Administration Of Donepezil Research Articles

Donepezil, a potential therapeutic agent for heart failure

Donepezil, an inhibitor of cholinesterase, has been used to treat Alzheimer's disease. We read with great interest the study by Li et al. who demonstrated that the addition of donepezil prevented the deterioration of heart dysfunction and improved the long-term survival in rats with chronic heart failure (CHF) beyond that seen with losartan alone.1 This suggested that combination treatment with losartan plus donepezil might be a potential therapeutic strategy for CHF. Earlier studies also conducted by Li's team revealed that donepezil decreased heart rate, improved haemodynamic parameters, prevented cardiac remodelling, and suppressed BNP, catecholamine, and inflammatory factors in rats with CHF.2, 3 A similar result was also obtained by Handa et al. in mice with CHF.4 Chronic administration of donepezil for 2 weeks could not only induce vagal nerve activation, but could also reduce sympathetic nerve activation, as demonstrated by Umegaki and Khookhor in a recent study.5 Cardiac autonomic imbalance is one of the most important features of CHF. Antiadrenergic drugs have been used to treat CHF for decades as an effective strategy. However, an agent that could increase parasympathetic nerve activation has not been tested in patients with CHF. The effect of donepezil on the balance of the autonomic nervous system during CHF demands our attention. Unfortunately, so far no prospective trial has proved the effect of donepezil in CHF patients. Nonetheless, a retrospective investigation indicated smaller hazard ratios for total and cardiovascular mortality among patients treated with donepezil.6 The association between cholinesterase inhibition and a reduced risk of myocardial infarction and death was also verified by Nordstrom et al. in a recent observational study.7 These experimental and clinical studies suggest that donepezil might be a novel agent to treat CHF. Randomized controlled trials are warranted to translate this into clinical use. Conflict of interest: none declared. Ao Chen Department of Cardiology Ren Ji Hospital School of Medicine Shanghai Jiao Tong University Shanghai China Ying-Min Chen Department of Cardiology Ren Ji Hospital School of Medicine Shanghai Jiao Tong University Dongfang Road Shanghai China, 200127 Tel: +86 136 81980901 Fax: +86 021 34611387 Email: [email protected]

Normal Hearing Ability but Impaired Auditory Selective Attention Associated with Prediction of Response to Donepezil in Patients with Alzheimer's Disease.

Background. Alzheimer's disease (AD) patients have a poor response to the voices of caregivers. After administration of donepezil, caregivers often find that patients respond more frequently, whereas they had previously pretended to be “deaf.” We investigated whether auditory selective attention is associated with response to donepezil. Methods. The subjects were40 AD patients, 20 elderly healthy controls (HCs), and 15 young HCs. Pure tone audiometry was conducted and an original Auditory Selective Attention (ASA) test was performed with a MoCA vigilance test. Reassessment of the AD group was performed after donepezil treatment for 3 months. Results. Hearing level of the AD group was the same as that of the elderly HC group. However, ASA test scores decreased in the AD group and were correlated with the vigilance test scores. Donepezil responders (MMSE 3+) also showed improvement on the ASA test. At baseline, the responders had higher vigilance and lower ASA test scores. Conclusion. Contrary to the common view, AD patients had a similar level of hearing ability to healthy elderly. Auditory attention was impaired in AD patients, which suggests that unnecessary sounds should be avoided in nursing homes. Auditory selective attention is associated with response to donepezil in AD.

Lumbar-Peritoneal Shunt followed by Donepezil Administration for Residual Cognitive Impairment in Idiopathic Normal Pressure Hydrocephalus: A Case Report

We often encounter idiopathic normal-pressure hydrocephalus (iNPH) and mild cognitive impairment (MCI) in the same patient. Four iNPH patients whose gait improved following placement of a lumbar-peritoneal shunt (LPS) and whose cognitive function improved after administration of donepezil are reported. LPS is useful for improvement of gait disturbance in iNPH, and donepezil is used to treat impaired memory in dementia of Alzheimer’s type (DAT). These four patients showed improvements in gait disturbances postoperatively, and just after donepezil administration, improvements in cognitive symptoms were recognized in the memory tests of the Mini-Mental State Examination (MMSE). The four patients (two males and two females) ranged in age from 72 to 81 years (mean age: 77 years). In all patients, disproportionately enlarged subarachnoid-space hydrocephalus (DESH) was recognized on imaging examinations, and improvements after the tap test were considered to be indications for surgery. The improvements in the Timed Up and Go Test (TUG) were from 25% to 36%. The patients’ mean MMSE score was 27 points preoperatively, 27 points at 1 week after LPS placement, and 30 points at 3 months after LPS placement. Treatment with donepezil appeared to be effective for residual cognitive impairments after LPS placement.

Donepezil-Induced Onset of Rheumatoid Arthritis: Case Report and Literature Review

Donepezil has been approved for treatment of Alzheimer's disease. The common adverse reactions of donepezil in the treatment of Alzheimer's disease include diarrhea and nausea. However, there are also some other rare clinical cases been reported on administration of donepezil, such as mania and delirious behavior. Here, we report a patient with Alzheimer’s disease who was induced the onset of rheumatoid arthritis upon treatment with donepezil.

Impact of nighttime donepezil administration on sleep in the older adult population: A retrospective study

Introduction . Although not definite, studies are finding Alzheimer's disease may be related to loss of cholinergic innervation. In order to impact this loss of function, therapeutic agents have been developed to reduce the breakdown of acetylcholine, a neurotransmitter vital in cognitive processes. Donepezil has been used in Alzheimer's disease for improving cognition. Although the package insert suggests nighttime administration to reduce the instance of daytime side effects, some patients report sleep disturbances.Methods . Patient charts at the Tallahassee Memorial Healthcare Neuroscience Center (TMH-NSC) were reviewed. Charts of those patients who met the inclusion criteria were used to determine the correlation between night time administration of donepezil and sleep disturbances.Results . A total of 186 patient charts were analyzed. Of those 186, 103 of the patients were taking donepezil as directed in the package labeling, at night time. Nearly half (47.6%) of the patients taking donepezil at night reported night time disturbances (NTD) and only 21 of the 83 patients taking donepezil in the morning reported NTD.Conclusion . This retrospective study showed that taking donepezil at night may be associated with sleep disturbances. Although labeling suggests administration in the evening, should NTDs occur, changing the medication administration to the morning should be explored before switching therapeutic agents.

CHARACTERIZATION OF D-ENANTIOMERIC PEPTIDES BINDING TO MONOMERIC AMYLOID BETA (1-42) IDENTIFIED BY A COMPETITIVE MIRROR IMAGE PHAGE DISPLAY

The aim of this study is to assess the convenience of exploring longterm synergistic effects when multiple AD therapeutics of different mechanisms, fundamental and symptomatic, are combined. Methods: As a symptomatic drug, we selected donepezil, which have significant clinical benefits by activating undamaged cholinergic systems. From our previous study, as a fundamental drug, we prepared a small molecule KMSB600 that disassembles neurotoxic Ab aggregates back to inert Ab monomers and reverses the behavioral deficits in 2xTG-AD mice (APP/ PS1). During the oral co-administration, we performed Y-maze tasks every week for 4 months and performed fear conditioning tasks after the last trial of Y-maze. Ab plaques were visualized by thioflavin-S staining. Results: Co-administration of donepezil and KMSB600 significantly improved the deficits in the both behavior tests and histology study, compared to individual administration of donepezil or KMSB600 at the same dosages. Conclusions: Here, we report that co-administration of donepezil and KMSB600 significantly enhanced cognitive deficits in aged-AD mice in a complementary manner. Our findings imply that the cure of AD may require cocktail therapy of multiple drugs with different modes of action: cholinergic system improvement and amyloidogenic pathology reduction.

Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors.

Donepezil Enhances Purkinje Cell Survival and Alleviates Motor Dysfunction by Inhibiting Cholesterol Synthesis in a Murine Model of Niemann Pick Disease Type C

Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3-hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC.

A new pharmacological role for donepezil: attenuation of morphine-induced tolerance and apoptosis in rat central nervous system.

BackgroundTolerance to the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. It has been shown that morphine-induced tolerance is associated with apoptosis in the central nervous system and neuroprotective agents which prevented apoptosis signaling could attenuate tolerance to the analgesic effects. On the other hand donepezil, an acetylcholinesterase inhibitor, has been reported to have neuroprotective effects. Therefore in this study, the effect of systemic administration of donepezil on morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord was evaluated. Various groups of rats received morphine (ip) and different doses of donepezil (0, 0.5, 1, 1.5 mg/kg/day). Nociception was assessed using tail flick apparatus. Tail flick latency was recorded when the rat shook its tail. For apoptosis assay other groups of rats received the above treatment and apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method.ResultsThe results showed that administration of donepezil (0.5, 1, 1.5 mg/kg, ip) delayed the morphine tolerance for 9, 12 and 17 days, respectively. Furthermore pretreatment injection of donepezil attenuated the number of apoptotic cells in the cerebral cortex and lumbar spinal cord compared to the control group.ConclusionIn conclusion, we found that systemic administration of donepezil attenuated morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord.

The effects of combine treatment of memantine and donepezil on Alzheimer's Disease patients and its relationship with cerebral blood flow in the prefrontal area

In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow. We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24. Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT. In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested.

Effects of thyroxin and donepezil on hippocampal acetylcholine content and syntaxin-1 and munc-18 expression in adult rats with hypothyroidism

Adult-onset hypothyroidism induces various impairments in hippocampus-dependent cognitive function, in which numerous synaptic proteins and neurotransmitters are involved. Donepezil (DON), an acetylcholinesterase inhibitor, has been shown to be efficient in improving cognitive function. The aim of the present study was to investigate the effects of adult-onset hypothyroidism on the expression levels of the synaptic proteins syntaxin-1 and munc-18, as well as the content of the neurotransmitter acetylcholine (ACh) in the hippocampus. In addition, the study explored the effects of thyroxin (T4) and DON treatment on the altered parameters. The study involved 55 Sprague-Dawley rats that were randomly divided into five groups: Control, hypothyroid (0.05% 6-n-propyl-2-thiouracil; added to the drinking water), hypothyroid treated with T4 (6 μg/100 g body weight once daily; intraperitoneal injection), hypothyroid treated with DON (0.005%; added to the drinking water) and hypothyroid treated with a combination of the two drugs (6 μg/100 g T4 and 0.005% DON). The concentration of ACh was determined in the homogenized hippocampus of each animal by alkaline hydroxylamine colorimetry. The protein levels of syntaxin-1 and munc-18 were determined by immunohistochemistry. The results showed that the content of ACh in the hippocampi of the hypothyroid rats was significantly decreased compared with that in the controls and that T4 monotherapy and DON administration restored the ACh content to normal values. In the hippocampi of the hypothyroid group, munc-18 was expressed at significantly lower levels, while the expression levels of syntaxin-1 were increased compared with the levels in the control group. Treatment with T4 alone restored the expression of syntaxin-1 but failed to normalize munc-18 expression levels. The co-administration of T4 and DON returned the munc-18 levels to normal values. These observations indicate that adult-onset hypothyroidism induces alterations in the levels of munc-18, syntaxin-1 and ACh in the hippocampus. Syntaxin-1 and ACh levels were restored by T4 monotherapy while munc-18 levels were not. In addition, the co-administration of T4 and DON resulted in more effective restoration than either alone. The thyroid hormone has a direct effect on metabolism of hippocampal ACh in adult rats and DON is helpful for treatment of synaptic protein impairment induced by hypothyroidism.

