The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Targeting α7-nAChR by galantamine mitigates reserpine-induced fibromyalgia-like symptoms in rats: Involvement of cAMP/PKA, PI3K/AKT, and M1/M2 microglia polarization.

Fibromyalgia (FM) is a pain disorder marked by generalized musculoskeletal pain accompanied by depression, fatigue, and sleep disturbances. Galantamine (Gal) is a positive allosteric modulator of neuronal nicotinic acetylcholine receptors (nAChRs) and a reversible inhibitor of cholinesterase. The current study aimed to explore the therapeutic potential of Gal against reserpine (Res)-induced FM-like condition along with investigating the α7-nAChR's role in Gal-mediated effects. Rats were injected with Res (1 mg/kg/day; sc) for 3 successive days then Gal (5 mg/kg/day; ip) was given alone and with the α7-nAChR blocker methyllycaconitine (3 mg/kg/day; ip), for the subsequent 5 days. Galantamine alleviated Res-induced histopathological changes and monoamines depletion in rats' spinal cord. It also exerted analgesic effect along with ameliorating Res-induced depression and motor-incoordination as confirmed by behavioral tests. Moreover, Gal produced anti-inflammatory effect through modulating AKT1/AKT2 and shifting M1/M2 macrophage polarization. The neuroprotective effects of Gal were mediated through activating cAMP/PKA and PI3K/AKT pathways in α7-nAChR-dependent manner. Thus, Gal can ameliorate Res-induced FM-like symptoms and mitigate the associated monoamines depletion, neuroinflammation, oxidative stress, apoptosis, and neurodegeneration through α7-nAChR stimulation, with the involvement of cAMP/PKA, PI3K/AKT, and M1/M2 macrophage polarization.

Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues.

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 µM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.

Enhanced parasympathetic cholinergic activity with galantamine inhibited lipid-induced oxidative stress in obese African Americans.

BACKGROUND: African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress. OBJECTIVE: To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs. METHODS: Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion. MAIN OUTCOME MEASURES: Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha). RESULTS: A total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. - 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. - 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025). CONCLUSIONS: In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02365285.

Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer's disease.

The Alzheimer's disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in practice. Galanthamine is one of the most commonly used drugs against the illness. The main aim of this work is design and synthesis of new derivatives of galanthamine comprising peptide moiety as well as study of their ß-secretase inhibitory activity and the anti-aggregating effect. All new derivatives of galanthamine containing analogues of Leu-Val-Phe-Phe (Aß17-Aß20) were synthesized in solution using fragment and consecutive condensation approaches. The new derivatives were characterized by melting points, NMR, and HPLC/MS. They were tested in vitro for ß-secretase inhibition activity by means of fluorescent method and were investigated in vitro for anti-aggregation activity on sheep platelet-rich plasma. Although the new compounds do not contain a structural element responsible for the ß-secretase inhibition, five of them show high or good ß-secretase inhibitory activity between 19.98 and 51.19% with IC50 between 1.95 and 5.26 nM. Four of the new molecules were able to inhibit platelet aggregation between 55.0 and 90.0% with IC50 between 0.69 and 1.36 µM. Four of the compounds were able to inhibit platelet aggregation and two of them have high anti-aggregating effects.

Neuroprotective Effects of Apocynin and Galantamine During the Chronic Administration of Scopolamine in an Alzheimer's Disease Model.

Alzheimer's disease (AD) is one of the most complicated neurodegenerative diseases, and several hypotheses have been associated with its development and progression, such as those involving glucose hypometabolism, the cholinergic system, calcium imbalance, inflammation, oxidative imbalance, microtubule instability, and the amyloid cascade, several of which are related to oxidative stress (free radical generation), which contributes to neuronal death. Therefore, several efforts have been made to establish a sporadic AD model that takes into account these hypotheses. One model that replicates the increase in amyloid beta (Aß) and oxidative stress in vivo is the scopolamine model. In the present work, the chronic administration (6 weeks) of scopolamine was used to analyze the neuroprotective effects of apocynin and galantamine. The results showed that scopolamine induced cognitive impairment, which was evaluated 24 h after the final dose was administered. In addition, after scopolamine administration, the Aß and superoxide anion levels were increased, and NADPH oxidase 2 (NOX2), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa B (NFkB) genes were overexpressed. These effects were not observed when either apocynin or galantamine was administered during the last 3 weeks of scopolamine treatment, and although the results from both molecules were related to lower Aß production and, consequently, lower superoxide anion production, they were likely realized through different pathways. That is, both apocynin and galantamine diminished NADPH oxidase expression, but their effects on transcription factor expression differed. Moreover, experiments in silico showed that galantamine did not interact with the active site of beta secretase, whereas diapocynin, an apocynin metabolite, interacted with the beta-site APP-cleaving enzyme (BACE1) at the catalytic site.

