Donepezil Treatment Research Articles

Impact of Donepezil and Memantine on Behavioral and Psychological Symptoms of Alzheimer Disease: Six-month Open-label Study.

Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the treatment of moderate AD. To evaluate the effects of donepezil and memantine in relieving BPSD in individuals with moderate AD. We conducted a prospective, randomized, 6-month clinical trial involving 85 individuals with moderate AD divided into two groups: group 1 (n = 42) was treated with donepezil; group 2 (n = 43) was treated with memantine. We used the Neuropsychiatric Inventory (NPI) to assess the prevalence and severity of BPSD at baseline and after 6 months of treatment with donepezil or memantine. The two groups' baseline characteristics, including age, sex, mean length of education, and disease duration, were comparable, as were their baseline Mini-Mental State Examination scores. The NPI Total score improved from baseline to month 6 in both groups (P < 0.0001). Analyses of the NPI subdomains revealed that both donepezil treatment and memantine treatment produced statistically significant improvement in all of the NPI domains except euphoria and apathy, for which no improvement was observed after memantine treatment. Both treatments were well tolerated, with mostly mild and transient adverse effects. Specific drugs for AD, including donepezil and memantine, may be effective in treating BPSD in individuals with moderate AD, with a favorable safety profile.

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.

The impact of ABCB1 gene polymorphism (C3435T) and its expression on response to Donepezil in Moroccan patients with Alzheimer's disease

Donepezil is a specific and potent acetylcholinesterase inhibitor; it can improve the cognitive and executive functions of patients with mild to moderately severe Alzheimer's disease (AD). P-glycoproteins (P-gp) are encoded by the ATP-binding cassette B1 (ABCB1) gene. Polymorphisms in ABCB1 gene could affect the response to donepezil. The present study aims to investigate the association between ABCB1 C3435T polymorphism and AD risk in Moroccan patients and to evaluate the ABCB1 gene expression in AD cases and its effect on clinicopathological parameters and response to donepezil treatment. A total of 54 Moroccan patients and 63 healthy controls were genotyped by PCR-RFLP method. Moreover, mRNA was quantified using the RT-qPCR approach. The results revealed that CT genotype and T allele were statistically more frequent in healthy controls than in AD patients (P = 0.015 and P = 0.04 respectively). Moderate AD, illiterate patients and some symptoms were significantly higher in drug resistant patients. In addition, ABCB1 gene expression was associated with diabetes (OR = 0.10; 95% CI = [0.01–0.53]; P = 0.015) and age (OR = 5.19, 95% CI = [1.07–32.9]; P = 0.054). However, no effect of the clinical parameters and symptoms has been observed on the resistance to Donepezil. This result could be used to predict the prognosis of patients before drug administration. However, further studies are needed to confirm or not these findings.

The association of changes of sleep architecture related to donepezil: A systematic review and meta-analysis

Donepezil had been recognized to have impact on sleep quality in demented patients. However, there was insufficient evidences about the actual effect of donepezil in the sleep architectures. Our meta-analysis aimed to evaluate the changes of sleep architectures related to donepezil use. Followed the PRISMA2020 and AMSTAR2 guidelines, electronic search had been performed on the databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane CENTRAL, ProQuest, Web of Science, and ClinicalTrials.gov. The outcome measurement was changes of sleep parameters detected by polysomnography. A random-effects meta-analysis was conducted. Total twelve studies had been involved. The percentage of REM sleep would significantly increase after donepezil treatment (Hedges' g=0.694, p<0.001). Compared to placebo/controls, subjects with donepezil would had significantly increased percentage of REM sleep stage (Hedges' g=0.556, p=0.018). Furthermore, donepezil was also associated with the decreased stage 2 sleep percentage, sleep efficiency, or total sleep time in different analysis conditions. Our meta-analysis provided detailed changes of sleep architectures related to donepezil treatment. Further larger sample size studies with stricter control of potential moderators are needed to clarify these issues.

Donepezil improves vascular function in a mouse model of Alzheimer's disease.

Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents the most effective drug in the treatment of AD. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Here, we assessed the impact of donepezil on the vascular phenotype of an established model of accelerated senescence that develops spontaneously AD, the SAMP8 mouse. Three groups of animals were included: SAMR1 (control strain), SAMP8, and SAMP8 treated with donepezil. Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests by Morris Water Maze, animals were euthanized, and their mesenteric arteries were processed for functional experiments. Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated cognitive dysfunction. SAMP8 exhibited a higher media‐to‐lumen ratio than SAMR1 and donepezil‐treated animals. Endothelial function was impaired in SAMP8 animals compared to SAMR1. The addition of vitamin C improved the vasodilatory response to acetylcholine in SAMP8. Treatment with donepezil improved endothelial function in SAMP8 animals and reduced the additional vasodilation induced by vitamin C. In conclusion, in the SAMP8 AD model, cognitive impairment is associated with endothelial dysfunction and vascular remodeling which could contribute to cardiovascular events in AD since the prodromal phases of the disease. Treatment with donepezil alleviates vascular dysfunction associated with AD through an increase in NO availability likely by counteracting inflammation and oxidative stress.

Evaluation of the effects of donepezil, memantine and α-lipoic acid combined administration in amnesia rats on impaired cognitive functions in terms of behavioural, apoptotic, cholinergic and glutamatergic systems

Objective: The aim of the study was to evaluate the possible protective effects of alpha-lipoic acid (α-LA), donepezil and memantine combined therapy in the scopolamine-induced amnesia rat model. &#x0D; Objective: The aim of the study was to evaluate the possible protective effect of donepezil, memantine and alpha-lipoic acid (α-LA) combined therapy in the scopolamine-induced amnesia rat model. &#x0D; Methods: In this study, the effect of combined therapy used in the treatment of scopolamine-induced amnesia on behavioural parameters was evaluated using Y-maze and new object recognition (NOR) test. In addition, muscarinic acetylcholine receptor subtype M1, N-methyl-D-aspartate receptor NR2B subunit, brain-derived neurotrophic factor (BDNF) and mitochondrial apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2) / Bcl-2 associated X (Bax) ratio, caspase (casp) -3, and -9] expression levels were evaluated using the western blot method in the frontal cortex and hippocampus regions. &#x0D; Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NOR test were reversed with the combined treatment of memantine, donepezil and α-LA. According to immunoblotting results in both brain regions, scopolamine-induced decreased M1, BDNF, Bcl-2 / Bax ratio and increased NR2B, casp-3 and -9 expression levels were found to be reversed to almost control values with combined treatment. &#x0D; Conclusion: Consistent with the literature, our study results suggest that the positive contribution of α-LA to the combined treatment of donepezil and memantine, which is used in the routine treatment of neurodegenerative diseases, may be a treatment option in the future.&#x0D; Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NORT test were reversed with the combined treatment of memantine, donepezil and α-LA. In addition, decreased BDNF, M1, bcl-2/bax ratio and increased NR2B, caspase-3 and caspase-9 expression levels due to scopolamine in both regions were improved with α-LA, donepezil and memantine combined therapy. &#x0D; Conclusion: The results of our study and other study results in the literature suggest that α-LA may be a future treatment option due to its positive contribution to the effects of other drugs used in the routine treatment of neurodegenerative diseases.

The additive memory and healthspan enhancement effects by the combined treatment of mature silkworm powders and Korean angelica extracts

Silkworm (Bombyx mori) and Korean angelica (KoAg; Angelica gigas Nakai) have been widely used as traditional oriental medicines in Korea, China, and Japan to treat various diseases such as anemia, cold, diabetes, palsy, stroke, etc. Steamed and freeze-dried mature silkworm powder, also known as HongJam (HJ), and extracts of KoAg root (KoAgE) are currently sold in Korea as functional foods to improve memory, cognition, and liver functions. However, the molecular and pharmacological basis for the improvement of brain functions of HJ and KoAgE has not yet been elucidated. This study aimed to elucidate the molecular basis underlying the memory-enhancing effects of HJ and KoAgE and determine whether administration of HJ and KoAgE complexes (HJ+KoAgC) has additive memory and healthspan-enhancing effects. The MCI mouse models generated by intraperitoneal injection of Scopolamine (Sco-IP) were orally administered with HJ and KoAgE alone or as complexes. Their memory-enhancing effects were examined on spatial, fear-aggravated, and social memories and compared with control or Donepezil (Dp) treatment. The activities of mitochondria complex (MitoCom) I-IV and acetylcholinesterase (AChE) and the amounts of ATP in the mouse brains were examined. The Drosophila model was used to investigate lifespan- and healthspan-promoting effects of HJ+KoAgC. Administration of HJ+KoAgC produced more memory-enhancing effects than administration of HJ or KoAgE alone or Dp. The increase in MitoCom I-IV activities and ATP amounts and the decrease in AChE activities in the mouse brains were the molecular basis for the memory enhancement. The greatest improvement in memory and mitochondrial function was observed when the mice were administered the 1:0.8 ratio of HJ+KoAgC. Administration of HJ+KoAgC to Drosophila prolonged the lifespan and the healthspan and increased the amounts of ATP. HJ+KoAgC had superior effects on memory improvement and healthspan extension by increasing mitochondrial activities and ATP amounts in treated animal models.

Functional connectivity and cognitive changes after donepezil treatment in healthy participants.

Donepezil is a potent, noncompetitive, reversible, clinically effective acetylcholinesterase inhibitor. The effects of this drug on healthy brains have seldom been investigated. The primary objective of the present study was to identify possible functional connectivity markers of the effect of donepezil in healthy young adult volunteers. The study had a double-blind, randomized, crossover design. 30 healthy adult volunteers underwent resting-state MRI scans during 15 days of donepezil or placebo treatment, in accordance with the design. Results showed significant differences in intrinsic functional connectivity between donepezil and placebo, mainly in the right executive control network (RECN). More specifically, we found a decrease in the connectivity of the right inferior parietal node with other RECN nodes. Analysis using the cingulate cortex and parahippocampal regions as seeds also revealed complex modulation of functional connectivity in the donepezil condition. In conclusion, donepezil treatment for 15 days may result in reorganization of resting-state networks, compared with placebo.

Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression.

This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.

Neuronal mitochondrial dysfunction in a cellular model of circadian rhythm disruption is rescued by donepezil

Human circadian rhythm refers to the intrinsic ∼24-h oscillation that regulates biological processes to adapt to environments. Disruption of rhythmicity causes mitochondrial dysfunction, changes metabolism, and is associated with neurodegenerative diseases and mental disorders. By employing cellular respiration analyses and mitochondrial membrane potential characterization, we confirmed that donepezil, a sigma-1 receptor agonist, restored mitochondrial function in neuronal cells with induced-circadian rhythm disruption (CRD). This protective effect was elicited by boosting oxidative respiration and increasing mitochondrial membrane potentials. Furthermore, donepezil treatment reinstated rhythmicity of core clock genes. Our findings suggest a novel countermeasure for treating CRD-related neurodegeneration and mental disorders.

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aβ25–35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aβ1–42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aβ25–35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aβ25–35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.

Impact of the CYP2D6 single nucleotide polymorphism on the concentration of and therapeutic response to donepezil in mild-to-moderate Alzheimer's disease

Donepezil was approved for the treatment of Alzheimer's disease (AD) but causes variable therapeutic responses. Thus, identifying specific genetic polymorphisms, which can predict a therapeutic response to donepezil, would enable a development of personalized strategy to treatment for patients with AD. The research aimed to exam the impact of the cytochrome P450 2D6 (CYP2D6) single nucleotide polymorphism (SNP) rs1080985 on the concentration of and therapeutic response to donepezil in AD. In total, 40 newly diagnosed AD patients who had a clinical dementia rating (CDR) of 0.5-2 and who were on donepezil were enrolled and followed up. Plasma concentrations of donepezil were determined after 6 months of donepezil treatment. Cognitive and functional statuses were evaluated annually during follow-up. The response to therapy was defined based on the change in CDR. At a mean of 21.8±5.7 months of follow-up, 10 of 40 patients (25.0%) were nonresponders to donepezil treatment. Patients who were homozygous for the G allele exhibited a higher concentration of donepezil and concentration-to-dose ratio than those with other genotypes. Furthermore, a significantly higher proportion of patients with the G/G genotype were responders than nonresponders (90.0% vs 50.0%, P=0.015, effect size of V: 0.457) to donepezil treatment. Conversely, patients carrying the C allele had a significantly high risk of poor responses to donepezil treatment (odds ratio: 9.00, 95% confidence interval: 1.611-50.275). The CYP2D6 SNP rs1080985 might be a useful pharmacogenetic marker of the long-term therapeutic response to donepezil in patients with AD.

