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Background: Blackcurrant ( Ribes nigrum L.) is a berry rich in anthocyanins, bioactive compounds known for their antioxidant and neuroprotective properties that benefit human health., Aims: This study aimed to investigate the effects of blackcurrant and its association with Donepezil on memory impairment, cholinergic neurotransmission, and antioxidant systems in a mouse model of amnesia induced by chronic administration of Scopolamine., Methods: Adult male Swiss mice were given saline, blackcurrant (50 mg/kg, orally), and/or Donepezil (5 mg/kg, orally) and/or Scopolamine (1 mg/kg, intraperitoneally)., Results: Behavioral tests revealed that blackcurrant and/or Donepezil prevented the learning and memory deficits induced by Scopolamine. In the cerebral cortex and hippocampus, blackcurrant and/or Donepezil treatments prevented the increase in acetylcholinesterase and butyrylcholinesterase activities induced by Scopolamine. Scopolamine also disrupted the glutathione redox system and increased levels of reactive species; nevertheless, blackcurrant and/or Donepezil treatments were able to prevent oxidative stress. Furthermore, these treatments prevented the increase in gene expression and protein density of acetylcholinesterase and the decrease in gene expression of the choline acetyltransferase enzyme induced by Scopolamine., Conclusions: Findings suggest that blackcurrant and Donepezil, either alone or in combination, have anti-amnesic effects by modulating cholinergic system enzymes and improving the redox profile. Therefore, blackcurrant could be used as a natural supplement for the prevention and treatment of memory impairment in neurodegenerative diseases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Alzheimer's Disease (AD) is a serious progressive neurodegenerative illness conducting to the decay of cognitive functions. A few drugs have been approved for the therapy of AD, including the acetylcholinesterase inhibitors (AChEIs) like donepezil. Their efficiency, however, is modest and their application is associated with toxicity. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, a rapidly acting antidepressant, has been proposed as a potential agent for the treatment of AD. The present study was designed to investigate the effects exerted by the combination of sub-threshold doses of donepezil with those of ketamine on rats' recognition memory abilities. For these experiments, the object recognition task (ORT) and the object location task (OLT), two procedures assessing non-spatial and spatial recognition memory respectively in rodents were used. Post-training acute administration of inactive doses of donepezil (0.3 mg/kg) and ketamine (1 mg/kg) counteracted non-spatial and spatial recognition memory impairments. The present findings, although preliminary, propose that the combined administration of ketamine and donepezil could represent a new strategy for the therapy of memory disorders, a common feature of AD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Parkinson's disease manifests as neurological alterations within dendritic spines in the striatal and neocortical brain regions, where their functionality closely correlates with morphology. However, the impact of current pharmacotherapy on dendritic spine neuroplasticity, crucial for novel drug development in neurological and psychiatric disorders, remains unclear. This study investigated the effects of 6-OHDA intrastriatal bilateral lesions in male adult rats on behavior and dendritic spine neuroplasticity in striatal and cortical neurons. Furthermore, it evaluated the influence of chronic co-administration of pramipexole (PPX), a D3 receptor agonist, and rasagiline (Ras), a selective MAO-B inhibitor, on these alterations. Lesioned animals exhibited impaired balance behavior, with no improvement following PPX-Ras treatment. The 6-OHDA lesion decreased dendritic spine density in caudate putamen (CPU) spiny projection neurons (SPNs), a change unaffected by treatment, though PPX-Ras increased mushroom spines and reduced stubby spines in these neurons. In nucleus accumbens (NAcc) SPNs and prefrontal cortex layer 3 (PFC-3) pyramidal cells, dendritic spine density remained unaltered, but PPX-Ras decreased mushroom spines and increased bifurcated spines in the NAcc, while increasing mushroom spines and decreasing stubby spines in PFC-3 in lesioned rats. These findings emphasize the importance of dendritic spines as promising targets for innovative pharmacotherapies for Parkinson's disease., Competing Interests: Declaration of Competing Interest None of the authors have conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ozanimod (Zeposia ® ), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P 1 and S1P 5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alzheimer's disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer's disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid-donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC 50  = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Activation of metabotropic glutamate 2 (mGlu 2 ) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as monotherapy or as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA), the mGlu 2 positive allosteric modulator (PAM) LY-487,379 alleviated parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates. Here, we sought to investigate the effect of biphenyl-indanone A (BINA), a highly selective mGlu 2 PAM whose chemical scaffold is unrelated to LY-487,379, to determine if a structurally different mGlu 2 PAM would also confer anti-parkinsonian benefit. In monotherapy experiments, MPTP-lesioned marmosets were injected with either vehicle, L-DOPA/benserazide (15/3.75 mg/kg, positive control) or BINA (0.1, 1, 10 mg/kg). In adjunct to a low L-DOPA dose experiments, MPTP-lesioned marmosets were injected with L-DOPA/benserazide (7.5/1.875 mg/kg) in combination with vehicle or BINA (0.1, 1, 10 mg/kg). Parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) were then quantified. When administered alone, BINA 1 and 10 mg/kg decreased parkinsonism severity by ~22% (p < 0.01) and ~47% (p < 0.001), when compared with vehicle, which was comparable with the global effect of a high L-DOPA dose. When administered in combination with a low L-DOPA dose, BINA 1 and 10 mg/kg decreased global parkinsonism by ~38% (p < 0.001) and ~53% (p < 0.001). BINA 10 mg/kg decreased global dyskinesia by ~94% (p < 0.01) and global PLBs by ~92% (p < 0.01). Our results provide additional evidence that mGlu 2 positive allosteric modulation elicits anti-parkinsonian effects. That this benefit is not related to a particular chemical scaffold suggests that it may be a class effect rather than the effect of a specific molecule., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR 2 ) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR 2 positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR 2 PAM, biphenylindanone A (BINA). Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and PLBs were administered L-DOPA with either vehicle or BINA (0.1, 1, and 10 mg/kg) in a randomised within-subject design and recorded. Behaviour was analysed by a blinded rater who scored the severity of each of parkinsonism, dyskinesia and PLBs. When added to L-DOPA, BINA 0.1 mg/kg, 1 mg/kg, and 10 mg/kg all significantly reduced the severity of global dyskinesia, by 40%, 52% and 53%, (all P < 0.001) respectively. BINA similarly attenuated the severity of global PLBs by 35%, 48%, and 50%, (all P < 0.001) respectively. Meanwhile, BINA did not alter the effect of L-DOPA on parkinsonism exhibited by the marmosets. The results of this study provide incremental evidence of positive allosteric modulation of mGluR 2 as an effective therapeutic strategy for alleviating dyskinesia and PLBs, without hindering the anti-parkinsonian action of L-DOPA. Furthermore, this therapeutic benefit does not appear to be confined to a particular chemical scaffold., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Sleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described., Methods: This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1)., Results: Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0., Conclusion: This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Donepezil and tadalafil, commonly prescribed among older persons to treat dementia and erectile dysfunction, respectively, are primarily metabolized by cytochrome P450 (CYP) 3A4. However, the drug-drug interactions (DDIs) of these drugs are unknown. Therefore, this study evaluated the CYP-mediated metabolic interaction between donepezil and tadalafil using pooled human liver microsomes (HLMs) to predict their DDI potential. Donepezil metabolism was tadalafil-concentration dependently changed in HLMs incubated with 0.1 μM donepezil and showed the maximum 32.3% increase in the donepezil half-life at 1 μM tadalafil. The formation rates of donepezil metabolites, such as N-desbenzyl donepezil and 3-hydroxy donepezil, decreased by 28.3% and 30.3%, respectively, in HLMs incubated with 1 μM tadalafil and 0.1 μM donepezil. In contrast, neither the half-life of tadalafil nor the production rate of its metabolite, desmethylene tadalafil, was changed by >20% in the presence of donepezil (up to 1 μM). CYP3A4 activity was inhibited by tadalafil with an IC 50 value of 22.6 μM but not by donepezil. After pre-incubating HLMs with tadalafil and NADPH, the tadalafil IC 50 value against CYP3A4 was approximately 7.04-fold lower, suggesting time-dependent tadalafil inhibition. This study shows that the DDI between donepezil and tadalafil is primarily due to time-dependent inhibition against CYP3A4 by tadalafil., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that influenced the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Bovine viral diarrhea virus (BVDV) is a widespread pathogen of cattle and other mammals that causes major economic losses in the livestock industry. N4-TSC and 6NO 2 -TSC are two thiosemicarbazones derived from 1-indanone that exhibit anti-BVDV activity in vitro. These compounds selectively inhibit BVDV and are effective against both cytopathic and non-cytopathic BVDV-1 and BVDV-2 strains. We confirmed that N4-TSC acts at the onset of viral RNA synthesis, as previously reported for 6NO 2 -TSC. Moreover, resistance selection and characterization showed that N4-TSC R mutants were highly resistant to N4-TSC but remained susceptible to 6NO 2 -TSC. In contrast, 6NO 2 -TSC R mutants were resistant to both compounds. Additionally, mutations N264D and A392E were found in the viral RNA-dependent RNA polymerase (RdRp) of N4-TSC R mutants, whereas I261 M was found in 6NO 2 -TSC R mutants. These mutations lay in a hydrophobic pocket within the fingertips region of BVDV RdRp that has been described as a "hot spot" for BVDV non-nucleoside inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recent research has indicated that parental use of central nervous system-targeting medications during periconceptional periods may affect offspring across various developmental and behavioral domains. The present study sought to investigate the potential influence of paternal use of donepezil, a specific reversible central acetylcholinesterase inhibitor that activates the cholinergic system to promote cognition, on offspring., Results: In this study, male rats were bred after 21 days of oral donepezil administration at a dose of 4 mg/kg to generate F1 offspring. Both male and female F₁ offspring displayed enhanced performance in learning and short-term memory tests, including novel object recognition, Y maze, and operant learning. Transcriptomic analysis revealed notable alterations in genes associated with the extracellular matrix in the hippocampal tissue of the F1 generation. Integration with genes related to intelligence identified potential core genes that may be involved in the observed behavioral enhancements., Conclusions: These findings indicate that prolonged paternal exposure to donepezil may enhance the learning and memory abilities of offspring, possibly by targeting nonneural, extracellular regions. Further research is required to fully elucidate any potential transgenerational effects., (© 2024. The Author(s).)