Combining CDP-choline and galantamine: Effects of a selective α7 nicotinic acetylcholine receptor agonist strategy on P50 sensory gating of speech sounds in healthy volunteers.

BACKGROUND: Schizophrenia (SCZ) patients and relatives have deficits in early cortical sensory gating (SG) typically measured by suppression of electroencephalography-derived P50 event-related potentials (ERPs) in a conditioning-testing (S1-S2) paradigm. Associated with alpha 7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction and shown to be improved with nicotine and α7 nAChR agonists, SG has recently been shown to be improved in low P50 suppressing SCZ patients following acute CDP-choline treatment. AIMS: This pilot study in healthy humans assessed the SG effects of an α7 nAChR strategy combining CDP-choline with galantamine, a positive allosteric modulator (PAM) of nAChRs, aimed at increasing and prolonging nicotinic receptor activity. METHODS: The combined effect of CDP-choline (500 mg) and galantamine (16 mg) on speech P50 gating indices rP50 (S2/S1) and dP50 (S1-S2) was examined in 30 healthy participants stratified into low and high baseline P50 suppressors in a randomized, double-blind, placebo-controlled and counterbalanced design. RESULTS: In low suppressors, CDP-choline/galantamine (vs. placebo) improved rP50 and dP50 gating, and reduced S2P50 amplitudes. No P50 gating effects were observed in high suppressors; however, CDP-choline/galantamine (vs. placebo) increased their S2P50 amplitudes. CONCLUSION: Findings from this pilot study with CDP-choline/galantamine in a healthy, SCZ-like surrogate deficient gating sample are consistent with the association of α7 nAChR mechanisms in SG impairment in SCZ and support further research trials with CDP-choline and galantamine targeting sensory processes.

Chronic treatment with galantamine rescues reversal learning in an attentional set-shifting test after experimental brain trauma.

Approximately 10 million new cases of traumatic brain injury (TBI) are reported each year worldwide with many of these injuries resulting in higher order cognitive impairments. Galantamine (GAL), an acetylcholine esterase inhibitor (AChEI) and positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), has been reported to ameliorate cognitive deficits after clinical TBI. Previously, we demonstrated that controlled cortical impact (CCI) injury to rats resulted in significant executive function impairments as measured by the attentional set-shifting test (AST), a complex cognitive task analogous to the Wisconsin Card Sorting Test (WCST). We hypothesized that chronic administration of GAL would normalize performance on the AST post-TBI. Isoflurane-anesthetized adult male rats were subjected to moderate CCI (2.8 mm tissue deformation at 4 m/s) or sham injury. Rats were then randomized into one of three treatment groups (i.e., 1 mg/kg GAL, 2 mg/kg GAL, or 1 mL/kg saline vehicle; VEH) or their respective sham controls. GAL or VEH was administered intraperitoneally daily commencing 24 hours post-surgery and until AST testing at 4 weeks post-injury. The AST data revealed significant impairments in the first reversal stage after TBI, seen as increased trials to reach criterion and elevated total errors (p < 0.05). These behavioral flexibility deficits were equally normalized by the administration of both doses of GAL (p < 0.05). Additionally, the higher dose of GAL (2 mg/kg) also significantly reduced cortical lesion volume compared to TBI + VEH controls (p < 0.05). In summary, daily GAL administration provides an efficacious treatment for cognitive deficits and histological recovery after experimental brain trauma. Clinically, these findings are promising considering robust results were attained using a pharmacotherapy already used in the clinic to treat mild dementia.

Galantamine reversed early postoperative cognitive deficit via alleviating inflammation and enhancing synaptic transmission in mouse hippocampus.

Postoperative cognitive dysfunction (POCD) is commonly seen in patients undergoing major surgeries and may persist. Although neuroinflammation is one of the important contributors to the development of POCD, the mechanisms underlying POCD remain unclear. We performed stabilized tibial fracture operation in male mice. In comparison with sham mice (anesthesia only), the surgery mice exhibited cognitive deficits in a fear conditioning paradigm at postsurgery day 3-7, and increased numbers of microglia and elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) without change of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Electrophysiological recordings from CA1 hippocampal neurons revealed that POCD mice exhibited impairment in AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) without alteration in the rectification property of AMPA receptors. Interestingly, daily intraperitoneal administration of galantamine, an inhibitor of acetylcholinesterase, reversed cognitive dysfunction in surgery mice and attenuated accumulation of microglia and protein levels of IL-1ß, IL-6 and TNF-α in the hippocampus. Additionally, galantamine potentiated AMPA receptor-mediated eEPSCs in the hippocampus more prominent in surgery mice than in sham mice. Therefore, enhancement of cholinergic tone in the hippocampus might be a therapeutic strategy for early POCD in terms of suppression of inflammation and normalization of excitatory synaptic transmission.

Effects of galantamine on smoking behavior and cognitive performance in treatment-seeking smokers prior to a quit attempt.

OBJECTIVE: Drugs that enhance cholinergic transmission have demonstrated promise treating addictive disorders. Galantamine, an acetylcholinesterase inhibitor, may reduce cigarette smoking in otherwise healthy treatment-seeking smokers. METHODS: The current study is a double-blind, placebo-controlled, study that randomized daily smokers (n = 60) to receive one of two doses of galantamine extended release (8 or 16 mg/day), or a placebo treatment. Participants completed a smoking choice task as well as study measures and cognitive tasks in the laboratory and daily life using ecological momentary assessment. Analysis focused on smoking behavior and satisfaction, cognitive performance, and decision to smoke prior to a quit attempt. RESULTS: Linear mixed models demonstrated that, compared with placebo, both doses of galantamine reduced smoking in a laboratory choice task (p = 0.006) and decreased urine cotinine levels, but not self-reported cigarettes, during the pre-quit period (p = 0.007). Treatment had minimal effect on smoking satisfaction or cognitive performance. CONCLUSIONS: The results suggest that galantamine reduces nicotine intake but it is unlikely that galantamine improves cognitive performance in otherwise healthy, treatment-seeking smokers. Larger randomized clinical trials can determine if galantamine adjunctive to addiction treatment can improve smoking treatment outcomes.

Acetylcholinesterase Inhibitors: Beneficial Effects on Comorbidities in Patients With Alzheimer's Disease.

Elderly patients with Alzheimer's disease (AD) and other dementias are at high risk of polypharmacy and excessive polypharmacy for common coexisting medical conditions. Polypharmacy increases the risk of drug-drug and drug-disease interactions in these patients who may not be able to communicate early symptoms of adverse drug events. Three acetylcholinesterase inhibitors (ACHEIs) have been approved for AD: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). They are also used off-label for other causes of dementia such as Lewy body and vascular dementia. We here report evidence from the literature that ACHEI treatment, prescribed for cognitive impairment, can reduce the load of medications in patients with AD by also addressing cardiovascular, gastrointestinal, and other comorbidities. Using one drug to address multiple symptoms can reduce costs and improve medication compliance.

Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine.

BACKGROUND: Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for > 6 hours, but not 2 or 4 hours, which more accurately reflects the daily amount of clinical rehabilitation. The lack of benefit with sub-therapeutic EE suggests that augmentation with galantamine (GAL), which enhances cognition after TBI, may be indicated to confer benefits. OBJECTIVE: To test the hypothesis that 2 and 4 hours of EE paired with GAL will provide benefits comparable to 24 hours of EE alone. Moreover, all EE groups will perform better than the standard (STD)-housed GAL group. METHODS: Anesthetized rats received a TBI or sham injury and then were randomized to receive intraperitoneal injections of GAL (2 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 hours after surgery and once daily while receiving EE for 2, 4, or 24 hours. Motor and cognitive assessments were conducted on postoperative days 1-5 and 14-19, respectively. RESULTS: Motor function was significantly improved in the TBI + 24-hour EE group versus the TBI + STD + VEH and TBI + STD + GAL groups ( P < .05). Cognitive performance was enhanced in all EE groups as well as in the TBI + STD + GAL versus TBI + STD + VEH ( P < .05). Moreover, the 2- and 4-hour EE groups receiving GAL did not differ from the 24-hour EE group ( P > .05) and performed better than GAL alone ( P < .05). CONCLUSIONS: The findings support the hypothesis and have clinical relevance because, often, only brief rehabilitation may be available in the clinic and, thus, augmenting with a pharmacotherapy such as GAL may lead to outcomes that are significantly better than either therapy alone.

Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.

Effects of Acetylcholinesterase Inhibitors on Nutritional Status in Elderly Patients with Dementia: A 6-month Follow-up Study.

OBJECTIVES: Nutritional status is one of the factors that affects disease progression, morbidity and mortality in elderly patients with dementia. The present study aimed to evaluate the effect of acetylcholinesterase inhibitor (AchEI) therapy on nutritional status and food intake in the elderly. DESIGN, SETTING AND PARTICIPANTS: Newly diagnosed patients with dementia, who underwent comprehensive geriatric assessment (CGA) and were followed at regular intervals, were retrospectively evaluated. A total of 116 patients, who began to receive AchEI therapy and completed 6-month follow-up period under this treatment, were enrolled in the study. MEASUREMENTS: Socio-demographic characteristics and data on comorbidity, polypharmacy, cognitive function, depression, activities of daily living and nutritional status (weight, Body Mass Index (BMI), Mini Nutritional Assessment (MNA)-Short Form) were recorded. RESULTS: The mean age of the patients was 78.0±8.9 years. There was no significant difference between baseline and 6-month BMI, weight and MNA scores of dementia patients who received AchEI therapy (p>0.05). With regard to the relation between changes in BMI, weight and MNA on the 6th month versus baseline, and donepezil, rivastigmine and galantamine therapies, no difference was determined (p>0.05). However, no worsening in food intake was observed (kappa: 0.377). When the effects of each AchEI on food intake were compared, food intake in rivastigmine treated patients was not decreased as much as it was in galantamine or donepezil treated patients (p<0.05). CONCLUSION: AchEI therapy has no unfavorable effect on nutritional status or weight in elderly patients with different types of dementia, but it seems that food intake is better in those treated by rivastigmine patch.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats.

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

Synthesis of New Peptide Derivatives of Galanthamine Designed for Prevention and Treatment of Alzheimer's Disease.

New derivatives of galanthamine containing peptide fragments with ß-secretase inhibitor activity were synthesized. In position 6 of the galanthamine new shortened analogues of ß-secretase inhibitor OM 99-2 (Boc-Val-Asn-Leu-Ala-OH and Boc-Val-Asn-Leu-Ala-Val-OH) were included. The new derivatives of the galanthamine in position 11 including Boc and norgalanthamine in P3 or P4 positions, Val in P2' position and benzylamin in P3'-position were also synthesized. All new peptides were investigated on mice for acute toxicity. The test compounds were administered to mice via intraperitoneal (i.p.) route. They have low toxicity (LD50>1000 mg/kg) after i.p. The compound 11-N-demethyl-11-N-N-[Boc-Asp(Asp-Leu-Ala-Val-NH-Bzl)]-Galanthamine was investigated by two way active avoidance method. The compound has good influence on the conditioned reflexes, which improved the processes of learning and memory. Inhibition activity of newly synthesized compounds was monitored against BuChE and IC50 values are determined. All compounds show activity in micromolar concentration. Compounds 5 and 6 have around 10 times higher activity than galanthamine. Compounds 4 and 9 also show good activity. All newly synthesized compounds show low acute toxicity.

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease.

OBJECTIVE: Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. METHODS: In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. RESULTS: A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. CONCLUSION: FOXO1 may influence the clinical response to AChEIs in AD patients.