Acetylcholinesterase Inhibitor Donepezil Research Articles

The pharmacoeconomic assessment of the rationality of the use of memantine and its combinations with acetylcholinesterase inhibitors in the treatment of dementia in Alzheimer’s disease in Ukraine

Aim. To conduct the pharmacoeconomic assessment of the rationality of using memantine and its combinations with acetylcholinesterase inhibitors in the treatment of dementia in Alzheimer’s disease in Ukraine. Materials and methods. Historical, analytical and comparative, systematic, graphic, logical, hypothetical-deductive, as well as marketing, pharmacoeconomic, and mathematical and statistical methods of analysis were used. The pharmacoeconomic studies were conducted using the cost-effectiveness method. CER and ICER indicators were calculated for dementia treatment regimens in Alzheimer’s disease containing memantine and its combinations with acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) in the period of 12 and 24 weeks of their use. The pharmacoeconomic analysis used data on the clinical effectiveness of dementia treatment regimens in Alzheimer’s disease presented in the Sochrane library (ID Number: CN-01071444; Accession Number: PUBMED 25932260e). Results. It was found that despite the clinical advantages of using the memantine+galantamine regimen proven by scientists according to the MMSE scale, the use of the memantine+rivastigmine regimen seemed to be rational (CER1 = 23.13 and CER2 = 34.57 USD/unit of increased efficiency). The clinical and economic benefits of using the memantine+galantamine regimen in the treatment of dementia patients with Alzheimer’s disease were proven in the 12- and 24-week regimen (MMSE scale). In the case of using the AADL scale, it was rational, from the point of view of economical use of resources, in the 12-week regimen of treating patients, the use of the memantine + rivastigmine regimen was less expensive (CER1 = 18.30 $/unit of AADL score reduction), while in the 24-week regime it was the memantine + placebo regimen (CER2 = $37.58 $/ unit of AADL score reduction). Conclusions. The research results presented can be used in forming drug purchases carried out by specialized healthcare institutions under the conditions of limited budget funding and growing needs of psychoneurological patients in effective medical and pharmaceutical care.

Distinct septo-hippocampal cholinergic projections separately mediate stress-induced emotional and cognitive deficits.

Patients suffering from chronic stress develop numerous symptoms, including emotional and cognitive deficits. The precise circuit mechanisms underlying different symptoms remain poorly understood. We identified two distinct basal forebrain cholinergic subpopulations in mice projecting to the dorsal hippocampus (dHPC) or ventral hippocampus (vHPC), which exhibited distinct input organizations, electrophysiological characteristics, transcriptomics, and responses to positive and negative valences of stimuli and were critical for cognitive and emotional modulation, respectively. Moreover, chronic stress induced elevated anxiety levels and cognitive deficits in mice, accompanied by enhanced vHPC but suppressed dHPC cholinergic projections. Chemogenetic activation of dHPC or inhibition of vHPC cholinergic projections alleviated stress-induced aberrant behaviors. Furthermore, we identified that the acetylcholinesterase inhibitor donepezil combined with blockade of muscarinic receptor 1-type muscarinic acetylcholine receptors in the vHPC rescued both stress-induced phenotypes. These data illuminated distinct septo-hippocampal cholinergic circuits mediated specific symptoms independently under stress, which may provide promising strategies for circuit-based treating of stress-related psychiatric disorders.

Joint administration of sub-threshold doses of the acetylcholinesterase inhibitor donepezil with those of the NMDA receptor antagonist ketamine improved rats’ recognition memory abilities

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.

Association between Polypharmacy and Adverse Events in Patients with Alzheimer's Disease: An Analysis of the Japanese Adverse Drug Event Report Database (JADER).

Background and Objectives: Alzheimer's disease is a global health concern, with a rising prevalence among the elderly. Current pharmacological treatments, including acetylcholinesterase inhibitors (AChEIs) and N-Methyl D-Aspartate (NMDA) receptor antagonists, are associated with adverse events (AEs), particularly in the context of polypharmacy. This study aimed to investigate the relationship between Alzheimer's disease treatment combinations, the number of concomitant medications, and the occurrence of AEs. Materials and Methods: Data from the Japanese Adverse Drug Event Report database, spanning from April 2004 to June 2020, were analyzed. Patients aged 60 and older with Alzheimer's disease treated with AChEIs (donepezil, galantamine, and rivastigmine) or the NMDA receptor antagonist memantine were included. Logistic regression models were employed to assess the association between AEs and Alzheimer's disease drug combinations, as well as the number of concomitant medications. Results: Among 2653 patients, 47.7% were prescribed five or more drugs. The frequency of AEs was 6.4% for bradycardia, 4.6% for pneumonia, 3.6% for altered state of consciousness, 3.5% for seizures, 3.5% for decreased appetite, 3.5% for vomiting, 3.4% for loss of consciousness, 3.4% for fracture, 3.2% for cardiac failure, and 3.0% for falls. The combination of memantine with AChEIs was associated with a higher risk of bradycardia, whereas donepezil alone was linked to a reduced risk of fractures and falls. Polypharmacy was significantly correlated with an increased incidence of AEs, particularly altered state of consciousness, decreased appetite, vomiting, and falls. The adjusted odds ratios for using five or more drugs compared to no drugs was 10.45 for altered state of consciousness, 7.92 for decreased appetite, 4.74 for vomiting, and 5.95 for falls. Conclusions: In the treatment of Alzheimer's disease, the occurrence of AEs is associated with the number of concurrent medications, independently of the known AEs of Alzheimer's disease drugs and their combination patterns.

Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain.

Deep brain stimulation (DBS), the direct electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine, is under consideration as a method to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain. 2-photon imaging was combined with deep brain stimulation. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRABACh-3.0 muscarinic acetylcholine receptor sensor, and blood vessels were imaged with Texas red. Experiments manipulating pulse train frequency demonstrated that integrated acetylcholine induced fluorescence was insensitive to frequency, and that peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor donepezil increased the peak response to 10s of stimulation at 60Hz, and the integrated response increased 57% with the 2 mg/kg dose, and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14 to 18 seconds in all experiments. These data demonstrate that acetylcholine receptor activation is insensitive to frequency between 60 and 130 Hz. High peak responses are achieved with up to 900 pulses. Donepezil increases total acetylcholine receptor activation associated with DBS but did not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume in addition to synaptic transmission.

Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Alzheimer’s and Parkinson’s disease drugs side effects

IntroductionAlzheimer’s and Parkinson’s disease are neurodegenerative disorders with life limiting conditions. The symptomatic pharmacological therapeutic strategies unfortunately are also related to undesirable side effects. Acetylcholinesterase inhibitors administered to Alzheimer’s disease patients increase cholinergic transmission in cortex and hippocampus.Antiparkinsonian drugs increase dopaminergic system activity, to compensate for dopaminergic neurons’ degeneration in corpus striatum, therefore supplying the imbalance of these neurotransmitters in these degenerative areas.But undesirable the increase of these neurotransmitters in other cerebral and peripheral areas brings us important side effectsObjectivesTo study Alzheimer’s cholinergic drugs and Parkinson’s dopaminergic drugs’ side effectsMethods This retrospective study included 107 geriatric patients enrolled in a private long-term care institution. 79 patients with Alzheimer’s disease had mean age of 88.11 ± 5,78 years old, mean weight of 61.62 ± 13.10 kg. 28 patients with Parkinson’s disease had mean age of 84.93 ± 5.71 years old, weight mean 66.36 ± 2.83 kg.ResultsAlzheimer’s disease patients 41.77% (33) received. Acetylcholinesterase inhibitors (Donepezil, galantamine and rivastigmine) Psychomotor agitation and aggressive behavior 63.666% and nausea (15%) were observed in the patients treated with these drugs. The association of L-DOPA and DOPA decarboxylase inhibitors (benserazide) were administered to 53%(15) of the Parkinson’s disease patients in doses between 2.0-19.0 mg/kg/day. L-DOPA associated to catechol-O-methyltransferase inhibitor (entacapone) 3 mg/kg/day were given to 7.14% (2) patients. Bromocriptine 0.04 mg/kg/day was given to 3.57% (1) patients. Mental confusion and hallucination side effects were observed in 53.33% (8) patients treated with L-DOPA associated with the DOPA decarboxylase inhibitor (benserazide).ConclusionsThe increase of cholinergic activity due to the acetylcholinesterase inhibitors in the Nigro- striatal pathway could be related to psychomotor agitation in Alzheimer’s disease patients in a similar way to akathisia induced by neuroleptics. The increase of dopamine levels due to the administration of L-DOPA, in corpus striatum improved Parkinson’s disease symptoms although the increase of dopaminergic activity at mesocortical pathways may be related to confusion and hallucination observed in these patients. Adjustments in dosage of these drugs could provide improvement in these patients’ daily life conditions.Disclosure of InterestNone Declared

Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction.

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/dtmax: 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.

Polypharmacological Potential of Phosphodiesterase 5 Inhibitors for the Treatment of Neurocognitive Disorders.

The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aβ deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.

Prescription profile of Alzheimer’s disease medications in the public health system in Southern Brazil

AbstractBackgroundAlzheimer’s disease (AD) accounts for 60‐70% of cases of dementia, and is characterized by progressive decline in cognition and functionality. Pharmacological treatment is fundamentally symptomatic, and consist mainly of three acetylcholinesterase (IChE) inhibitors (donepezil, galantamine and rivastigmine) and one N‐methyl‐D‐aspartate (NMDA) receptor, memantine. Although these drugs are freely available in the public health system in Brazil, there may be barriers to accessing them. We aim to evaluate the profile of prescription of AD medication in the public health system in the state of Rio Grande do Sul (RS), Southern Brazil.MethodsWe analyzed all AD medications requested in the state of RS during October/2021 in the public health system. Sociodemographic, Mini Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale data were collected. We described the variables as median (interquartile range ‐ IQR) or frequencies. We also performed a spatial autocorrelation analysis of the medication prescribed in the RS municipalities. All analyses were performed in R.ResultsThe total of 2,382 AD patients were using any AD medication. Most were female (65.6%), had elementary education (71.7%) and a median age of 79 (73‐84) years. The patients' MMSE median was 15 [12‐18] and most had a CDR = 2 (55.2%, 1133). The most prescribed medication was donepezil, 42.6% (1014), alone or in combination with memantine (Table 1). The distribution of the variable patient/100,000/municipality was clustered, with Moran’s I of 0.17562 (p&lt;0.001) (Figure 1).ConclusionsMost patients using AD medications in the public health system had moderate dementia. The distribution pattern of these medications in the RS state was uneven. The identification of factors related to these patterns may provide valuable information about the barriers to the access to AD treatment in the state of RS.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aβ aggregation.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p=0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p=0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. The study was pre-registered on PROSPERO (CRD42021258376).

Donepezil to lecanemab-advancements in targeted therapy of Alzheimer’s disease so far

Alzheimer's disease (AD) first identified as Alois Alzheimer in 1907, is a slowly progressing dementia that affects cognition, behaviour and functional status. There is no cure for AD since precise pathophysiological mechanisms underlying it is not completely known. Drugs may temporarily reduce the symptoms associated with disorder, but condition is ultimately fatal. Objective of treatment of AD is to reduce behaviour issues associated with memory loss and improve cognition. Single acetylcholinesterase inhibitors donepezil and galantamine, as well as the dual AChE and butyrylcholinesterase (BuChE) inhibitor rivastigmine, are now utilized in treatment of AD. Cholinesterase inhibitors have shown dose-dependent impact on cognition and functional activities in clinical trials. Memantine NMDA receptor antagonist is used to minimize neurotoxicity that's suspected to contribute to conditions like Alzheimer's and other neurodegenerative disorders. Estrogen administration post menopause can result in modulation of synaptogenesis, enhanced cerebral blood flow, mediation of crucial neurotransmitters and hormones, protection against apoptosis. Aducanumab is 1st disease modifying drug and monoclonal antibody that targets beta-amyloid clusters in mild AD. Recent advancement in therapy, lecanemab, a recombinant IgG1 monoclonal antibody is targeted against aggregated soluble and insoluble forms of amyloid beta, thereby minimizing Aβ plaques and preventing Aβ deposition in the brain. As research advances, molecular basis of disease becomes more apparent leading to the advent of plausible targeted therapy.

M1-selective muscarinic allosteric modulation enhances cognitive flexibility and effective salience in nonhuman primates

Acetylcholine (ACh) in cortical neural circuits mediates how selective attention is sustained in the presence of distractors and how flexible cognition adjusts to changing task demands. The cognitive domains of attention and cognitive flexibility might be differentially supported by the M1 muscarinic acetylcholine receptor (mAChR) subtype. Understanding how M1 mAChR mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimer's disease or schizophrenia. Here, we tested this question by assessing how the subtype-selective M1 mAChR positive allosteric modulator (PAM) VU0453595 affects visual search and flexible reward learning in nonhuman primates. We found that allosteric potentiation of M1 mAChRs enhanced flexible learning performance by improving extradimensional set shifting, reducing latent inhibition from previously experienced distractors and reducing response perseveration in the absence of adverse side effects. These procognitive effects occurred in the absence of apparent changes of attentional performance during visual search. In contrast, nonselective ACh modulation using the acetylcholinesterase inhibitor (AChEI) donepezil improved attention during visual search at doses that did not alter cognitive flexibility and that already triggered gastrointestinal cholinergic side effects. These findings illustrate that M1 mAChRpositive allosteric modulation enhances cognitive flexibility without affecting attentional filtering of distraction, consistent with M1 activity boosting the effective salience of relevant over irrelevant objects specifically during learning. These results suggest that M1 PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimer's diseases.

An update on potential pharmacotherapies for cognitive impairment in bipolar disorder

ABSTRACT Introduction Cognitive impairment is a core feature of bipolar disorder (BD) that impedes recovery by preventing the return to optimal socio-occupational functioning and reducing quality of life. Presently, there are no efficacious treatments for cognitive impairment in BD, but many pharmacological interventions are being considered as they have the potential to target the underlying pathophysiology of the disorder. Areas covered This review summarizes the available evidence for pharmacological interventions for cognitive impairment in bipolar disorder. We searched PubMed, MedLine, and PsycInfo from inception to December 1st, 2022. Traditional treatments, such as lithium, anticonvulsants (lamotrigine), antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, and olanzapine), antidepressants (vortioxetine, fluoxetine, and tianeptine) and psychostimulants (modafinil), and emerging interventions, such as acetylcholinesterase inhibitors (galantamine and donepezil), dopamine agonists (pramipexole), erythropoietin, glucocorticoid receptor antagonists (mifepristone), immune modulators (infliximab, minocycline and doxycycline), ketamine, metabolic agents (insulin, metformin, and liraglutide), probiotic supplements, and Withania somnifera are discussed. Expert opinion The investigation of interventions for cognitive impairment in BD is a relatively under-researched area. In the past, methodological pitfalls in BD cognition trials have also been a critical limiting factor. Expanding on the existing literature and identifying novel pharmacological and non-pharmacological treatments for cognitive impairment in BD should be a priority.

The effects of donepezil on anxiety- and depression-like behaviors in diabetic rats and the role of nitric oxide modulators

Aims: The aim of the present study was to evaluate the effect of an acetylcholinesterase inhibitor donepezil on the diabetes-induced anxiety and depression and the role of nitric oxide in these effects. Methods: Thirty male Wistar rats were randomly divided into 2 groups at first; the control group (n=6) and the diabetic group (n=24). The diabetic group divided into four groups, a single dose of streptozotocin was used to induce experimental type 1 diabetes. After 30 days, one group was separated as diabetic control, while the other three received 4 mg/kg p.o. donepezil for 20 days. One of the DON groups was administered 20 mg/kg i.p., L-NAME for 20 days, while the other group was administered 40 mg/kg i.p., L-arginine for 20 days. Results: Anxiety-like behaviors were assessed using the open field test (OFT), and depression-like behaviors were estimated using the forced swim test (FST). In the OFT, all diabetic rats spent less time in the center and engaged in less exploratory behavior than the control group. The number of lines crossed where locomotor activity was assessed did not differ significantly between groups. In the FST, duration of immobility increased significantly in diabetic groups compared to the control. Donepezil administration did not affect either depression or anxiety responses. Moreover, donepezil plus L-arginine increased diabetes-induced depression significantly. Conclusion: These findings may suggest that cholinergic and nitrergic systems may interact on depression-like behaviors in diabetic rats.

M1/M4-Preferring Muscarinic Cholinergic Receptor Agonist Xanomeline Reverses Wake and Arousal Deficits in Nonpathologically Aged Mice.

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer’s disease

BackgroundThe 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.

Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.