The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Indanone is a versatile scaffold that has a number of pharmacological properties. The successful development and ensuing approval of indanone-derived donepezil as a drug of choice for Alzheimer's disease attracted significant scientific interest in this moiety. Indanones could act as small molecule chemical probes as they have strong affinity towards several critical enzymes associated with the pathophysiology of various neurological disorders. Inhibition of these enzymes elevates the levels of neuroprotective brain chemicals such as norepinephrine, serotonin and dopamine. Further, indanone derivatives are capable of modulating the activities of both monoamine oxidases (MAO-A and -B) and acetylcholinesterase (AChE), and thus could be useful in various neurodegenerative diseases. This review article presents a panoramic view of the research carried out on the indanone nucleus in the development of potential neuroprotective agents., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1β, IL-6, and TNF-α. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1α/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue., (© 2024 The Wound Healing Society.)

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC 50  = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 μM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 μM concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic β-amyloid (Aβ42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c , which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD 50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule., Competing Interests: The authors declare no conflicts of interest.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 ( 4 , 14 , 15 , 22 , 26 , 35 , 36 , 37 , 48 , 49 , and 52 ) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 μM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dt max : 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 μm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Fernandoa adenophylla, due to the presence of phytochemicals, has various beneficial properties and is used in folk medicine to treat many conditions. This study aimed to isolate indanone derivative from F. adenophylla root heartwood and assess in-vitro anti-inflammatory and anti-diabetic characteristics at varying concentrations. Heat-induced hemolysis and glucose uptake by yeast cells assays were conducted to evaluate these properties. Besides, docking analyses were performed on four molecular targets. These studies were combined with molecular dynamics simulations to elucidate the time-evolving inhibitory effect of selected inhibitors within the active pockets of the target proteins (COX-1 and COX-2). Indanone derivative (10-100 µM) inhibited the lysis of human red blood cells from 9.12 ± 0.75 to 72.82 ± 4.36% and, at 5-100 µM concentrations, it significantly increased the yeast cells' glucose uptake (5.16 ± 1.28% to 76.59 ± 1.62%). Concluding, the isolated indanone might act as an anti-diabetic agent by interacting with critical amino acid residues of 5' adenosine monophosphate-activated protein kinase (AMPK), and it showed a binding affinity with anti-inflammatory targets COX-1, COX-2, and TNF-α. Besides, the obtained results may help to consider the indanone derivative isolated from F. adenophylla as a promising candidate for drug delivery, subject to outcomes of further in vivo and clinical studies., (© 2024. The Author(s).)

Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.

