Administration Of Donepezil Research Articles

Cholinergic Potentiation Alters Perceptual Eye Dominance Plasticity Induced by a Few Hours of Monocular Patching in Adults.

A few hours of monocular deprivation with a diffuser eye patch temporarily strengthens the contribution of the deprived eye to binocular vision. This shift in favor of the deprived eye is characterized as a form of adult visual plasticity. Studies in animal and human models suggest that neuromodulators can enhance adult brain plasticity in general. Specifically, acetylcholine has been shown to improve certain aspects of visual function and plasticity in adulthood. We investigated whether a single administration of donepezil (a cholinesterase inhibitor) could further augment the temporary shift in perceptual eye dominance that occurs after 2 h of monocular patching. Twelve healthy adults completed two experimental sessions while taking either donepezil (5 mg, oral) or a placebo (lactose) pill. We measured perceptual eye dominance using a binocular phase combination task before and after 2 h of monocular deprivation with a diffuser eye patch. Participants in both groups demonstrated a significant shift in favor of the patched eye after monocular deprivation, however our results indicate that donepezil significantly reduces the magnitude and duration of the shift. We also investigated the possibility that donepezil reduces the amount of time needed to observe a shift in perceptual eye dominance relative to placebo control. For this experiment, seven subjects completed two sessions where we reduced the duration of deprivation to 1 h. Donepezil reduces the magnitude and duration of the patching-induced shift in perceptual eye dominance in this experiment as well. To verify whether the effects we observed using the binocular phase combination task were also observable in a different measure of sensory eye dominance, six subjects completed an identical experiment using a binocular rivalry task. These results also indicate that cholinergic enhancement impedes the shift that results from short-term deprivation. In summary, our study demonstrates that enhanced cholinergic potentiation interferes with the consolidation of the perceptual eye dominance plasticity induced by several hours of monocular deprivation.

CGY-1, a biflavonoid isolated from cardiocrinum giganteum seeds, improves memory deficits by modulating the cholinergic system in scopolamine-treated mice

Certain biflavonoids have been proven to protect against cognitive dysfunction. A new biflavonoid, CGY-1, isolated from Cardiocrinum giganteum seeds, has not yet been reported to have any neuroprotective effect. In this study, a scopolamine-induced memory deficit model was used to explore the neuroprotective effect of CGY-1. Behavioral experiments, such as tests using the Morris water maze, the Y-maze and the fear conditioning test, were conducted. The results revealed that oral administration of CGY-1 (20 and 40 mg/kg) and donepezil shortened the escape latency, improved the percentage of spontaneous alternation, and increased the freezing times, respectively. CGY-1 decreased the levels of reactive oxygen species and malondialdehyde and increased the activities of superoxide dismutase and glutathione peroxidase in the hippocampus. In addition, CGY-1 decreased the activity of acetylcholinesterase and increased the activities of choline acetyltransferase and acetylcholine in the hippocampus. Furthermore, qPCR and western blot results revealed that the expressions of neurotrophic factors, brain-derived neurotrophic factor and nerve growth factor were upregulated in the hippocampus after CGY-1 treatment. In conclusion, CGY-1 could be a promising candidate for the treatment of cognitive dysfunction.

Neurophysiological signals as predictive translational biomarkers for Alzheimer\u2019s disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats

BackgroundTranslational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment.MethodsBrainstem nucleus pontis oralis stimulation-induced hippocampal oscillations were recorded under urethane anesthesia in adult (6-month-old) and aged (12-month-old) TgF344-AD and wild-type rats. Spontaneous cortical activity was monitored in a cohort of freely behaving aged rats implanted with frontal and occipital cortical electroencephalography (EEG) electrodes.ResultsSubcutaneous administration of donepezil significantly augmented stimulation-induced hippocampal theta oscillation in aged wild-type rats and both adult and aged TgF344-AD rats, which have been previously shown to have diminished response to nucleus pontis oralis stimulation. Moreover, in adult TgF344-AD rats, donepezil also significantly increased theta phase-gamma amplitude coupling in the hippocampus during stimulation. However, neither of these effects were significantly changed in adult wild-type rats. Under freely behaving conditions, donepezil treatment had the opposite effect on cortical oscillatory connectivity in TgF344-AD and wild-type rats, and it reduced the occurrence of high-voltage spindle activity in TgF344-AD rats.ConclusionsTogether, these results imply that pharmacologically enhancing cholinergic tone with donepezil could partially reverse oscillatory abnormalities in TgF344-AD rats, which is in line with its clinical effectiveness in AD patients. Therefore, our study suggests good translational opportunities for these neurophysiological signals recorded in TgF344-AD rats, and their application could be considered in drug discovery efforts for developing therapies with disease-modifying potential.