Donepezil-induced Cervical Dystonia in Alzheimer's Disease: A Case Report and Literature Review of Dystonia due to Cholinesterase Inhibitors

We herein report an 81-year-old woman with Alzheimer's disease (AD) in who donepezil, a cholinesterase inhibitor (ChEI), caused cervical dystonia. The patient had a two-year history of progressive memory disturbance fulfilling the NINCDS-ADRDA criteria for probable AD. Mini-Mental State Examination score was 19/30. The remaining examination was normal. After a single administration of donepezil (5 mg/day) for 10 months, she complained of dropped head. Neurological examination and electrophysiological studies supported a diagnosis of cervical dystonia. Antecollis disappeared completely at 6 weeks after cessation of donepezil. Dystonic posture can occur at various timings of ChEI use. Physicians should pay more attention to rapidly progressive cervical dystonia in ChEI-treated AD patients.

Recommendations for the safe administration of donepezil.

# {#article-title-2} Safe administration of a medicine depends on individual differences in tolerance and appropriate, consistent instructions from the physician, pharmacist, and package directions. When patients receive written and oral dosing directions that disregard individual differences and are inconsistent, the therapeutic benefits of the medication may be reduced and adverse effects may result. A specific example occurs with the written and oral directions to patients (and caregivers) for the administration of donepezil. The Aricept Patient Package Insert (paper) under the section “How should the patient take ARICEPT?” instructs as follows: “Give ARICEPT one time each day. ARICEPT can be taken with or without food.”1 In the same package, the second larger insert reads: “Full Prescribing Information, 2) Dosage and Administration”: “ARICEPT should be taken in the …

Network dynamics predict improvement in working memory performance following donepezil administration in healthy young adults

Attentional selection in the context of goal-directed behavior involves top-down modulation to enhance the contrast between relevant and irrelevant stimuli via enhancement and suppression of sensory cortical activity. Acetylcholine (ACh) is believed to be involved mechanistically in such attention processes. The objective of the current study was to examine the effects of donepezil, a cholinesterase inhibitor that increases synaptic levels of ACh, on the relationship between performance and network dynamics during a visual working memory (WM) task involving relevant and irrelevant stimuli. Electroencephalogram (EEG) activity was recorded in 14 healthy young adults while they performed a selective face/scene working memory task. Each participant received either placebo or donepezil (5mg, orally) on two different visits in a double-blinded study. To investigate the effects of donepezil on brain network dynamics we utilized a novel EEG-based Brain Network Activation (BNA) analysis method that isolates location–time–frequency interrelations among event-related potential (ERP) peaks and extracts condition-specific networks. The activation level of the network modulated by donepezil, reflected in terms of the degree of its dynamical organization, was positively correlated with WM performance. Further analyses revealed that the frontal–posterior theta–alpha sub-network comprised the critical regions whose activation level correlated with beneficial effects on cognitive performance. These results indicate that condition-specific EEG network analysis could potentially serve to predict beneficial effects of therapeutic treatment in working memory.

Long-Term Safety and Efficacy of Donepezil in Patients with Dementia with Lewy Bodies: Results from a 52-Week, Open-Label, Multicenter Extension Study

Background/Aims: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB). Methods: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout. Results: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear. Conclusion: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Acute mood effect of donepezil in young, healthy volunteers

Chronic use of the acetylcholinesterase inhibitor donepezil has been found to improve mood or to induce mania/hypomania in many neuropsychiatric patients with altered cholinergic and dopaminergic tone. Our aim was to determine whether acutely administered donepezil would alter mood in volunteers with no such alterations. This investigation was a double-blind, crossover design study of 15 young, healthy male participants who were allocated in random order to three oral treatments: placebo and 5-mg and 7.5-mg donepezil (doses which exert clinical and acute cognitive effects without considerable peripheral side effects). At the theoretical peak-plasma concentrations of donepezil, volunteers rated how they felt on validated questionnaires, which included various dimensions of subjective feelings. We also assessed changes in brain-derived neurotrophic factor (BDNF), which is increased by donepezil after chronic regimes and is related to modulation of mood. Donepezil significantly increased ratings of vigour and anxiety symptoms (medium effect sizes). No changes in bodily symptoms or BDNF were observed. Acute donepezil administration in participants with unaltered cholinergic and dopaminergic tone led to positive and negative changes in affect. These results call for further research on the direct mood effects of donepezil.

Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats

Ginsenoside Rg1, one of the major active ingredients isolated from Panax Ginseng, has been shown notable neuroprotective effects in memory impairment animals. However, the role of ginsenoside Rg1 on cognition capacity damaged by neurofibrillary tangles (NFTs) is still poorly understood, and the underlying mechanism remain to be fully elucidated. Okadaic acid (OKA), a potent phosphatase inhibitor, often apply to imitate Alzheimer's disease-like symptom damaged by neurofibrillary tangles, was used to investigate the effects of ginsenoside Rg1 on memory impairment and the related mechanisms in Sprague Dawley (SD) rats. The anti-dementic drug donepezil was used as a positive contrast. The results showed that OKA intracerebroventricular (i.c.v.) injection induced memory impairment, including changes in the ability of orientation navigate, spatial probe and relearning memory in behavioral test of Morris water maze (MWM). However, treatment with Rg1 and donepezil remarkably alleviated these changes. Also OKA treated rats showed memory impairment including increasing of phospho-tau, decreasing of phospho-GSK3β and the formation of β-amyloid in special brain regions, which were reversed by Rg1 (20mg/kg) and donepezil (1mg/kg) administration. All these indicating that ginsenoside Rg1 protects rats against OKA-induced neurotoxicity. The possible neuroprotective mechanism may be that Rg1 decreases OKA-induced memory impairment through GSK3β/tau signaling pathway and/or attenuating Aβ formation. Thus, these studies indicate that ginsenoside Rg1 might be a potential preventive drug for Alzheimer's disease.

Donepezil Is Ineffective in Promoting Motor and Cognitive Benefits after Controlled Cortical Impact Injury in Male Rats

The acetylcholinesterase (AChE) inhibitor donepezil is used as a therapy for Alzheimer's disease and has been recommended as a treatment for enhancing attention and memory after traumatic brain injury (TBI). Although select clinical case studies support the use of donepezil for enhancing cognition, there is a paucity of experimental TBI studies assessing the potential efficacy of this pharmacotherapy. Hence, the aim of this pre-clinical study was to evaluate several doses of donepezil to determine its effect on functional outcome after TBI. Ninety anesthetized adult male rats received a controlled cortical impact (CCI; 2.8 mm cortical depth at 4 m/sec) or sham injury, and then were randomly assigned to six TBI and six sham groups (donepezil 0.25, 0.5, 1.0, 2.0, or 3.0 mg/kg, and saline vehicle 1.0 mL/kg). Treatments began 24 h after surgery and were administered i.p. once daily for 19 days. Function was assessed by motor (beam balance/walk) and cognitive (Morris water maze) tests on days 1-5 and 14-19, respectively. No significant differences were observed among the sham control groups in any evaluation, regardless of dose, and therefore the data were pooled. Furthermore, no significant differences were revealed among the TBI groups in acute neurological assessments (e.g., righting reflex), suggesting that all groups received the same level of injury severity. None of the five doses of donepezil improved motor or cognitive function relative to vehicle-treated controls. Moreover, the two highest doses significantly impaired beam-balance (3.0 mg/kg), beam-walk (2.0 mg/kg and 3.0 mg/kg), and cognitive performance (3.0 mg/kg) versus vehicle. These data indicate that chronic administration of donepezil is not only ineffective in promoting functional improvement after moderate CCI injury, but depending on the dose is actually detrimental to the recovery process. Further work is necessary to determine if other AChE inhibitors exert similar effects after TBI.

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day-old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 μg/kg physostigmine or 200 μg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1β and TNF-α in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain.