Acetylcholinesterase Inhibitor Donepezil Research Articles

Abstract 11205: Pharmacological and Non-Pharmacological Parasympathomimetic Interventions Prevent Trastuzumab-Induced Cardiotoxicity Through Attenuating Impaired Mitochondrial Function

Introduction: Although the use of trastuzumab (Trz) has effectively reduced the mortality rate in breast cancer patients, Trz-induced cardiotoxicity (TIC) has become a serious complication. Parasympathetic activations via either electrical vagus nerve stimulation (VNS) device or acetylcholinesterase inhibitor donepezil (DPZ), have been shown to exert cardioprotection in various heart diseases. However, the cardioprotective effects of VNS and DPZ on left ventricular (LV) function, autonomic function, and mitochondrial function in TIC rats are unknown. Hypothesis: Both VNS and DPZ protect the heart against TIC by reducing LV dysfunction, sympathovagal imbalance, and mitochondrial dysfunction. A combination of VNS and DPZ treatment exerts a better benefit than either single intervention. Methods: Adult male Wistar rats (N=25) were subjected to VNS device implantation. Then, rats were assigned into five groups (N=5/group), including (i) control without VNS (C), (ii) Trz (4 mg/kg/day, I.P., 7 days), (iii) Trz+DPZ (5 mg/kg/day, P.O., 7 days) (TrzD), (iv) Trz with VNS (TrzV), and (v) Trz+DPZ with VNS (TrzVD). LV function and heart rate variability (HRV) were performed. All hearts were collected to determine mitochondrial reactive oxygen species (ROS) levels and mitochondrial morphology. Results: Trz rats had a reduced LV ejection fraction, impaired HRV as shown by increased LF/HF ratio, and mitochondrial dysfunction shown by increased ROS levels and dysmorphology (Figures 1A-D). Treatment with either DPZ, VNS, or the combined treatment exerted similar cardioprotection via reducing sympathovagal imbalance and mitochondrial injury, leading to improved LV function, (Figures 1A-D). Conclusions: Promoting parasympathetic activity using VNS, DPZ, or the combined treatment similarly protected the heart against TIC via improving HRV, mitochondrial function, and mitochondrial morphology, suggesting a novel potential strategy for patients receiving Trz.

Donepezil prevents olfactory dysfunction and α-synuclein aggregation in the olfactory bulb by enhancing autophagy in zinc sulfate-treated mice

Alzheimer’s disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO4) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the subventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-α-synuclein (Ser129), α-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 Ⅱ/Ⅰ, and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO4-treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-α-synuclein (Ser129), and α-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO4-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 Ⅱ/Ⅰ, and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces α-synuclein aggregation via the AMPK/mTOC1 pathway.

Donepezil and α‐synuclein Constipation: A 60 Month Follow-Up

In a longitudinal case study, the acetylcholinesterase inhibitor (AChEI) Donepezil was used to address the symptoms of constipation, obstipation and impaction in four patients diagnosed at different stages of disease progression with the α‐synuclein or Lewy body disorders Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB). For each of the four patients, the use of Donepezil was associated with significant symptom reduction. Symptom improvement was maintained in follow-up studies conducted at intervals of six, twelve, eighteen, thirty-six, forty-eight and sixty months, with no apparent reduction in bowel motility. After four or five years, even with progression of other α‐synucleinopathy, bowel motility was preserved. The results suggest that patients with α‐synuclein disorders can experience long-term benefit in the reduction of symptoms including constipation, obstipation and impaction with the use of the AChEI Donepezil. Keywords: Neurocognitive Disorder with Lewy Bodies, Parkinson’s disease, constipation, Donepezil, acetylcholinesterase inhibitor

Natural Inhibition of β-secretase in Alzheimer’s Disease by Medicinal Plants

Alzheimer’s disease (AD) is the most common type of dementia, an irreversible neurodegenerative disease that worsens over time. It frequently affects the elderly population and, therefore, its prevalence is soaring in countries with a high proportion of the aging population. The incidence of AD is likely to increase further with increasing life expectancy throughout the world. There is still no sight of therapies that could stop or slow the progression of AD despite the significant expansion in our understanding of the disease at molecular, cellular, and system levels in the last 50 years. The only medications approved by the Food and Drug Administration (FDA), for the treatment of AD are acetylcholinesterase inhibitors (donepezil, galantamine, tacrine, and rivastigmine) and glutamate receptor antagonist (memantine). Apart from acetylcholinesterase inhibition, another important therapeutic target for treating AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the proteolysis of the amyloid precursor protein (APP) leading to the formation of neurotoxic amyloid β (Aβ) protein. Extensive research following this approach has led to the rationally designed synthetic, and potent BACE1 inhibitors, several of which are in clinical trials. However, the high failure rate of the BACE1 inhibitors in clinical trials necessitates finding a different source of BACE1 inhibitors. In this review, we discuss the most promising phytocompounds and plant extracts showing potent BACE1 inhibitory activity. Future research directions are suggested and recommendations are made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.

Cognitive deficits and altered cholinergic innervation in young adult male mice carrying a Parkinson's disease Lrrk2G2019S knockin mutation

Impaired executive function is a common and debilitating non-motor symptom of idiopathic and hereditary Parkinson's disease (PD), but there is little understanding of the underlying pathophysiological mechanisms and circuits. The G2019S mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2) greatly increases risk for late-onset PD, and non-manifesting LRRK2G2019S carriers can also exhibit early and significant cognitive impairment. Here, we subjected young adult male mice carrying a Lrrk2G2019S knockin mutation to touchscreen-based operant tasks that measure attention, goal-directed learning and cognitive flexibility, all of which rely on frontal-striatal connectivity and are strongly modulated by cholinergic innervation. In a visuospatial attention task, mutant mice exhibited significantly more omissions and longer response latencies than controls that could not be attributed to deficits in motivation, visual sensory perception per se or locomotion, thereby suggesting impairments in divided attention and/or action-selection as well as generally slower information processing speed. Pretreating mice with the acetylcholinesterase inhibitor donepezil normalized both higher omission rates and longer response latencies in the mutants, but did not affect any performance metric in controls. Strikingly, cholinergic fiber density in cortical areas PL/IL and DMS (dorsomedial striatum) was significantly sparser in mutants than in controls, while further behavioral interrogation of the mutants revealed significant impairments in action-outcome associations but preserved cognitive flexibility. These data suggest that the Lrrk2G2019S mutation negatively impacts cholinergic innervation anatomically and functionally by young adulthood, impairing corticostriatal network function in ways that may contribute to early PD-associated executive function deficits.

Association Between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in the Treatment of Depression in Patients with Alzheimer's Disease.

Background:Depressive symptoms are common in Alzheimer’s disease (AD) patients and are associated with an increased functional decline. Selective serotonin reuptake inhibitor antidepressants showed a limited efficacy.Objective:The purpose of this work was to evaluate if a higher brain cholinergic stimulation induced by the association between the acetylcholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate has any effect on depression in AD patients.Methods:Patients were selected among those recruited in the ASCOMALVA (association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in AD) trial. Depressive symptoms were investigated in 90 AD patients through the neuropsychiatric inventory at baseline and after 3, 6, 9, 12, 18, and 24 months of treatment. Patients were randomized in a group association therapy (45 subjects) receiving donepezil 10 mg plus choline alphoscerate 1,200 mg/day, and a group monotherapy (45 subjects) receiving donepezil 10 mg/day plus placebo. Based on the results of the MMSE at the recruitment patients were divided into 3 groups: severely impaired (score < 15); moderately impaired (score 19-16); mild-moderately impaired (score 24-20).Results:Depression symptoms were significantly lower (p < 0.05) in patients treated with donepezil plus choline alphoscerate compared to patients treated with donepezil alone. Subjects of the group having mild to moderate cognitive impairment were those more sensitive to the association treatment.Conclusion:Depression symptoms of AD patients in the mild to moderate stage probably could to benefit of a stronger cholinergic stimulation induced by associating donepezil with the cholinergic precursor choline alphoscerate.

Alzheimer’s Disease Therapy, and the Effects of Genetic Polymorphisms on Its Efficacy and Safety

Alzheimer’s disease (AD) continues to be a significant health burden worldwide as the global population is getting older and health care costs are escalating. AD is a heterogeneous condition having diverse phenotypes and genotypes, which is a major challenge in understanding disease etiopathogenesis. The difficulty in understanding the intricacies of the disease has led to recurrent failure of therapeutic agents in clinical trials resulting in an extremely slow and low success in the new drug discovery process for the AD. Currently approved agents for AD therapy are acetyl cholinesterase inhibitors (AchEIs) (donepezil, galantamine and rivastigmine) and n-methyl d-aspartate (NMDA) antagonist (memantine) that provide symptomatic relief only. However, extensive inter-individual variability in drug responsiveness is observed. ‘Pharmacogenomics’ which refers to how the genome of a patient might affect the treatment response to a drug, appears to play an important role in this inter-individual variability. By bringing pharmacogenomics profile of patients on AD therapy into consideration, it might be possible to gain maximum benefits from available treatments in terms of safety, therapeutic optimization and minimizing adverse effects. The purpose of this review is to provide better understanding of AD pathogenesis, challenges of current AD therapy and insight into the role of genetic polymorphism in drug response with focus on available therapeutic options in AD.

Age and circadian rhythm‐dependent effects of M1 muscarinic acetylcholine receptor positive allosteric modulators and donepezil on sleep‐wake architecture and arousal

AbstractBackgroundDegeneration of basal forebrain cholinergic signaling in aging and Alzheimer's disease (AD) is linked with abnormalities in arousal, sleep/wake architecture, and cognition. While acetylcholinesterase inhibitors (AChEIs) are approved for the treatment of AD, they produce dose‐limiting adverse effects due to nonselective activation of peripheral muscarinic acetylcholine receptors (mAChRs). Selectively targeting the M1 mAChR using M1 positive allosteric modulators (PAMs) has shown promise for boosting cognitive performance and arousal across preclinical species. We evaluate the effects of the M1 PAM VU0453595 on arousal and sleep/wake architecture in aged and young mice across both the active and inactive phases of the circadian cycle. We hypothesize that dosing an M1 PAM during the active phase in aged mice will produce a greater enhancement of arousal and wakefulness, normalizing deficits observed in aged mice.MethodUtilizing electroencephalography, we examined the effects of the M1 PAM VU0453595 in comparison with the AChEI Donepezil on sleep‐wake architecture and state dependent spectral power in young and aged C57/BL6 mice following dosing in either the active or inactive phases of the circadian cycle.ResultWhen compared to young mice, aged mice displayed several alterations in normal sleep‐wake architecture; in the inactive phase, reductions in rapid eye movement (REM) sleep, while in the active phase increases in non‐REM (NREM) sleep and decreases in wakefulness. Aged mice also displayed reductions in slow delta power during NREM sleep and increased delta power during wake. In young mice, dosing with both compounds increased wakefulness and arousal during wake in the inactive phase, with reduced effects in the active phase. In the aged mice VU0453595 increased arousal during wake in the inactive phase, and both wakefulness and arousal during wake when dosed in the active phase. Donepezil in contrast produced increased wakefulness in the inactive period, but reduced wakefulness in the active period and limited effects on arousal during wake.ConclusionThe M1 PAM VU0453595 produced increases in wakefulness and arousal in aged mice during the active phase, suggesting that selective M1 PAMs may be suitable for dosing during the active phase in aging and AD populations to normalize disruptions in wakefulness and arousal.

Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer's Disease: Nexus of Cholinergic and Nerve Growth Factor Dysfunction.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is increasingly viewed as a complex multi-dimensional disease without effective treatments. Recent randomized, placebo-controlled studies have shown volume losses of ~0.7% and ~3.5% per year, respectively, in the basal cholinergic forebrain (CBF) and hippocampus in untreated suspected prodromal AD. One year of donepezil treatment reduced these annualized rates of atrophy to about half of untreated rates. Similar positive although variable results have also been found in volumetric measurements of the cortex and whole brain in patients with mild cognitive impairment as well as more advanced AD stages after treatments with all three currently available acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, and galantamine). Here we review the anti-neurodegenerative benefits of AChE inhibitors and the expected parallel disease-accelerating impairments caused by anticholinergics, within a framework of the cholinergic hypothesis of AD and AD-associated loss of nerve growth factor (NGF). Consistent with the "loss of trophic factor hypothesis of AD," we propose that AChE inhibitors enhance acetylcholine-dependent release and uptake of NGF, thereby sustaining cholinergic neuronal viability and thus slowing AD-associated degeneration of the CBF, to ultimately delay dementia progression. We propose that improved cholinergic therapies for AD started early in asymptomatic persons, especially those with risk factors, will delay the onset, progression, or emergence of dementia. The currently available competitive and pseudo- irreversible AChE inhibitors are not CNS-selective and thus induce gastrointestinal toxicity that limits cortical AChE inhibition to ~30% (ranges from 19% to 41%) as measured by in vivo PET studies in patients undergoing therapy. These levels of inhibition are marginal relative to what is required for effective symptomatic treatment of dementia or slowing AD-associated neurodegeneration. In contrast, because of the inherently slow de novo synthesis of AChE in the CNS (about one-- tenth the rate of synthesis in peripheral tissues), irreversible AChE inhibitors produce significantly higher levels of inhibition in the CNS than in peripheral tissues. For example, methanesulfonyl fluoride, an irreversible inhibitor reduces CNS AChE activity by ~68% in patients undergoing therapy and ~80% in cortical biopsies of non-human primates. The full therapeutic benefits of AChE inhibitors, whether for symptomatic treatment of dementia or disease-slowing, thus would benefit by producing high levels of CNS inhibition. One way to obtain such higher levels of CNS AChE inhibition would be by using irreversible inhibitors.

Scopolamine and MK-801 impair recognition memory in a new spontaneous object exploration task in monkeys

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task.

The effects of galangin in prepulse inhibition test and experimental schizophrenia models.

Acetylcholinesterase inhibitors are the focus of interest in the management of schizophrenia. We aimed to investigate the effects of acute galangin administration, a flavonoid compound with acetylcholinesterase inhibiting activity, on schizophrenia-associated cognitive deficits in rats and schizophrenia models in mice. Apomorphine-induced prepulse inhibition (PPI) disruption for cognitive functions, nicotinic, muscarinic, and serotonergic mechanism involvement, and brain acetylcholine levels were investigated in Wistar rats. Apomorphine-induced climbing, MK-801-induced hyperlocomotion, and catalepsy tests were used as schizophrenia models in Swiss albino mice. The effects of galangin were compared with acetylcholinesterase inhibitor donepezil, and typical and atypical antipsychotics haloperidol and olanzapine, respectively. Galangin (50,100 mg/kg) enhanced apomorphine-induced PPI disruption similar to donepezil, haloperidol, and olanzapine (p < 0.05). This effect was not altered in the combination of galangin with the nicotinic receptor antagonist mecamylamine (1 mg/kg), the muscarinic receptor antagonist scopolamine (0.05 mg/kg), or the serotonin-1A receptor antagonist WAY-100635 (1 mg/kg) (p > 0.05). Galangin (50,100 mg/kg) alone increased brain acetylcholine concentrations (p < 0.05), but not in apomorphine-injected rats (p > 0.05). Galangin (50 mg/kg) decreased apomorphine-induced climbing and MK-801-induced hyperlocomotion similar to haloperidol and olanzapine (p < 0.05), but did not induce catalepsy, unlike them. We suggest that galangin may help enhance schizophrenia-associated cognitive deficits, and nicotinic, muscarinic cholinergic, and serotonin-1A receptors are not involved in this effect. Galangin also exerted an antipsychotic-like effect without inducing catalepsy and may be considered as an advantageous antipsychotic agent.

Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling.

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.

Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer's disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.

Antimuscarinic Cascade Across Individual Cholinesterase Inhibitors in Older Adults with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)-an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia. This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia. We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates. The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents-donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31-1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses. This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia.

Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test

There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.

Donepezil and α-synuclein Constipation: A 48 Month Follow-Up

In a case study, four patients diagnosed at different stages of disease progression with the α‐synuclein or Lewy body disorders Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB) were treated with the acetylcholinesterase inhibitor (AChEI) Donepezil to address the symptoms of constipation, obstipation and impaction. The use of Donepezil was associated with significant symptom reduction for each of the four patients. In follow-up studies conducted at intervals of six, twelve, eighteen, thirty-six and forty-eight months, symptom improvement was maintained with no apparent reduction in bowel motility, nor the emergence of any new symptoms. The results suggest that the AChEI Donepezil can have long-term benefit in reducing the symptoms of constipation, obstipation and impaction in patients with α-synuclein disorders. Keywords: Neurocognitive Disorder with Lewy Bodies, Parkinson’s disease, constipation, Donepezil, acetylcholinesterase inhibitor

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.

Dual Effect of Prussian Blue Nanoparticles on Aβ40 Aggregation: β-Sheet Fibril Reduction and Copper Dyshomeostasis Regulation.

Alzheimer's disease (AD), affecting almost 50 million individuals worldwide, is currently the first cause of dementia. Despite the tremendous research efforts in the last decade, only four supportive or palliative drugs, namely, acetylcholinesterase (AChE) inhibitors donepezil, galantamine, and rivastigmine and the glutamate NMDA receptor antagonist memantine, are currently available. New therapeutic strategies are becoming prominent, such as the direct inhibition of amyloid formation or the regulation of metal homeostasis. In the present report, the potential use of Prussian blue (PB), a drug that is in the World Health Organization Model List of Essential Medicines, in AD treatment is demonstrated. Both in vitro and in cellulo studies indeed suggest that PB nanoparticles (PBNPs) are capable of reducing the formation of typical amyloid-β fibers (detected by thioflavin T fluorescence) and restoring the usual amyloid fibrillation pathway via chelation/sequestration of copper, which is found in high concentrations in senile plaques.

Alzheimer’s disease: clinical management errors

The management of patients with Alzheimer’s disease (AD) is one of the urgent problems of modern medicine, however, not only general practitioners, but also neurologists in our country are not sufficiently aware of modern methods of AD therapy, which largely determines the errors in patient management. The disease is rarely diagnosed, patients are often observed with an erroneous diagnosis of chronic cerebrovascular disease (chronic cerebral ischemia, discirculatory encephalopathy) and do not receive the necessary treatment. It is relatively rare for AD patients to receive advice on non-drug therapies that include cognitive stimulation, cognitive training, regular physical activity, and antioxidant-rich nutrition. Anti dementic agents are rarely prescribed to patients: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine, an NMDA receptor blocker. Only a relatively small percentage of people who developed Alzheimer’s disease receive effective antidement therapy. This may be due to the fact that AD is not diagnosed or is diagnosed at more advanced stages of the disease when antidement therapy is not so effective, or that doctors do not have sufficient knowledge about antidement drugs and, finally, that the price of drugs is relatively high and the prescribing process for preferential provision of drugs is rather complicated. Unfortunately, antipsychotics and benzodiazepines are often unreasonably prescribed to patients with AD, the use of which impairs cognitive functions. The article presents a clinical observation of a relatively young patient with AD, who was followed up for a long time with an erroneous diagnosis of discirculatory encephalopathy. The issues of optimizing the management of AD patients in our country are discussed, and the data of the Cochrane review on the use of donepezil at different stages of the disease are analyzed.

Enhancing Therapeutic Efficacy of Donepezil by Combined Therapy: A Comprehensive Review.

Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer's disease (AD) has also attracted the attention of many pharmaceuticals due to its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep inducer. Recently, a combination of donepezil with other agents has displayed better desirable results in managing several disorders, including the most common Alzheimer's disease (AD). This study involves all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets and mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combination therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for treating multiple pathological disorders. To the best of our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.