Hypercholesterolemia impairs contextual fear conditioning memory formation in female mice: evidence for cholinergic dysfunction.

The present study evaluated the effects of hypercholesterolemia in response to conditioned aversive stimuli in mice. Specifically, (a) young (3 months old) and aged (24 months old) female C57Bl/6 mice were fed daily for 4 weeks with a standard rodent diet or an enriched cholesterol diet (ECD) and then subjected to the contextual fear conditioning test. In another experimental set, 3-month-old C576Bl/6 female mice, fed daily during the 4 weeks with the standard rodent diet or ECD, were subjected to the contextual fear conditioning test and received vehicle or scopolamine (0.37 mg/kg; intraperitoneally) immediately after the training session. (b) 12-month-old C576Bl/6 and low-density lipoprotein receptor knockout mice (LDLr) female mice were subjected to the contextual fear conditioning test. In another experimental set, they were subjected to the contextual fear conditioning test and received vehicle or donepezil (3.0 mg/kg; intraperitoneally) immediately after the training session. The present results show that (a) the ECD specifically impaired retrieval of contextual fear memory in aged mice; (b) an ineffective dose of scopolamine impaired fear memory consolidation in young mice fed the ECD; (c) LDLr mice presented impaired contextual fear memory retrieval; and (d) boosting cholinergic neurotransmission with a single donepezil administration at the consolidation window led to improved fear memory consolidation in LDLr mice. These findings suggest that high levels of cholesterol induced by either an ECD or a genetic deletion of LDLr decreased freezing behavior on the contextual fear conditioning test, which seemed to involve dysfunction of the cholinergic system.

The effect of donepezil on the cognitive ability early in the course of recovery from traumatic brain injury

ABSTRACTObjective: To investigate the effect of donepezil on cognitive ability in patients who have sustained a traumatic brain injury (TBI). We hypothesized that donepezil, an acetylcholinesterase inhibitor, would enhance cognitive recovery beyond that of usual care in an acute rehabilitation facility.Methods: This retrospective, longitudinal analysis included 55 patients who were non-randomly prescribed donepezil during acute care and compared them to 74 patients who received usual rehabilitation treatment. All 129 patients completed neuropsychological assessment at two time points. Donepezil was increased from 5 to 10 mg 7–10 days after initiation and maintained until follow-up cognitive assessment.Main outcomes: Primary cognitive abilities of interest included processing speed, attention and memory. Cognitive and functional abilities were assessed by a standard neuropsychological battery for TBI.Results: Propensity scores were used to adjust for differences between groups. Mixed effect model analysis showed no significant differences between treatment and control groups on all neuropsychological subtests over time.Conclusions: Acute administration of donepezil did not significantly improve measures of cognitive or functional ability beyond that of treatment as usual in patients with moderate-to-severe TBI.

Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys

Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.

Systemic administration of donepezil attenuates the efficacy of environmental enrichment on neurobehavioral outcome after experimental traumatic brain injury.

The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits. The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone. Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 19. DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05). These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.

Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat

With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Electrocardiogram Changes of Donepezil Administration in Elderly Patients with Ischemic Heart Disease.

Objective Donepezil, a widely used cholinesterase inhibitor for treating Alzheimer's disease, has been reported to induce bradyarrhythmias and torsade de pointes. In this study, we aimed at determining electrocardiogram changes of donepezil administration in elderly patients with ischemic heart disease, who tend to suffer from cognitive disorders. Methods Sixty patients with ischemic heart disease and mild cognitive impairment were treated with donepezil (5 mg/day) and followed up for at least four weeks. A twenty-four-hour ambulatory electrocardiogram was performed for the analysis of heart rate variability. The ECG parameters including heart rate (HR), PR and RR intervals, QT interval, and QRS duration were recorded at the baseline and after donepezil administration. Results Donepezil administration resulted in significant reduction in mean HR and the lowest HR and prolongation of PR and RR intervals, whereas it had no significant effects on QRS duration and QT parameters including QT, corrected QT interval, QT dispersion, and Tpeak-end interval. HRV analysis showed that donepezil administration significantly improved parasympathetic function, indicated by decreased low/high frequency (LF/HF) ratio and high frequency (HF) components and oscillation of RR intervals. Conclusions These data demonstrated that donepezil administration decreased HR, prolonged PR interval, and increased parasympathetic function without affecting QRS duration and QT intervals, suggesting that it can be used safely in elderly patients with ischemic heart disease.

