memantine; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Neurons
PubMed: 38674927
DOI: 10.3390/nu16081237 -
Biomedicines Mar 2024Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is...
Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, -methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4 T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes' mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.
PubMed: 38672073
DOI: 10.3390/biomedicines12040717 -
The Journal of Neuroscience : the... Jun 2024The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, noninvasive physiological...
The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, noninvasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in the human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under a placebo. The GABA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA blocker memantine. Our findings indicate that the 40 Hz ASSR in the auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition.
Topics: Humans; Auditory Cortex; Male; Female; Adult; Magnetoencephalography; Evoked Potentials, Auditory; GABAergic Neurons; Young Adult; Neural Inhibition; Acoustic Stimulation
PubMed: 38670804
DOI: 10.1523/JNEUROSCI.2029-23.2024 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
MedRxiv : the Preprint Server For... Apr 2024has been proposed as a modifier of disease risk in FTLD-TDP, particularly in mutation carriers. Furthermore, has been investigated as a disease modifier in the...
BACKGROUND AND OBJECTIVES
has been proposed as a modifier of disease risk in FTLD-TDP, particularly in mutation carriers. Furthermore, has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients.
METHODS
Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in , symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR+NACC-FTLD sum of boxes. Subsequently, associations between and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by predictor interactions were fitted.
RESULTS
The minor allele of rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic mutation carriers only. The minor allele of rs1990622 also associated with greater cognitive scores among all mutation carriers and in presymptomatic mutation carriers, under the recessive dosage model.
DISCUSSION
We identified associations of with gray matter volume and cognition in the presence of and mutations. This further supports as modifier of TDP-43 pathology. The association of with outcomes of interest in presymptomatic and mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
PubMed: 38633784
DOI: 10.1101/2024.04.05.24305253 -
Clinical Psychopharmacology and... May 2024Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics,... (Review)
Review
Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (-5.2 [95%CrI: -7.7, -2.7]) and memantine (-2.1 [95%CrI: -4.0, -0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.
PubMed: 38627071
DOI: 10.9758/cpn.23.1119 -
Substance Abuse and Rehabilitation 2024Illicitly manufactured fentanyl (IMF) is a significant contributor to the increasing rates of overdose-related deaths. Its high potency and lipophilicity can complicate... (Review)
Review
Illicitly manufactured fentanyl (IMF) is a significant contributor to the increasing rates of overdose-related deaths. Its high potency and lipophilicity can complicate opioid withdrawal syndromes (OWS) and the subsequent management of opioid use disorder (OUD). This scoping review aimed to collate the current OWS management of study populations seeking treatment for OWS and/or OUD directly from an unregulated opioid supply, such as IMF. Therefore, the focus was on therapeutic interventions published between January 2010 and November 2023, overlapping with the period of increasing IMF exposure. A health science librarian conducted a systematic search on November 13, 2023. A total of 426 studies were screened, and 173 studies were reviewed at the full-text level. Forty-nine studies met the inclusion criteria. Buprenorphine and naltrexone were included in most studies with the goal of transitioning to a long-acting injectable version. Various augmenting agents were tested (buspirone, memantine, suvorexant, gabapentin, and pregabalin); however, the liberal use of adjunctive medication and shortened timelines to initiation had the most consistently positive results. Outside of FDA-approved medications for OUD, lofexidine, gabapentin, and suvorexant have limited evidence for augmenting opioid agonist initiation. Trials often have low retention rates, particularly when opioid agonist washout is required. Neurostimulation strategies were promising; however, they were developed and studied early. Precipitated withdrawal is a concern; however, the rates were low and adequately mitigated or managed with low- or high-dose buprenorphine induction. Maintenance treatment continues to be superior to detoxification without continued management. Shorter induction protocols allow patients to initiate evidence-based treatment more quickly, reducing the use of illicit or non-prescribed substances.
PubMed: 38623317
DOI: 10.2147/SAR.S433358