Treatment of aging rats for 6 months with ladostigil (1 mg/kg/day) prevented a decline in recognition and spatial memory and suppressed the overexpression of gene-encoding pro-inflammatory cytokines, TNFα, IL1β, and IL6 in the brain and microglial cultures. Primary cultures of mouse microglia stimulated by lipopolysaccharides (LPS, 0.75 µg/mL) and benzoyl ATPs (BzATP) were used to determine the concentration of ladostigil that reduces the secretion of these cytokine proteins. Ladostigil (1 × 10 -11 M), a concentration compatible with the blood of aging rats in, prevented memory decline and reduced secretion of IL1β and IL6 by ≈50%. RNA sequencing analysis showed that BzATP/LPS upregulated 25 genes, including early-growth response protein 1, (Egr1) which increased in the brain of subjects with neurodegenerative diseases. Ladostigil significantly decreased Egr1 gene expression and levels of the protein in the nucleus and increased TNF alpha-induced protein 3 (TNFaIP3), which suppresses cytokine release, in the microglial cytoplasm. Restoration of the aberrant signaling of these proteins in ATP/LPS-activated microglia in vivo might explain the prevention by ladostigil of the morphological and inflammatory changes in the brain of aging rats.

Sphingosine-1 phosphate (S1P) modulators have received recent FDA-approval for the treatment of moderate-to-severe ulcerative colitis, including agents ozanimod, approved in 2021, and etrasimod, approved in 2023. These oral drugs are uniquely efficacious in UC as they have multimodal mechanisms contributing to their beneficial immunomodulatory effects, while preserving host response to pathogens and attenuating toxicities observed with less specific agents. In this review, the discovery and development of the first approved S1P modulator, ozanimod, is described in detail: from design of initial screens to discover unique binding agents, to extensive chemical modifications to improve pharmacokinetic and safety profiles, and through preclinical and clinical studies validating mechanism and establishing safety and efficacy. Ultimately, this review will not only inform the reader of the unique path to development of a clinical S1P modulator for UC, but will also highlight advances made and gaps remaining to individualize therapeutic approaches for inflammatory bowel disease., (Copyright © 2024. Published by Elsevier Inc.)

Background: Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL., Objective: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms., Methods: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes., Results: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells., Conclusions: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.

Introduction: To investigate the inhibition properties and structure-activity relationship between monoamine oxidase (MAO) and selected monoamine oxidase inhibitors (MAOIs, including selegiline, rasagiline and clorgiline)., Methods: The inhibition effect and molecular mechanism between MAO and MAOIs were identified via the half maximal inhibitory concentration (IC 50 ) and molecular docking technology., Results: It was indicated that selegiline and rasagiline were MAO B inhibitors, but clorgiline was MAO-A inhibitor based on the selectivity index (SI) of MAOIs (0.000264, 0.0197 and 14607.143 for selegiline, rasagiline and clorgiline, respectively). The high-frequency amino acid residues of the MAOIs and MAO were Ser24, Arg51, Tyr69 and Tyr407 for MAO-A and Arg42 and Tyr435 for MAO B. The MAOIs and MAO A/B pharmacophores included the aromatic core, hydrogen bond acceptor, hydrogen bond donor-acceptor and hydrophobic core., Conclusion: This study shows the inhibition effect and molecular mechanism between MAO and MAOIs and provides valuable findings on the design and treatment of Alzheimer's and Parkinson's diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The indandione nucleus, is one of the most amazing nuclei in medicinal chemistry, is used to design new derivatives. Methods & materials: Novel indandione derivatives are prepared with different electrophilic and nucleophilic reagents to yield 3 , 4 , 8 , 11 , 14 , 16, 19, 20, 21, 22 and 23 . Compounds 8, 11, 16, 20 and 23 are investigated against OVCAR-3 and HeLa, using LLC-MK2 and cis -Pt as references. in silico and spectral studies were analyzed for the selected compounds. Results: Compounds 20 and 23 at 100 ns were the most potent compounds, so molecular dynamics studies were performed. Conclusion: Compound 23 was the most active toward the HeLa cervical cell line, and compound 20 was the most active toward the Ovcar-3 cell line.

Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC 50  = 0.054 ± 0.004 μM; MAO-B: IC 50  = 3.25 ± 0.20 μM), moderate inhibitory effects on self-mediated amyloid-β (Aβ) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [ 3 H]dopamine release without influencing the resting [ 3 H]dopamine release from rat striatal slices in 10 -10 -10 -9 mol/L concentrations. Rasagiline added in 10 -13 to 10 -5 mol/L concentrations did not alter the resting or electrically stimulated [ 3 H]dopamine release. Rasagiline (10 -9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [ 3 H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10 -8 -10 -7 mol/L) also inhibited the stimulatory effect of selegiline on [ 3 H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (-)methamphetamine (10 -9 mol/L) also exhibited enhancer activity on [ 3 H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogs as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC 50 values) for the synthesized compounds ranged from 0.12 to 11.92 μM and 0.04 to 24.36 μM against AChE and BChE, respectively. Compound 5 c showed the highest AChE inhibitory potency with IC 50 value of 0.12 μM, whereas the highest BChE inhibition was achieved by structure 7 b (IC 50 =0.04 μM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5 c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7 b. The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine>piperidine>morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5 c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery against Alzheimer's disease., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Vegetable viruses are difficult to prevent and control in the field, causing massive economic losses of agricultural production in the world. A new natural product-based antiviral agent would be an effective means to control viral diseases. As a class of natural products, 1-indanones present various pharmacologically actives, while their application in agriculture remains to be found., Results: A series of novel 1-indanone derivatives were designed and synthesized and the antiviral activities were systematically evaluated. Bioassays showed that most compounds exhibited good protective activities against cucumber mosaic virus (CMV), tomato spotted wilt virus (TSWV), and pepper mild mottle virus (PMMoV). Notably, compound 27 exhibited the best protective effects against PMMoV with EC 50 values of 140.5 mg L -1 , superior to ninanmycin (245.6 mg L -1 ). Compound 27 induced immunity responses through multilayered regulation on mitogen-activated protein kinase, plant hormone signal transduction and phenylpropanoid biosynthesis pathways., Conclusion: These 1-indanone derivatives especially compound 27 can be considered as potential immune activators to resist plant virus. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

To investigate the clinical effect of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with Alzheimer disease (AD), a total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. The control group was treated with donepezil tablets, while the observation group was treated with donepezil tablets combined with hydrogen-oxygen mixture inhalation. The scores of mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognition, activity of daily living scale (ADL) and the P300 event-related potential were compared between the 2 groups. After treatment, MMSE score, MoCA score, and ADL score in both groups increased after treatment (P < .01), while the improvement in the observation group was more significant than that in the control group (P < .001 for MMSE, P = .003 for MoCA, and P = .013 for ADL). The scores of Alzheimer's Disease Assessment Scale-Cognition in the observation group decreased after treatment (P < .05), while the improvement in the observation group was more significant than that in the control group (P = .005). After treatment, the latency of P300 in both groups was shortened (P < .01), and the improvement in the observation group was more significant than that in the control group (P < .001). The amplitude of the observation group increased after treatment (P < .01), and the improvement of the observation group was significant than that of the control group (P = .007). The clinical efficacy of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of AD is better than that of donepezil alone, which is worthy of further study., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate., Methods: Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points., Results: Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups., Conclusion: The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ozanimod is approved in multiple countries for the treatment of adults with either relapsing multiple sclerosis or moderately to severely active ulcerative colitis. Ozanimod is metabolized in humans to form seven active plasma metabolites, including two major active metabolites CC112273 and CC1084037, and an inactive metabolite. Here, the binding and activity of ozanimod and its metabolites across human sphingosine 1-phosphate receptors were determined. Binding affinity was assessed in Chinese hamster ovary cell membranes expressing recombinant human sphingosine 1-phosphate receptors 1 and 5 via competitive radioligand binding using tritium-labeled ozanimod; selectivity via functional potency assessment was performed using [ 35 S]-guanosine-5'-(γ-thio)-triphosphate binding assays. Receptor internalization was assessed in human embryonic kidney 293 cells overexpressing sphingosine 1-phosphate receptor 1-green fluorescent protein and Chinese hamster ovary cells overexpressing sphingosine 1-phosphate receptor 5-hemagglutinin via fluorescence activated cell sorting. Functional activity was assessed in primary cultures of human astrocytes via phosphorylation assays. Ozanimod and its functionally active metabolites bound to the same sites within sphingosine 1-phosphate receptors 1 and 5, with metabolites displaying the same selectivity profile as ozanimod. Agonism at sphingosine 1-phosphate receptor 1 induced receptor internalization, whereas sphingosine 1-phosphate receptor 5 did not. Ozanimod, CC112273, and CC1084037 elicited functional intracellular signaling in human astrocytes, pharmacologically characterized to be mediated by sphingosine 1-phosphate receptor 1. The active plasma metabolites of ozanimod bound to sphingosine 1-phosphate receptors 1 and 5 and displayed similar pharmacologic profiles as their parent compound, likely contributing to clinical efficacy in patients with relapsing multiple sclerosis or moderately to severely active ulcerative colitis., Competing Interests: Declaration of competing interest YGY, NC, and RH are employees of Bristol Myers Squibb. JVS and KP were employees of Bristol Myers Squibb at the time of this study., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders., Methods: A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects., Results: The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents., Conclusion: The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In an attempt to identify small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC) and prostate cancer (PCa), new arylidene indanones (1-10) were synthesized via the Claisen-Schmidt condensation of 5,6-methylenedioxy-1-indanone with p-substituted benzaldehyde. Compounds 1-10 were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human pancreatic ductal carcinoma (PANC-1) cells as well as human normal lung fibroblast (CCD-19Lu) and human normal pancreatic ductal epithelial (hTERT-HPNE) cells. Among them, compounds 2, 4 and 10 were more effective on A549 and PANC-1 cells than cisplatin. Compounds 1 and 9 also showed more potent cytotoxic activity towards PANC-1 cells than cisplatin. In vitro assays were performed to assess their effects on DNA synthesis, apoptosis, caspase-3, mitochondrial membrane potential, intracellular calcium levels, morphological changes in cancer cells. Furthermore, all compounds were investigated for their inhibitory effects on cathepsin L (CatL) and cathepsin D (CatD). Compounds 2 and 4 exerted potent anti-NSCLC action through caspase-independent apoptosis induced by an increase in intracellular calcium level and correspondingly the disruption of the ΔΨm. These compounds also caused apoptotic morphological alterations in A549 cells. Compound 4 also inhibited both cathepsins but its inhibitory potency on CatL was more significant. Based on in vitro mechanistic assays, compound 4 was identified as a promising anticancer agent for targeted therapy of NSCLC. On the other hand, the marked anti- PCa activity of compound 1 mediated by apoptotic cell death is also noteworthy, but further enzymatic assays are required to elucidate its main mechanism of action., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component. Cereblon is a well-known target of thalidomide and its derivatives. Cereblon is involved in multiple myeloma cell apoptosis. When ligands such as thalidomide and lenalidomide bind to cereblon, it recognizes various neosubstrates based on the ligand shape and properties. We have identified novel CRBN inhibitors, namely DHFO and its analogs, with structural features that are slightly different from thalidomide but stronger cereblon-binding affinity. We selected indanedione and indanone derivatives from the literature to understand and compare their cereblon-mediated substrate recognition potential., Methods: Computational investigations of possible CRBN inhibitors were investigated by molecular docking with Autodock Vina and DockThor programs. The properties of the compounds' ADME/T and drug-likeness were investigated. A molecular dynamics study was carried out for four selected molecules, and the molecular interactions were analyzed using PCA-based FEL methods. The binding affinity was calculated using the MM/PBSA method., Results: We conducted computational investigations on 68 indanedione and indanone derivatives binding with cereblon. Ten molecules showed better CRBN binding affinity than thalidomide. We studied the drug-likeness properties of the selected ten molecules, and four of the most promising molecules (DHFO, THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor, has the highest binding affinity of - 163.16 kJ/mol with cereblon., Conclusion: The selected CRBN inhibitor DHFO has demonstrated the highest binding affinity with cereblon protein compared to other molecules. Thalidomide and its derivatives have a new substitute in the form of DHFO, which produces an interaction hotspot on the surface of the cereblon. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHFO analogs provide an opportunity for exploring clinical alternatives with versatile therapeutic potential for a new category of indanedione molecules as novel modulators of E3 ubiquitin ligases., Competing Interests: Declaration of Interest The authors declare no financial or personal relationships that are received for this work from any commercial institutions or industry. Conflict of Interest The writers affirm that they have received no compensation from commercial organizations or industries for this research work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ± standard deviation (SD) of 80.33 ± 7.98 years (78.97 ± 8.26 for males and 81.04 ± 7.98 for females), as compared to 79.95 ± 7.67 (78.87 ± 7.61 for males and 80.61 ± 7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans., Methods: In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model., Results: We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity., Conclusion: Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Background: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD., Methods: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes., Results: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE)., Conclusion: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy., Clinical Trial Registration Numbers: NCT03440372, NCT03440385, NCT03464097, NCT03467958., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Brian G. Feagan has consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, enGene, Ferring Pharma, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GSK, Ironwood, Janssen, Johnson & Johnson, Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB, and is a director at Robarts Clinical Trials. Stefan Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. Anita Afzali has served as a consultant for AbbVie, Takeda, Janssen, Pfizer, Bristol Myers Squibb, Eli Lilly, Gilead, TLL Pharmaceuticals, Arena Pharmaceuticals, and DiaSorin, and has received speaker fees from AbbVie, Takeda, Janssen, Pfizer, and Bristol Myers Squibb. Florian Rieder has consulted for Adnovate, AgomAb, Allergan, AbbVie, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CDISC, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, GuidePoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Janssen, Koutif, Mestag Therapeutics, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, Redx Pharma, Roche, Samsung, Surmodics, Surrozen, Takeda, TechLab, Theravance, Thetis, UCB, Ysios Capital, and 89bio. Jeffrey Hyams served on advisory boards for Janssen, Pfizer, and Boehringer Ingelheim and as a consultant to Takeda, Bristol Myers Squibb, Thetis, and Eli Lilly. Kanthi Kollengode, Jared Pearlman, Vladimir Son, and Cecilia Marta are employees of Bristol Myers Squibb. Douglas C. Wolf has received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB. Geert G. D'Haens has consulted for AbbVie, Cellceutix, Celgene, Endo, Ferring, Gilead, Janssen Ortho Biotech, Eli Lilly, American Regent, Merck, Morphic, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for UCB, Janssen Ortho Biotech; editor (honorarium) Gastroenterology and Hepatology (Gastro-Hep Communications), Springer Science and Business Media; received book royalties from SLACK, Inc., and Professional Communications, Inc., (Copyright © 2022. Published by Elsevier Inc.)

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.

Some bioactive derivatives of indeno[1,2-c]pyrazolones were synthesized through the reaction of phenylhydrazine, different aldehydes and indan-1,2,3-trione at room temperature in acetonitrile. Analytical and spectroscopic studies have confirmed the structural characteristics of the synthesized compounds. In addition, the target compounds were screened for the in-vitro antiproliferative properties against the B16F10 melanoma cancer cell lines by the standard MTT assay. The effect on inflammatory marker cyclooxygenase 2 and matrix metalloproteinase 2, 9 was also checked to determine the anti-inflammatory and anti-cell migratory properties of these compounds. The final compounds were also tested for their tyrosinase inhibitory activity. Among all compounds, screened for anticancer activity, three compounds 4e, 4f and 4h reduced the cell proliferation significantly comparable to that of the positive standard drug erlotinib (IC 50 =418.9±1.54 μM) with IC 50 values ranging from 20.72-29.35 μM. The compounds 4c-4h decreased the COX-2 expression whereas the MMP 2, 9 expressions were significantly reduced by 4a, 4b and 4h. This was confirmed by molecular docking studies, as 4e, 4f and 4h displayed good interactions with the active site of BRAF protein. The compounds 4b, 4f and 4h exhibited moderate tyrosinase inhibition effect as compared to α-MSH. Collectively, compound 4h can be considered as a candidate for further optimization in the development of anticancer therapies based on the results of biological investigations in this study., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC 50  = 0.721 µM) compared to MAO-B (IC 50  = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly., (© 2022. The Author(s).)

Introduction: Ozanimod is a sphingosine-1-phosphate (S1P) modulator that inhibits lymphocyte trafficking from lymph nodes to the circulation. It is approved by the US Food and Drug Administration (FDA) for the treatment of relapsing multiple sclerosis and most recently for the management of moderate-severe ulcerative colitis (UC)., Areas Covered: Here we review the status of drugs approved for moderate-severe UC, the unmet needs in the management of UC, proposed mechanisms of action of S1P modulators, clinical data regarding ozanimod in UC, and emerging S1P modulators being evaluated in inflammatory bowel disease., Expert Opinion: Ozanimod is superior to placebo in inducing and maintaining clinical and endoscopic remission in UC. Adverse events include transient asymptomatic bradycardia, first-degree atrioventricular blocks, transient asymptomatic hepatotoxicity, macular edema in patients with preexisting risk factors, and increased risk of nasopharyngitis. Ozanimod is contraindicated in patients with clinically significant cardiovascular diseases, type II second-, or third-degree atrioventricular blocks, and females of childbearing age who do not use contraception. Ozanimod is the first S1P modulator to be approved for UC, offering a new therapeutic class option for patients. It has the advantages of being convenient with a once-daily oral administration, non-immunogenic, and overall safe when used in patients without contraindications.

Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is present. The inappropriate accumulation of HIF2 drives tumor formation by VHL tumor suppressor protein (pVHL)–defective ccRCC. Belzutifan, a first-in-class allosteric HIF2 inhibitor, has advanced to phase 3 testing for advanced ccRCC and is approved for ccRCCs arising in patients with VHL disease, which is caused by germline VHL mutations. HIF2 can suppress p53 function in some settings and preliminary data suggested that an intact p53 pathway, as measured by activation in response to DNA damage, was necessary for HIF2 dependence. Here, we correlated HIF2 dependence and p53 status across a broader collection of ccRCC cell lines. We also genetically manipulated p53 function in ccRCC lines that were or were not previously HIF2-dependent and then assessed their subsequent sensitivity to HIF2 ablation using CRISPR-Cas9 or the HIF2 inhibitor PT2399, which is closely related to belzutifan. From these studies, we conclude that p53 status does not dictate HIF2 dependence, at least in preclinical models, and thus is unlikely to be a useful biomarker for predicting which ccRCC patients will respond to HIF2 inhibitors.

Psychometric network analysis is an alternative theoretically-driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer's disease differently than was previously assumed and consequently detect unknown treatment effects. Based on individual participant data, extracted from three double-blind, randomized placebo-controlled clinical trials, psychometric networks were computed on observed Alzheimer's Disease Assessment Scale Cognitive Subscale scores at baseline (N=1,554) and on predicted change scores at 24 weeks of follow-up for participants who received donepezil (N=797) or placebo (N=484). A novel conceptualization of cognitive impairment in Alzheimer's disease was displayed through the baseline network, that had 90% (n=27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change score networks. The donepezil network had more statistically significant (p<0.05) positive associations and a higher global strength (n=15; S=1.22; p=0.03), than the placebo network (n=8; S=0.57). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer's disease, points to previously unknown treatment effects and highlights well-defined aspects of cognitive impairment  that may translate into future treatment targets., Competing Interests: Declaration of Competing Interest Drs Rotstein, Levine, Yoshida, Samara and Goldberg have nothing to disclose. Dr. Iwatsubo: has served as a consultant of Eisai, Roche and Biogen in the last 3 years. Dr. Cipriani: has received research and consultancy fees from INCiPiT (Italian Network for Pediatric Trials), CARIPLO Foundation and Angelini Pharma. Dr. Leucht has received honoraria as a consultant or for lectures for LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson & Johnson, TEVA, MSD, Sandoz, Sanofi-Aventis, Angelini, Sunovion, Recordati and Gedeon Richter. Dr. Furukawa reports personal fees from Mitsubishi-Tanabe, MSD and Shionogi, a grant from Mitsubishi-Tanabe, outside the submitted work, and has a patent 2018-177688 pending., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = -4.13, 95% CI = -5.93, -2.32; placebo MM = 1.81, 95% CI = -4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To explore the effect of resveratrol (RES) combined with donepezil hydrochloride on inflammatory factor level and cognitive function level of patients with Alzheimer's disease (AD)., Methods: A total of 90 AD patients treated in our hospital from June 2019 to June 2020 were selected as the study objects and divided into the control group (CG) and experimental group (EG) by the randomized and double-blind method, with 45 cases each. Patients in CG received donepezil hydrochloride treatment, and on this basis, those in EG received additional RES treatment, so as to compare the clinical indicators between the two groups., Results: Compared with CG after treatment, EG obtained significantly higher good rate, MMSE score, and FIM score ( P < 0.05) and obviously lower clinical indicators and ADAS-cog score ( P < 0.001), and between CG and EG, no obvious difference in total incidence rate of adverse reactions was observed after treatment ( P > 0.05)., Conclusion: Combining RES with donepezil hydrochloride has significant clinical efficacy in treating AD, which can effectively improve patients' inflammatory factor indicators, promote their cognitive function, and facilitate patient prognosis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Xincui Fang et al.)

Anti-dementia medications are widely prescribed to patients with Alzheimer's dementia (AD) in South Korea. This study investigated the pattern of medical management in newly diagnosed patients with AD using a standardized data format-the Observational Medical Outcome Partnership Common Data Model from five hospitals. We examined the anti-dementia treatment patterns from datasets that comprise > 5 million patients during 2009-2019. The medication utility information was analyzed with respect to treatment trends and persistence across 11 years. Among the 8653 patients with newly diagnosed AD, donepezil was the most commonly prescribed anti-dementia medication (4218; 48.75%), followed by memantine (1565; 18.09%), rivastigmine (1777; 8.98%), and galantamine (494; 5.71%). The rising prescription trend during observation period was found only with donepezil. The treatment pathways for the three cholinesterase inhibitors combined with N-methyl-D-aspartate receptor antagonist were different according to the drugs (19.6%; donepezil; 28.1%; rivastigmine, and 17.2%; galantamine). A 12-month persistence analysis showed values of approximately 50% for donepezil and memantine and approximately 40% for rivastigmine and galantamine. There were differences in the prescribing pattern and persistence among anti-dementia medications from database using the Observational Medical Outcome Partnership Common Data Model on the Federated E-health Big Data for Evidence Renovation Network platform in Korea., (© 2022. The Author(s).)