Lifetime Expectancy in Dementia with Lewy Bodies: Effects of Donepezil Administration and Special Nursing Home Replacement. A Retrospective Analysis in the Tajiri Project

Objective: Cholinesterase inhibitors (ChEIs) can delay the progression of Alzheimer disease (AD). We previously demonstrated a positive effect of donepezil (DNP) administration and a Special Nursing Home (SNH) replacement on lifetime expectancy after the onset of AD. Recently DNP has been indicated for use in the treatment of dementia with Lewy Bodies (DLB); however, the effect on lifetime expectancy remains unclear. Herein, we analyzed the effects of DNP on DLB. Methods: All outpatients at the Tajiri Clinic with available medical records and death certificates from 1999- 2012 were included in this retrospective analysis. The entry criteria were a diagnosis of dementia based on DSM-IV criteria and diagnosis of DLB using the international consensus criteria; medical treatment for more than 3 months and follow up to less than 1 year before death. Results: We identified 510 subjects based upon medical records and death certificates, of which 360 had a diagnosis of dementia that met the entry criteria. Of 51 patients diagnosed with DLB, 23 had taken DNP and 28 patients had not undergone drug treatment due to treatment prior to the introduction of DNP in 1999 in Japan. The lifetime expectancies after onset were 6.4 years in the DNP group and 3.6 years in the non-DNP group; with a significant drug effect. However, in contrast with the previous AD data, no significant effect of SNH residency was noted. Conclusion: Although this report has the limitation that all analyses were retrospective and lacked randomization, we found a positive effect of DNP on lifetime expectancy after the onset of DLB. The lower life expectancy compared with that of AD and the lack of an effect of SNH residency suggest the cholinergic deficiency in DLB is greater than that in AD.

Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus).

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

Acute caffeine ingestion affects surround suppression of perceived contrast.

Caffeine is a widely used psychostimulant that is associated with increased acetylcholine levels in mammalian brain and acetycholinesterase antagonism. Acetylcholine, a neuromodulator, plays an important role in the processing of visual information. One key example in human vision, thought to at least partly involve cholinergic neuromodulation, is perceptual surround suppression of contrast, whereby the perceived contrast of a pattern is altered by the presence of a neighbouring pattern. Perceptual surround suppression is weaker with pharmacological administration of donepezil (a centrally-acting acetylcholine enzyme inhibitor) in healthy human observers. Here, we test whether temporarily manipulating caffeine levels (from complete washout to a controlled dose of caffeine) has a similar effect on perceptual surround suppression in 21 healthy young adults (aged 20-24 years, 11 females). Neither ingestion of a caffeine pill nor placebo altered contrast judgments when the target pattern was presented on a uniform grey background ( p=0.54). With caffeine ingestion, perceptual surround suppression strength was reduced relative to baseline (prior to pill ingestion, p=0.003) and placebo ( p=0.029), irrespective of whether the surround was oriented parallel or orthogonal to the central target. While daily habitual caffeine consumption of low-to-moderate doses (<400 mg/day, estimated from a written questionnaire) is not predictive of performance, our study indicates that acute consumption of caffeine on the day of testing influences perceptual surround suppression strength. Perceptual surround suppression is predominantly attributed to inhibitory processes involving the major cortical inhibitory neurotransmitter, gamma-aminobutyric acid. Our results point to the involvement of other neuromodulators, possibly cholinergic, in perceptual surround suppression.