Donepezil Reduces Amyloid Precursor Protein Endocytosis by Resulting from Increase in the Expression of Sorting Nexin Protein 33

Donepezil, the most widely used drug for the treatment of Alzheimer's disease (AD), is an acetylcholinesterase (AChE) inhibitor and is thought to improve cognition by stimulating cholinergic neurotransmission. However, no correlation has yet been established between the inhibitory role of AChE inhibitors and their therapeutic effects when used in AD patients. The cleavage pathway of amyloid precursor protein (APP) includes amyloidgenic (β, γ-cleavage) and non-amyloidgenic (α-cleavage) pathways. The intracellular transportation of APP is important in determining these cleavage pathways. It has been suggested that sorting nexin (SNX) family proteins regulates the intracellular transport of APP, thereby enhancing α-cleavage. In this study, we examined the effects of donepezil on SNX33 expression changes and APP processing in primary cultures of fetal rat cortical neurons. While donepezil treatment increased the levels of SNX33 expression and soluble APPα (sAPPα) in culture media, no changes were observed regarding full-length APP expression in the cell lysate. Donepezil also reduced the release of amyloid β (Aβ) into culture media in a concentration- and time-dependent manner. This reduction was not affected by acetylcholine receptor antagonists. The membrane surface expression of APP was elevated by donepezil. Furthermore, SNX knockdown by antisense morpholino oligos prevented the effects of donepezil. These results indicated that donepezil increased APP expression at the surface of the plasma membrane by decreasing APP endocytosis through upregulation of SNX33, suggesting donepezil might stimulate the non-amyloidogenic pathway. This new mechanism of action for the currently used anti-AD drug may provide a valuable basis for future drug discovery.

Effects of donepezil on the amplitude of low-frequency fluctuations in the brain of patients with Alzheimer's disease: evidence from resting-state functional magnetic resonance imaging.

ObjectivesTo monitor the effects of donepezil on spontaneous neuronal activity (SNA), and the mechanisms underlying these effects in patients with mild-to-moderate Alzheimer’s disease, using the amplitude of low-frequency fluctuations (ALFFs), a metric of resting-state functional MRI (rs-fMRI).MethodsEleven patients with Alzheimer’s disease were treated with donepezil for 6 months. Before and after treatment, the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Clinical Dementia Rating (CDR), Neuropsychiatric Inventory and Activities of Daily Living scores, along with rs-fMRI of patients were assessed. Eleven age-, sex-, and education-matched controls underwent MMSE and CDR assessments and rs-fMRI at enrollment. The ALFFs of the whole brain were obtained and compared between the groups.ResultsFollowing donepezil treatment, MMSE scores increased (P = 0.043) and ADAS-cog scores decreased (P = 0.010). Regarding SNA post-treatment, ALFF increased significantly in the right triangular part of the inferior frontal gyrus (IFGtriang; P = 0.030; d = −0.595) and the right orbital part of the inferior frontal gyrus (P = 0.044; d = −0.628) and decreased significantly in the left medial orbital part of the superior frontal gyrus (P = 0.039; d = 0.606) and the right gyrus rectus (P = 0.010; d = 0.609). Furthermore, the changes in ADAS-cog scores from before to after treatment were positively correlated with the changes in ALFF in the right IFGtriang (r = 0.645; P = 0.032).ConclusionsDonepezil improved SNA in the frontal lobe of patients with Alzheimer’s disease. Therefore, ALFF was demonstrated to be a potential tool for assessing the effectiveness of Alzheimer’s disease treatment.

DONEPEZIL IMPROVES VASCULAR FUNCTION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE

Objective: Donepezil represents the most effective drug in the treatment of Alzheimer's Disease (AD). Recent reports suggest that it might have free radical scavenging properties, which could potentially improve the vascular alterations commonly associated with AD and partially account for the cognitive benefits observed during treatment. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Objective: to assess the impact of donepezil on the vascular phenotype of an established model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone). Design and method: 3 groups of animals were included: SAMP8 (n = 4), SAMP8 treated with Donepezil for 8 weeks (n = 4) and SAMR1 (Senescence-Accelerated Mouse-Resistant, a mouse model which does not develop the disease, n = 4). Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests, animals were euthanized, their mesenteric arteries were isolated and mounted on a pressurised myograph to assess endothelial function by means of dose-response curves to acetylcholine (Ach) alone or in combination with L-NAME or Vitamin C. Media-to-lumen ratio (M/L ratio) was also measured. In subsequent experiments (n = 4), donepezil was coincubated directly on the arteries isolated from untreated SAMP8 together with Ach. Results: Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated the cognitive dysfunction. SAMP8 had higher M/L ratio than SAMR1 and donepezil treated animals (p &lt; 0.001 for both differences, Fig. 1). Endothelial function was impaired in SAMP8 animals compared to SAMR1 (Fig. 1). Addition of Vitamin C improved the vasodilatory response to Ach in SAMP8 (p &lt; 0.001 vs Ach alone). Treatment with donepezil improved endothelial function in SAMP8 animals (p &lt; 0.001 vs untreated SAMP8) and reduced the additional vasodilation induced by Vitamin C (Fig. 1). Acute incubation of mesenteric arteries from SAMP8 animals with donepezil induced a significant improvement of endothelial function from baseline (p &lt; 0.001)and the subsequent addition of Vitamin C did not induce further vasodilation. Conclusions: The beneficial effects of donepezil on vascular function and structure might provide a novel mechanism explaining its positive effects on cognitive decline. These effects might be mediated by antioxidant mechanisms.

White Matter Connectivity and Gray Matter Volume Changes Following Donepezil Treatment in Patients With Mild Cognitive Impairment: A Preliminary Study Using Probabilistic Tractography.

The donepezil treatment is associated with improved cognitive performance in patients with mild cognitive impairment (MCI), and its clinical effectiveness is well-known. However, the impact of the donepezil treatment on the enhanced white matter connectivity in MCI is still unclear. The purpose of this study was to evaluate the thalamo-cortical white matter (WM) connectivity and cortical thickness and gray matter (GM) volume changes in the cortical regions following donepezil treatment in patients with MCI using probabilistic tractography and voxel-based morphometry. Patients with MCI underwent magnetic resonance examinations before and after 6-month donepezil treatment. Compared with healthy controls, patients with MCI showed decreased WM connectivity of the thalamo-lateral prefrontal cortex, as well as reduced thickness in the medial/lateral orbitofrontal cortices (p < 0.05). The thalamo-lateral temporal cortex connectivity in patients with MCI was negatively correlated with Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) (r = −0.76, p = 0.01). The average score of the Korean version of the mini-mental state examination (K-MMSE) in patients with MCI was improved by 7.9% after 6-months of donepezil treatment. However, the patterns of WM connectivity and brain volume change in untreated and treated patients were not significantly different from each other, resulting from multiple comparison corrections. These findings will be valuable in understanding the neurophysiopathological mechanism on MCI as a prodromal phase of Alzheimer's disease in connection with brain functional connectivity and morphometric change.

Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation.

Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated.Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated.Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation.Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

Donepezil for mild cognitive impairment in Parkinson\u2019s disease

We investigated the efficacy of donepezil for mild cognitive impairment in Parkinson’s disease (PD-MCI). This was a prospective, non-randomized, open-label, two-arm study. Eighty PD-MCI patients were assigned to either a treatment or control group. The treatment group received donepezil for 48 weeks. The primary outcome measures were the Korean version of Mini-Mental State Exam and Montreal Cognitive Assessment scores. Secondary outcome measures were the Clinical Dementia Rating, Unified Parkinson’s Disease Rating Scale part III, Clinical Global Impression scores. Progression of dementia was assessed at 48-week. Comprehensive neuropsychological tests and electroencephalography (EEG) were performed at baseline and after 48 weeks. The spectral power ratio of the theta to beta2 band (TB2R) in the electroencephalogram was analyzed. There was no significant difference in the primary and secondary outcome measures between the two groups. However, the treatment group showed a significant decrease in TB2R at bilateral frontotemporoparietal channels compared to the control group. Although we could not demonstrate improvements in the cognitive functions, donepezil treatment had a modulatory effect on the EEG in PD-MCI patients. EEG might be a sensitive biomarker for detecting changes in PD-MCI after donepezil treatment.

Impact of an Education Program for Caregivers of Patients with Alzheimer's Disease on Treatment Discontinuation and Compliance in Korea.

Background and PurposeReportedly 30–50% of patients being treated for chronic illnesses do not adhere to their medication regimen. We assessed the impact of a nurse-led education program for caregivers of Korean de novo Alzheimer's disease patients who had newly been prescribed donepezil.MethodsThis multicenter study analyzed 93 participants in a caregiver education group and 92 participants in a caregiver no-education group. At every visit up to the end of the study (1 year), caregivers in the education group were given educational brochures regarding Alzheimer's disease and the efficacy and adverse events of donepezil treatment. The primary endpoint was the discontinuation rate of donepezil treatment during the 1-year observation period. The secondary endpoints included the effect of education on compliance with donepezil treatment assessed at each visit using a clinician rating scale (CRS) and visual analog scale (VAS), and changes from baseline in cognitive assessment tests.ResultsThe donepezil discontinuation rates at 1 year were 5.38% (5/93) and 6.52% (6/92) in the caregiver education and no-education groups, respectively (p=0.742). No significant between-group differences in donepezil compliance rates on the CRS and VAS were observed, but significant changes were observed in some cognitive tests from baseline to the end of the study.ConclusionsCaregiver education had no significant effect on treatment discontinuation, but this may have been due to the low severity of cognitive impairment among the included population at baseline. In addition, the low discontinuation rates meant that no significant difference in treatment compliance was observed.

Discontinuation Rate of Newly Prescribed Donepezil in Alzheimer's Disease Patients in Asia.

Background and PurposeThe rate of donepezil discontinuation and the underlying reasons for discontinuation in Asian patients with Alzheimer's disease (AD) are currently unknown. We aimed to determine the treatment discontinuation rates in AD patients who had newly been prescribed donepezil in routine clinical practice in Asia.MethodsThis 1-year observational study involved 38 institutions in seven Asian countries, and it evaluated 398 participants aged 50–90 years with a diagnosis of probable AD and on newly prescribed donepezil monotherapy. The primary endpoint was the rate of donepezil discontinuation over 1 year. Secondary endpoints included the reason for discontinuation, treatment duration, changes in cognitive function over the 1-year study period, and compliance as assessed using a clinician rating scale (CRS) and visual analog scale (VAS).ResultsDonepezil was discontinued in 83 (20.9%) patients, most commonly due to an adverse event (43.4%). The mean treatment duration was 103.67 days in patients who discontinued. Among patients whose cognitive function was assessed at baseline and 1 year, there were no significant changes in scores on the Mini-Mental State Examination, Montreal Cognitive Assessment, and Trail-Making Test–Black and White scores, whereas the Clinical Dementia Rating score increased significantly (p<0.001). Treatment compliance at 1 year was 96.8% (306/316) on the CRS and 92.6±14.1% (mean±standard deviation) on the VAS.ConclusionsIn patients on newly prescribed donepezil, the primary reason for discontinuation was an adverse event. Cognitive assessments revealed no significant worsening at 1 year, indicating that continuous donepezil treatment contributes to the maintenance of cognitive function.