Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice

Background and purpose

Galantamine, a weak acetylcholine esterase (AChE) inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves apomorphine-induced deficits in prepulse inhibition (PPI), sensory information-processing deficits, via a nAChR-independent mechanism. The present study examined the role of muscarinic ACh receptors (mAChRs) in the effect of galantamine, and studied the mechanism of galantamine-induced increases in prefrontal ACh levels in mice.

Experimental approach

Apomorphine (1 mg kg⁻¹) was administered to male ddY mice (9–10 weeks old) to create a PPI deficit model. Extracellular ACh concentrations in the prefrontal cortex were measured by in vivo microdialysis.

Key results

Galantamine- and donepezil-mediated improvements in apomorphine-induced PPI deficits were blocked by the preferential M₁ mAChR antagonist telenzepine. The mAChR agonist oxotremorine also improved apomorphine-induced PPI deficits. Galantamine, like donepezil, increased extracellular ACh concentrations in the prefrontal cortex. Galantamine-induced increases in prefrontal ACh levels were partially blocked by the dopamine D₁ receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, but not by antagonists of mAChRs (telenzepine) and nAChRs (mecamylamine). Galantamine increased dopamine, but not 5-HT, release in the prefrontal cortex.

Conclusions and implications

Galantamine improves apomorphine-induced PPI deficits by stimulating mAChRs through increasing brain ACh levels via a dopamine D₁ receptor-dependent mechanism and AChE inhibition.     

Donepezil treatment of topiramate-related cognitive dysfunction

Six migraine patients experienced significant topiramate-related cognitive and language dysfunction that improved with donepezil treatment and allowed uninterrupted topiramate use. These patients represent the first report of topiramate-related cognitive and language dysfunction that improved with a cholinesterase inhibitor. Although, the mechanism responsible for this effect is uncertain, cholinesterase inhibition resulting in cholinergic augmentation and enhanced cognition probably account for some if not most of the improvement.     

Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of ��7 nicotinic receptors and internalization of NMDA receptors

BACKGROUND AND PURPOSE

Glutamate excitotoxicity may be involved in ischaemic injury to the CNS and some neurodegenerative diseases, such as Alzheimer''s disease. Donepezil, an acetylcholinesterase (AChE) inhibitor, exerts neuroprotective effects. Here we demonstrated a novel mechanism underlying the neuroprotection induced by donepezil.

EXPERIMENTAL APPROACH

Cell damage in primary rat neuron cultures was quantified by lactate dehydrogenase release. Morphological changes associated with neuroprotective effects of nicotine and AChE inhibitors were assessed by immunostaining. Cell surface levels of the glutamate receptor sub-units, NR1 and NR2A, were analyzed using biotinylation. Immunoblot was used to measure protein levels of cleaved caspase-3, total NR1, total NR2A and phosphorylated NR1. Immunoprecipitation was used to measure association of NR1 with the post-synaptic protein, PSD-95. Intracellular Ca²⁺ concentrations were measured with fura 2-acetoxymethylester. Caspase 3-like activity was measured using enzyme substrate, 7-amino-4-methylcoumarin (AMC)-DEVD.

KEY RESULTS

Levels of NR1, a core subunit of the NMDA receptor, on the cell surface were significantly reduced by donepexzil. In addition, glutamate-mediated Ca²⁺ entry was significantly attenuated by donepezil. Methyllycaconitine, an inhibitor of α7 nicotinic acetylcholine receptors (nAChR), inhibited the donepezil-induced attenuation of glutamate-mediated Ca²⁺ entry. {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, a phosphatidyl inositol 3-kinase (PI3K) inhibitor, had no effect on attenuation of glutamate-mediated Ca²⁺ entry induced by donepezil.

CONCLUSIONS AND IMPLICATIONS

Decreased glutamate toxicity through down-regulation of NMDA receptors, following stimulation of α7 nAChRs, could be another mechanism underlying neuroprotection by donepezil, in addition to up-regulating the PI3K-Akt cascade or defensive system.     

Pseudoginsenoside-F11 attenuates cognitive dysfunction and tau phosphorylation in sporadic Alzheimer’s disease rat model

We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, significantly ameliorated Alzheimer’s disease (AD)-associated cognitive defects in APP/PS1 and SAMP8 mice by inhibiting Aβ aggregation and tau hyperphosphorylation, suggesting a potential therapeutic effect of PF11 in the treatment of AD. In the present study we further evaluated the therapeutic effects of PF11 on relieving cognitive impairment in a rat model of sporadic AD (SAD). SAD was induced in rats by bilateral icv infusion of streptozotocin (STZ, 3 mg/kg). The rats were treated with PF11 (2, 4, 8 mg·kg⁻¹·d⁻¹, ig) or a positive control drug donepezil (5 mg·kg⁻¹·d⁻¹, ig) for 4 weeks. Their cognitive function was assessed in the nest building, Y-maze, and Morris water maze tests. We showed that STZ icv infusion significantly affected the cognitive function, tau phosphorylation, and insulin signaling pathway in the hippocampus. Furthermore, STZ icv infusion resulted in significant upregulation of the calpain I/cyclin-dependent protein kinase 5 (CDK5) signaling pathway in the hippocampus. Oral administration of PF11 dose-dependently ameliorated STZ-induced learning and memory defects. In addition, PF11 treatment markedly reduced the neuronal loss, protected the synapse structure, and modulated STZ-induced expression of tau phosphorylation by regulating the insulin signaling pathway and calpain I/CDK5 signaling pathway in the hippocampus. Donepezil treatment exerted similar beneficial effects in STZ-infused rats as the high dose of PF11 did. This study highlights the excellent therapeutic potential of PF11 in managing AD.     