Changes in brain amyloid-β accumulation after donepezil administration

Recent studies using the mouse model of Alzheimer’s disease (AD) have shown that donepezil administration reduces brain amyloid-β (Aβ) accumulation. This study investigated whether donepezil administration can reduce brain Aβ accumulation in human patients with AD. Ten patients with AD underwent two 11C-Pittsburgh Compound B positron emission tomography sessions approximately one year apart to measure brain Aβ accumulation before and after donepezil treatment. Volumes-of-interest were placed on Aβ-preferred regions, and the standardized uptake value ratio (SUVR) was calculated considering the cerebellum as a reference region. Three and seven patients received 10mg and 5mg of donepezil, respectively. SUVR was significantly higher in the second than in the first session (P=0.026). This study showed that one year of donepezil administration does not reduce brain Aβ accumulation in human patients with AD.

Donepezil Does Not Enhance Perceptual Learning in Adults with Amblyopia: A Pilot Study.

Amblyopia is a developmental disorder that results in a wide range of visual deficits. One proven approach to recovering vision in adults with amblyopia is perceptual learning (PL). Recent evidence suggests that neuromodulators can enhance adult plasticity. In this pilot study, we asked whether donepezil, a cholinesterase inhibitor, enhances visual PL in adults with amblyopia. Nine adults with amblyopia were first trained on a low-contrast single-letter identification task while taking a daily dose (5 mg) of donepezil throughout training. Following 10,000 trials of training, participants showed improved contrast sensitivity for identifying single letters. However, the magnitude of improvement was no greater than, and the rate of improvement was slower than, that obtained in a previous study in which six adults with amblyopia were trained using an identical task and protocol but without donepezil (Chung et al., 2012). In addition, we measured transfer of learning effects to other tasks and found that for donepezil, the post-pre performance ratios in both a size-limited (acuity) and a spacing-limited (crowding) task were not significantly different from those found in the previous study without donepezil administration. After an interval of several weeks, six participants returned for a second course of training on identifying flanked (crowded) letters, again with concurrent donepezil administration. Although this task has previously been shown to be highly amenable to PL in adults with amblyopia (Chung et al., 2012; Hussain et al., 2012), only one observer in our study showed significant learning over 10,000 trials of training. Auxiliary experiments showed that the lack of a learning effect on this task during donepezil administration was not due to either the order of training of the two tasks or the use of a sequential training paradigm. Our results reveal that cholinergic enhancement with donepezil during training does not improve or speed up PL of single-letter identification in adults with amblyopia, and importantly, it may even halt learning and transfer related to a crowding task.Clinical Trial Registration: This study was registered with ClinicalTrials.gov (NCT03109314).

Bushen-Yizhi formula ameliorates cognitive dysfunction through SIRT1/ER stress pathway in SAMP8 mice.

The Chinese formula Bushen-Yizhi (BSYZ) has been reported to ameliorate cognitive dysfunction. However the mechanism is still unclear. In this study, we employ an aging model, SAMP8 mice, to explore whether BSYZ could protect dementia through SIRT1/endoplasmic reticulum (ER) stress pathway. Morris water maze and the fearing condition test results show that oral administration of BSYZ (1.46 g/kg/d, 2.92 g/kg/d and 5.84 g/kg/d) and donepezil (3 mg/kg/d) shorten the escape latency, increase the crossing times of the original position of the platform and the time spent in the target quadrant, and increase the freezing time. BSYZ decreases the activity of acetylcholinesterase (AChE), and increases the activity of choline acetyltransferase (ChAT) and the concentration of acetylcholine (Ach) in both hippocampus and cortex. In addition, western blot results (Bcl-2, Bax and Caspase-3) and TUNEL staining show that BSYZ prevents neuron from apoptosis, and elevates the expression of neurotrophic factors, including nerve growth factor (NGF), postsynapticdensity 95 (PSD95) and synaptophysin (SYN), in both hippocampus and cortex. BSYZ also increases the protein expression of SIRT1 and alleviates ER stress-associated proteins (PERK, IRE-1α, eIF-2α, BIP, PDI and CHOP). These results indicate that the neuroprotective mechanism of BSYZ might be related with SIRT1/ER stress pathway.

The efficacy of donepezil administration on acetylcholinesterase activity and altered redox homeostasis in Alzheimer’s disease

Alzheimer’s disease (AD) is a serious multifactorial disorder with progressive neurodegenerative outcomes related with impaired redox homeostasis. Inhibition of the enzyme acetylcholinesterase (AChE), as one of the major therapeutic strategies, is considered to be offering only symptomatic relief and moderate disease modifying effect. We intended to investigate the effects of acetylcholinesterase inhibition via donepezil on protein carbonyl (PCO), advanced protein oxidation products (AOPP) and ischemia modified albumin (IMA) as protein oxidation markers and ferric reducing antioxidant power (FRAP), prooxidant–antioxidant balance (PAB), total thiol (T-SH), protein thiol (P-SH) as antioxidant status markers and also kynurenine (KYN), N-formyl kynurenine (N-FKYN) and protein bound dityrosine (DT) levels all in one demonstrating the redox homeostasis in Alzheimer patients also correlated with AChE activity. The AChE activity and PCO, KYN, N-FKYN and DT levels were found to be significantly higher in the AD group than the control group. The FRAP, T-SH and P-SH levels were significantly lower in the AD group than in the control group. The AChE activity was significantly higher both in donepezil treated and untreated groups when compared with the control group. PCO levels were significantly higher in Alzheimer’s untreated group than the healthy control and donepezil treated groups. AChE activity was positively correlated with PCO, IMA, PAB, KYN and N-FKYN levels and negatively correlated with FRAP, T-SH and P-SH levels in all participants. Our data showed that treatment with donepezil had ameliorating effects on redox homeostasis in Alzheimer patients. AChE inhibition seems to be exhibiting a potent antioxidant role and may inhibit protein oxidation by decreasing AChE activity in AD, thus medicinal natural substances exhibiting the similar mechanism of action with their antioxidant behaviours can be recommended for the emphasis on new drug new drug development. Further clinical and experimental studies are needed to support our current findings and conclusions.

Calcitonin gene-related peptide (CGRP): A novel target for Alzheimer's disease.

Alzheimer's disease (AD) is leading cause of death among older characterized by neurofibrillary tangles, oxidative stress, progressive neuronal deficits, and increased levels of amyloid-β (Aβ) peptides. Cholinergic treatment could be the best suitable physiological therapy for AD. Calcitonin gene-related peptide (CGRP) is a thirty-seven-amino acid regulatory neuropeptide resulting from different merging of the CGRP gene, which also includes adrenomedullin, amylin, calcitonin, intermedin, and calcitonin receptor-stimulating peptide. It is a proof for a CGRP receptor within nucleus accumbens of brain that is different from either the CGRP1 or CGRP2 receptor in which it demonstrates similar high-affinity binding for salmon calcitonin, CGRP, and amylin, a possession which is not shared by any extra CGRP receptors. Binding of CGRP to its receptor increases activated cAMP-dependent pkA and PI3 kinase, resulting in N-terminal fragments that are shown to exert complex inhibitory as well facilitator actions on nAChRs. Fragments such as CGRP1-4, CGRP1-5, and CGRP1-6 rapidly as well as reversibly improve agonist sensitivity of nAChRs without straight stimulating those receptors and produce the Ca2+ -induced intracellular Ca2+ mobilization. Renin-angiotensin-aldosterone system (RAAS)-activated angiotensin-type (AT4) receptor is also beneficial in AD. It has been suggested that exogenous administration of CGRP inhibits infiltration of macrophages and expression of various inflammatory mediators such as NFkB, IL-1b, TNF-α, iNOS, matrix metalloproteinase (MMP)-9, and cell adhesion molecules like intercellular adhesion molecule (ICAM)-1 which attenuates consequence of inflammation in AD. Donepezil, a ChEI, inhibits acetylcholinesterase and produces angiogenesis and neurogenesis, in the dentate gyrus of the hippocampus of WT mice after donepezil administration. However, none of the results discovered in CGRP-knockout mice and WT mice exposed to practical denervation. Therefore, selective agonists of CGRP receptors may become the potential candidates for treatment of AD.

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats.

The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism-induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin-1 (syt-1) and SNAP-25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 administration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt-1 and SNAP-25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult-onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Effects of the 5-HT6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6 receptor (Ki 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).

Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study.

Objective(s):It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP.Methods:We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 µg of DNP, respectively, while one patient was scanned following the oral administration of 30 µg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT.Results:In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 µg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 µg of DNP, or no DNP.Conclusion:The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP.