Beneficial Effect Of Donepezil Research Articles

Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum-hippocampus cholinergic pathway.

Tau accumulation and cholinergic impairment are characteristic pathologies in Alzheimer's disease (AD). However, the causal role of tau accumulation in cholinergic lesion is elusive. Here, we observed an aberrant tau accumulation in the medial septum (MS) of 3xTg and 5xFAD mice, especially in their cholinergic neurons. Overexpressing hTau in mouse MS (MShTau) for 6 months but not 3 months induced spatial memory impairment without changing object recognition and anxiety‐like behavior, indicating a specific and time‐dependent effect of MS‐hTau accumulation on spatial cognitive functions. With increasing hTau accumulation, the MShTau mice showed a time‐dependent cholinergic neuron loss with reduced cholinergic projections to the hippocampus. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month ameliorated the MS‐hTau‐induced spatial memory deficits with preservation of MS–hippocampal cholinergic pathway and removal of tau load; and the beneficial effects of donepezil was more prominent at low dose. Proteomics revealed that MS‐hTau accumulation deregulated multiple signaling pathways with numerous differentially expressed proteins (DEPs). Among them, the vacuolar protein sorting‐associated protein 37D (VP37D), an autophagy‐related protein, was significantly reduced in MShTau mice; the reduction of VP37D was restored by donepezil, and the effect was more significant at low dose than high dose. These novel evidences reveal a causal role of tau accumulation in linking MS cholinergic lesion to hippocampus‐dependent spatial cognitive damages as seen in the AD patients, and the new tau‐removal and autophagy‐promoting effects of donepezil may extend its application beyond simple symptom amelioration to potential disease modification.

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 < 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 < 0.001 vs Ach alone). Treatment with donepezil improved endothelial function in SAMP8 animals (p < 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 < 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.

Pharmacotherapy of Traumatic Childhood Aphasia: Beneficial Effects of Donepezil Alone and Combined With Intensive Naming Therapy.

At present, language therapy is the only available treatment for childhood aphasia (CA). Studying new interventions to augment and hasten the benefits provided by language therapy in children is strongly needed. CA frequently emerges as a consequence of traumatic brain injury and, as in the case of adults, it may be associated with dysfunctional activity of neurotransmitter systems. The use of cognitive-enhancing drugs, alone or combined with aphasia therapy, promotes improvement of language deficits in aphasic adults. In this study we report the case of a 9-year-old right-handed girl, subject P, who had chronic anomic aphasia associated with traumatic lesions in the left temporal-parietal cortex. We performed a single-subject, open-label study encompassing administration of the cholinergic agent donepezil (DP) alone during 12 weeks, followed by a combination of DP and intensive naming therapy (INT) for 2 weeks and thereafter by a continued treatment of DP alone during 12 weeks, a 4-week washout period, and another 2 weeks of INT. Four comprehensive language and neuropsychological evaluations were performed at different timepoints along the study, and multiple naming evaluations were performed after each INT in order to assess performance in treated and untreated words. Structural magnetic resonance imaging (MRI) was performed at baseline. MRI revealed two focal lesions in the left hemisphere, one large involving the posterior inferior and middle temporal gyri and another comprising the angular gyrus. Overall, baseline evaluation disclosed marked impairment in naming with mild-to-moderate compromise of spontaneous speech, repetition, and auditory comprehension. Executive and attention functions were also affected, but memory, visuoconstructive, and visuoperceptive functions were preserved. Treatment with DP alone significantly improved spontaneous speech, auditory comprehension, repetition, and picture naming, in addition to processing speed, selective, and sustained attention. Combined DP-INT further improved naming. After washout of both interventions, most of these beneficial changes remained. Importantly, DP produced no side effects and subject P attained the necessary level of language competence to return to regular schooling. In conclusion, the use of DP alone and in combination with INT improved language function and related cognitive posttraumatic deficits in a child with acquired aphasia. Further studies in larger samples are warranted.

Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis

The authors examined research on effects, costs, and patient and caregiver views of pharmacological management strategies for Lewy body dementia. Studies were identified through bibliographic databases, trials registers, gray literature, reference lists, and experts. The authors used the search terms "Lewy or parkinson" and "dementia" through March 2015 and used the following inclusion criteria: participants with diagnoses of Lewy body dementia, dementia with Lewy bodies, or Parkinson's disease dementia (or participants' caregivers); investigation of pharmacological management strategies; outcome measures and test scores reported. Data extraction and quality assessment were conducted by at least two authors. Meta-analyses were conducted, and when studies could not be combined, summaries were provided. Forty-four studies examining 22 strategies were included in the review. Meta-analysis indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with greater risk of adverse events. Meta-analysis of memantine suggested that it is well tolerated but with few benefits. Descriptive summaries provide some evidence of benefits for galantamine, modafinil, levodopa, rotigotine, clozapine, duloxetine, clonazepam, ramelteon, gabapentin, zonisamide, and yokukansan. Piracetam, amantadine, selegiline, olanzapine, quetiapine, risperidone, and citalopram do not appear to be effective. High-level evidence related to pharmacological strategies for managing Lewy body dementia is rare. Strategies for important areas of need in Lewy body dementia, such as autonomic symptoms and caregiver burden, have not been investigated, nor have the views of patients and caregivers about pharmacological strategies.

Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

Potential Role of the Sigma-1 Receptor Chaperone in the Beneficial Effects of Donepezil in Dementia with Lewy Bodies

Potential Role of the Sigma-1 Receptor Chaperone in the Beneficial Effects of Donepezil in Dementia with Lewy Bodies

Beneficial effect of donepezil on obstructive sleep apnea: A double-blind, placebo-controlled clinical trial

Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients. A randomized, double-blind, placebo-controlled study was conducted. The final sample consisted of 21 male patients with mild to severe OSA and AHI >10 divided into two groups, a donepezil-treated group (n=11) and a placebo-treated group (n=10). The dosage was one tablet/day (5 mg) for the first two weeks and two tablets/day (10 mg) for the last two weeks. Polysomnography and sleepiness evaluations were performed at baseline and after one month of treatment. Groups were compared using two-way ANOVA for repeated measures with treatment-group and treatment-time as the main factors and time-treatment as an interaction effect. Considering the effect of the interaction with time-treatment, there was a significant improvement in the obstructive apnea/hypopnea index, desaturation index, percentage of time with O(2) saturation ≤3% lower than baseline, lowest oxygen saturation, and the Epworth Sleepiness Scale (ESS) scores with donepezil treatment (p<0.05). Sleep efficiency significantly decreased (p<0.01). Donepezil treatment improved obstructive sleep apnea index, oxygen saturation, and sleepiness in parallel with a reduction in sleep efficiency. Our findings support the concept that cholinergic transmission may influence breathing regulation in OSA patients.

Cholinergic Enhancement Augments Magnitude and Specificity of Visual Perceptual Learning in Healthy Humans

Learning through experience underlies the ability to adapt to novel tasks and unfamiliar environments. However, learning must be regulated so that relevant aspects of the environment are selectively encoded. Acetylcholine (ACh) has been suggested to regulate learning by enhancing the responses of sensory cortical neurons to behaviorally relevant stimuli. In this study, we increased synaptic levels of ACh in the brains of healthy human subjects with the cholinesterase inhibitor donepezil (trade name: Aricept) and measured the effects of this cholinergic enhancement on visual perceptual learning. Each subject completed two 5 day courses of training on a motion direction discrimination task, once while ingesting 5 mg of donepezil before every training session and once while placebo was administered. We found that cholinergic enhancement augmented perceptual learning for stimuli having the same direction of motion and visual field location used during training. In addition, perceptual learning with donepezil was more selective to the trained direction of motion and visual field location. These results, combined with previous studies demonstrating an increase in neuronal selectivity following cholinergic enhancement, suggest a possible mechanism by which ACh augments neural plasticity by directing activity to populations of neurons that encode behaviorally relevant stimulus features.

Beneficial Effects of Donepezil on Vascular Endothelial Dysfunction-Associated Dementia Induced by L-Methionine in Rats

Donepezil (acetyl cholinesterase inhibitor) is a mainstay of clinical intervention to contain memory deficits of Alzheimer's disease. However, its beneficial role in endothelial dysfunction-associated dementia i.e. vascular dementia still needs to be explored. The present study was designed to investigate the effect of donepezil on vascular endothelial dysfunction, and associatedmemory deficits in rats. Atorvastatin (3-hydroxy-4-methyl-glutaryl (HMG)-CoA inhibitor) was taken as the standard. Rats were administered L-methionine (1.7 g/kg per day, p.o., 4 weeks and 4 days i.e. chronic treatment) to produce endothelial dysfunction and dementia. Serum nitrite level was estimated as a marker of endothelial function. Morris water maze (MWM) test was employed for assessment of memory. Brain tissue thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were estimated to assess oxidative stress. Brain acetylcholine esterase (AChE) activity and serum total cholesterol level were also estimated. L-methionine produced endothelial dysfunction as reflected by significant decrease of serum nitrite concentration. L-methionine-treated rats performed poorly on MWM indicating impairment of memory as well. These rats also showed a significant rise in brain oxidative stress, AChE activity and serum total cholesterol levels. Donepezil (0.1 mg/kg p.o.) and atorvastatin (10 mg/kg p.o.) attenuated L-methionine-induced endothelial dysfunction. This intervention reversed L-methionine-induced rise of brain oxidative stress and AChE activity. Furthermore, atorvastatin produced a reduction of L-methionine-induced rise in serum cholesterol. The beneficial effects of donepezil may be attributed to its multiple effects and this study highlights the potential of donepezil in vascular dementia.

Measurement of meaningful treatment effects in CADASIL

I read with interest Martin Dichgans and colleagues' study of donepezil in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), in the April issue of The Lancet Neurology. 1 Dichgans M Markus HS Salloway S et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomized double-blind trial in CADASIL. Lancet Neurol. 2008; 7: 310-318 Summary Full Text Full Text PDF PubMed Scopus (191) Google Scholar The researchers found significant effects on two measures of executive control function, including the executive interview (EXIT25). 2 Royall DR Mahurin RK Gray K Bedside assessment of executive cognitive impairment: the executive interview (EXIT). J Am Geriatr Soc. 1992; 40: 1221-1226 PubMed Google Scholar The EXIT25 effect of −1·5 points out of 50 was comparable to that in an earlier study by Auchus and co-workers 3 Auchus AP, Brashear HR, Salloway S, et al. Results of a trial of galantamine in subjects with vascular dementia confirmed by central MRI reading. American Academy of Neurology Meeting, San Francisco, CA, USA. April 27, 2004. Google Scholar of galantamine in patients with vascular dementia as defined by the National Institute of Neurological Disorders and Stroke (NINDS). Measurement of meaningful treatment effects in CADASIL – Authors' replyWe appreciate Dr Royall's comments on the EXIT25. We agree that the beneficial effect of donepezil on the EXIT25 scores, albeit statistically significant, might not be clinically meaningful. In fact, the lack of treatment effects on instrumental activities of daily living and global dementia rating, as assessed by the disability assessment for dementia and the sum of boxes of the clinical dementia rating scale seems to support this view. We also agree that, on average, patients in the current trial were mildly affected and that this might have limited our ability to detect clinically meaningful improvements in both executive function and instrumental activities of daily living. Full-Text PDF

Beneficial Effect of Donepezil in the Treatment of Elderly Patients With Tardive Movement Disorders

Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD. A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter. The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects. The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

DONEPEZIL FOR NURSING HOME PATIENTS WITH DEMENTIA: A REINTERPRETATION OF THE EVIDENCE ‐ Response to the Editor

The above letter was referred to the authors of the original paper; their reply follows. To the Editor: Patients had to have behavioral problems to be enrolled in this trial. As clearly stated in the paper, both groups exhibited improvements in behavior as measured by changes in the total score of the Neuropsychiatric Inventory—Nursing Home version (NPI-NH) and there were no significant drug-placebo differences on this measure. The categorical analysis of improvement, no change and worsening for each of the assessed behaviors, was a planned secondary analysis. Only agitation was significant in this analysis. We agree with the caveats raised by Drs. Steinman and Kovinsky regarding the statistical robustness of this finding. Nevertheless, agitation was the most prevalent symptom, present in 64% of the patients, and, in our clinical experience, any degree of improvement of this behavior is of clinical importance to patient management in the nursing home setting. Given the consistent findings of beneficial effects of cholinesterase inhibitors (ChEIs) on behavior in outpatients,1–3 the absence of a drug-placebo difference on the NPI-NH total score was surprising to us. For example, a study of donepezil in patients with moderate-to-severe Alzheimer's disease (AD) reported improvements in total score at the 24-week endpoint for the drug-treated group only, with all 12 measured symptoms improving relative to placebo.3 In a 5-month trial of galantamine in patients with mild-to-moderate AD, total scores progressively worsened in the placebo group.2 In attempting to account for the discrepant findings in the nursing home, it is reasonable to suggest that the use of psychoactive medication (in about 60% of these patients) and nonpharmacological methods of behavioral management as employed in skilled nursing homes may have contributed to the observed placebo group improvement. Beneficial effects of donepezil on cognition were evident in this study despite the known limited sensitivity of the Mini-Mental State Examination (MMSE) in detecting decline in untreated patients with advanced dementia. The lack of progressive decline was apparent in the placebo group in this study. Furthermore, an improvement of at least 3 points at any time during the study was observed in 51% of the donepezil-treated patients, compared with 36% of the placebo patients (P < .05). Statistical significance favoring donepezil was also reached on the cognitive subscale of the Clinical Dementia Rating (CDR) at Week 24. This is the only placebo-controlled trial of ChEI in the nursing home setting. The use of ChEIs has consistently been shown to lead to behavior and functional benefits. The differential pattern of findings for the CDR functional subscale (P = .057) and the lack of effect on the physical self-examination scale in these nursing home patients reinforces the importance of appropriate instrument selection in patient cohorts with high comorbidity and limited mobility. The paper is thorough in its presentation of safety and tolerability findings. The importance of weight loss in these patients is not underestimated. Clinically significant weight loss (≥7% baseline weight) occurred in 9% and 6% of donepezil- and placebo-treated patients, respectively. The percentage of patients who discontinued because of weight loss was 1% and 4% of donepezil- and placebo-treated patients, respectively. The mean weight decrease of 3 kg in patients with weight loss as an adverse event was observed in both treatment groups, indicating that this degree of weight loss was not specific to donepezil. We conclude that these data provide further evidence of the stabilization of cognition and overall dementia severity consistently reported with donepezil, an effect that is clinically important in a progressive neurodegenerative disease. Donepezil was safe and generally well tolerated in these nursing home patients, despite their advanced age and high comorbidity and concomitant medication usage.

Beneficial effect of Donepezil on tardive dyskinesia in a schizophrenic patient with Aizheimer's disease

Beneficial effect of Donepezil on tardive dyskinesia in a schizophrenic patient with Aizheimer's disease