A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (Aricept) for reducing the incidence of postoperative delirium after elective total hip replacement

OBJECTIVES: This was a pilot, phase 2a study to assess methodological feasibility and the safety and efficacy of donepezil in preventing postoperative delirium after elective total hip replacement surgery in older people without pre-existing dementia. The hypothesis was that donepezil would reduce the incidence of postoperative delirium. METHODS: A double blind, placebo controlled, parallel group randomized trial was undertaken. Patients were block randomized pre-operatively to receive placebo or donepezil 5 mg immediately following surgery and every 24 h thereafter for a further three days. The main outcome was the incidence of delirium (using the Delirium Symptom Interview). The secondary outcome was length of hospital stay. RESULTS: Thirty-three patients (mean age 67 years; 17 males, 16 females) completed the study (19 donepezil, 14 placebo). Donepezil was well tolerated with no serious adverse events. Postoperative delirium occurred in 21.2% of subjects. Donepezil did not significantly reduce the incidence of delirium. The unadjusted risk ratio (donepezil vs placebo) for delirium was 0.29 (95% CI = 0.06,1.30) (chi(2) ([1]) = 3.06; p = 0.08). Mean length of hospital stay was 9.9 days for the donepezil group vs 12.1 days in the placebo group; difference in means = -2.2 days (95% CI = -0.39,4.78) (t([31]) = 1.73: p = 0.09). CONCLUSIONS: The experimental paradigm was feasible and acceptable. Donepezil did not significantly reduce the incidence of delirium or length of hospital stay, however for both outcomes there was a consistent trend suggesting possible benefit. The sample size required for a definitive trial (99% power, alpha 0.05) would be 95 subjects per arm.     

Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer's disease

OBJECTIVE: This 132-week, open-label extension study assessed the long-term efficacy and safety of donepezil in 579 patients with mild to moderate Alzheimer's disease (AD) who had previously participated in a 24-week double-blind study of 5 or 10 mg/day donepezil vs placebo. METHOD: Patients enrolled in the present study had a 6-week single-blind placebo washout period followed by treatment with donepezil 5 mg/day for 6 weeks with an optional increase in dosage to 10 mg/day between weeks 6 and 32. RESULTS: After 6 weeks of open-label treatment with donepezil 5 mg/day, mean Alzheimer's Disease Assessment Scale -- cognitive subscale scores (ADAS-cog) improved by approximately two points, while after 12 weeks of open-label treatment (with a majority of patients receiving 10 mg/day), the mean ADAS-cog score was 1 point better than the score at the end of the placebo washout period. Scores then declined gradually over the remainder of the study. Mean changes in Clinical Dementia Rating-Sum of Boxes scores showed slight improvement over the first 12 weeks of open-label treatment and then slowly declined for the remainder of the study period. Donepezil was well tolerated over the entire 162-week study period. Overall, 85% of patients experienced at least one adverse event (AE). The most common included diarrhoea (12%), nausea (11%), infection (11%) and accidental injury (10%). Some patients discontinued the study due to AEs (15%). CONCLUSIONS: These results support the conclusion that donepezil is safe and effective for the long-term treatment of patients with mild to moderate AD.     

盐酸多奈哌齐治疗轻、中型脑外伤后认知障碍的临床研究

目的探讨盐酸多奈哌齐对轻、中型脑外伤患者伤后认知障碍及临床预后的影响。方法本组轻、中型脑外伤合并认知障碍患者78例,随机分成治疗组和对照组,治疗组应用盐酸多奈哌齐,对照组应用吡拉西坦,两组的治疗周期为12周。治疗前及治疗后分别应用简明精神状态检测量表（MMSE）、国人修订成人韦氏智力量表（WAIS-RC）和格拉斯哥预后评分（GOS）评价疗效。结果两组治疗后12周MMSE和WAIS-RC评分均较治疗前提高（P〈0.05）。治疗组MMSE和WAIS-RC评分提高较对照组明显（P〈0.05）,治疗组GOS预后优良率优于对照组（P〈0.05）。结论盐酸多奈哌齐对轻、中型脑外伤后认知障碍有积极治疗作用,并能改善临床预后。     

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Background:  Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease.
Methods:  We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated.
Results:  The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials.
Conclusions:  The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.     

Improvement in Tc-99m HMPAO brain SPECT findings during donepezil therapy in a patient with pure akinesia

A 58-year-old man presented with a history of disturbance in initiating gait. His history revealed meningoencephalitis five years prior to admission. Neurological examination included gait disturbance as difficulty in initiation and a hesitating speech with many freezing episodes and micrographia Magnetic resonance imaging (MRI) showed diffuse hyperintensity of frontal subcortical white matter on T2 weighted images. He was diagnosed with PA. L-Dopa up to the dosages of 1000 mg/ day and selegiline 10 mg/day were given. First brain SPECT using technetium-99m labeled D,L-hexamethylpropylene amine oxime (Tc-99m HMPAO) was performed when he was taking L-dopa and selegiline. In visual evaluation, hypoperfusion in bilateral frontoparietal cortex was seen (Fig. 2). Treatment with L-dopa and selegiline produced no benefit. Donepezil 10 mg/day was begun. This therapy regimen resulted in dramatic clinical improvement within several days that was confirmed by blinded raters who watched the patient's video recordings. During this response second brain perfusion SPECT study was repeated during donepezil therapy. Markedly increased perfusion in bilateral frontoparietal cortex was observed. This is the first case of PA to develop possibly after an episode of bacterial pneumococcal meningoencephalitis and who responded to donepezil as documented by changes in clinical findings and Tc-99m HMPAO brain SPECT studies.