AChE inhibitory activity of N-substituted natural galanthamine derivatives.

Galanthamine derivatives are known for their AChE inhibitory activity. Among them, galanthamine has been approved for treatment of Alzheimer's disease. N-Acetylnorgalanthamine (narcisine) and N-(2'-methyl)allylnorgalanthamine (the most potent natural AChE inhibitor of galanthamine type) were synthetized using N-norgalanthamine as a precursor. The NMR data described previously for narcisine were revised by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. AChE inhibitory assays showed that N-acetylnorgalanthamine and N-formylnorgalanthamine (with previously unknown activity) are 4- and 43-times, respectively, less potent than galanthamine. In vitro (AChE inhibitory) and in silico (docking, ADME) assays and comparison of N-(2'-methyl)allylnorgalanthamine with galanthamine prove that this molecule is a very promising natural AChE inhibitor (33-times more potent than galanthamine) which further in vivo studies would provide better estimation about its applicability as a drug.

Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.

Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

Innovative assessment of lipid-induced oxidative stress and inflammation in harvested human endothelial cells.

Studying acute changes in vascular endothelial cells in humans is challenging. We studied ten African American women and used the J-wire technique to isolate vein endothelial cells before and after a four-hour lipid and heparin infusion. Dynamic changes in lipid-induced oxidative stress and inflammatory markers were measured with fluorescence-activated cell sorting. We used the surface markers CD31 and CD144 to identify human endothelial cells. Peripheral blood mononuclear cells isolated from blood were used as a negative control. The participants received galantamine (16 mg/day) for 3 months. We previously demonstrated that galantamine treatment effectively suppresses lipid-induced oxidative stress and inflammation. In this study, we infused lipids to evaluate its potential to increase the activation of endothelial cells, as assessed by the levels of CD54+ endothelial cells and expression of Growth arrest-specific 6 compared to the baseline sample. Further, we aimed to investigate whether lipid infusion led to increased expression of the oxidative stress markers IsoLGs and nitrotyrosine in endothelial cells. This approach will expedite the in vivo identification of novel pathways linked with endothelial cell dysfunction induced by oxidative stress and inflammatory cytokines. This study describes an innovative method to harvest and study human endothelial cells and demonstrates the dynamic changes in oxidative stress and inflammatory markers release induced by lipid infusion.

Distinct fungal communities affecting opposite galanthamine accumulation patterns in two Lycoris species.

Lycoris radiata is the main source of galanthamine, a clinical drug used in Alzheimer's disease; however, the galanthamine content in L. radiata is low. Lycoris aurea is another Lycoris species with high galanthamine content. Fungal endophytes can enhance plant secondary metabolite accumulation; thus, we compared the fungal communities in these two Lycoris species to identify certain fungal taxa in L. aurea capable of enhancing galanthamine accumulation. Several fungal endophytes, which were enriched in, exclusively isolated from L. aurea, or showed significant correlations with galanthamine, were demonstrated to enhance the accumulation of only galanthamine but no other Amaryllidaceae alkaloids (AAs) in L. radiata. These fungal endophytes mainly upregulated the downstream genes in the biosynthesis pathways of AAs in L. radiata, suggesting that they may allocate more precursors for galanthamine biosynthesis. This study demonstrated that fungal endophytes from L. aurea with higher galanthamine content can specifically enhance the accumulation of this medicinal alkaloid in other Lycoris species, thereby increasing the galanthamine source and reducing galanthamine separation and purification costs. This study broadens our understanding of the complex interactions between plant secondary metabolites and fungal endophytes.

The protective effect of Astaxanthin on scopolamine - induced Alzheimer's model in mice.

OBJECTIVES: To investigate the fundamental mechanisms of the neuroprotective impact of Astaxanthin (AST) in a mouse model of Alzheimer's disease (AD) induced by scopolamine. METHODS: This research constituted an in vivo animal study encompassing 36 adult male mice, divided into 6 groups: Control, 100 mg/kg AST, 2 mg/kg scopolamine (AD group), 100 mg/kg AST+2 mg/kg scopolamine, 3 mg/kg galantamine+2 mg/kg scopolamine, and 100 mg/kg AST+3 mg/kg galantamine+2 mg/kg scopolamine. After 14 days, the mice's short-term memory, hippocampus tissue, oxidative and inflammatory markers were evaluated. RESULTS: The AST demonstrated a beneficial influence on short-term memory and a reduction in acetylcholinesterase activity in the brain. It exhibited neuroprotective and anti-amyloidogenic properties, significantly decreased pro-inflammatory markers and oxidative stress, and reversed the decline of the Akt-1 and phosphorylated Akt pathway, a crucial regulator of abnormal tau. Furthermore, AST enhanced the effect of galantamine in reducing inflammation and oxidative stress. CONCLUSION: The findings indicate that AST may offer therapeutic benefits against cognitive dysfunction in AD. This is attributed to its ability to reduce oxidative stress, control neuroinflammation, and enhance Akt-1 and pAkt levels, thereby underscoring its potential in AD treatment strategies.

Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

Synthesis and molecular docking studies of 5-trifluoromethoxy-2-indolinones as cholinesterase dual inhibitors.

Background: In Alzheimer's disease, butyrylcholinesterase (BuChE) activity gradually increases, while acetylcholinesterase (AChE) activity decreases or remains unchanged. Dual inhibitors have important roles in regulation of synaptic acetylcholine levels and progression of Alzheimer's disease. Methods: 1-(Thiomorpholin-4-ylmethyl)/benzyl-5-trifluoromethoxy-2-indolinones (6-7) were synthesized. AChE and BuChE inhibitory effects were investigated with Ellman's method. Molecular docking studies were performed for analyzing the possible binding interactions at active sites. Results: Compound 6g was the strongest inhibitor against both AChE (Ki = 0.35 µM) and BuChE (Ki = 0.53 µM). It showed higher inhibitory effects than both donepezil and galantamine. Moreover, compound 7m had a higher inhibitory effect than galantamine and the effect was comparable to that of donepezil against both AChE (Ki = 0.69 µM) and BuChE (Ki = 0.95 µM). Conclusion: The benzyl substitution compared with 1-(thiomorpholin-4-ylmethyl) group significantly increased both AChE and BuChE inhibitory effects.

Recent advances in the total synthesis of galantamine, a natural medicine for Alzheimer's disease.

Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.

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.

Metabolite profiling and histochemical localization of alkaloids in Hippeastrum papilio (Ravena) van Scheepen.

Hippeastrum papilio (Amaryllidaceae) is a promising new source of galanthamine - an alkaloid used for the cognitive treatment of Alzheimer's disease. The biosynthesis and accumulation of alkaloids are tissue - and organ-specific. In the present study, histochemical localization of alkaloids in H. papilio's plant organs with Dragendorff's reagent, revealed their presence in all studied samples. Alkaloids were observed in vascular bundles, vacuoles, and intracellular spaces, while in other plant tissues and structures depended on the plant organ. The leaf parenchyma and the vascular bundles were indicated as alkaloid-rich structures which together with the high proportion of alkaloids in the phloem sap (49.3% of the Total Ion Current - TIC, measured by GC-MS) indicates the green tissues as a possible site of galanthamine biosynthesis. The bulbs and roots showed higher alkaloid content compared to the leaf parts. The highest alkaloid content was found in the inner bulb part. GC-MS metabolite profiling of H. papilio's root, bulb, and leaves revealed about 82 metabolites (>0.01% of TIC) in the apolar, polar, and phenolic acid fractions, including organic acids, fatty acids, sterols, sugars, amino acids, free phenolic acids, and conjugated phenolic acids. The most of organic and fatty acids were in the peak part of the root, while the outermost leaf was enriched with sterols. The outer and middle parts of the bulb had the highest amount of saccharides, while the peak part of the middle leaf had most of the amino acids, free and conjugated phenolic acids.

Accuracy of Labeling of Galantamine Generic Drugs and Dietary Supplements.

This study examines the accuracy of labeling for galantamine products formulated as both generic drugs and dietary supplements, as well as tests for contamination with microorganisms.

Galantamine mitigates neurotoxicity caused by doxorubicin via reduced neuroinflammation, oxidative stress, and apoptosis in rat model.

OBJECTIVE: Doxorubicin (DXR) is commonly used as a drug for cancer treatment. However, there have been reports of neurotoxicity associated with chemotherapy. Galantamine (GLN) is a medication that inhibits cholinesterase activity, providing relief from the neurotoxic effects commonly seen in individuals with Alzheimer's disease. This study explored the potential ameliorative effect of GLN on brain neurotoxicity induced by DXR. MATERIALS AND METHODS: Forty rats were allocated into four separate groups for a study that lasted for a period of fourteen days. The control group was given normal saline, DXR group was given 5 mg/kg DXR every three days (cumulative dose of 20 mg/kg) through intraperitoneal injection. The GLN group was given 5 mg/kg GLN through oral gavage daily, while the DXR+GLN group was given DXR+GLN simultaneously. An analysis of brain proteins using ELISA to assess apoptosis through the concentration of inflammation and oxidative injury markers. RESULTS: The DXR treatment led to increased neuroinflammation by elevation of nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2), oxidative stress by rise of malondialdehyde (MDA), and decline of superoxide dismutase (SOD), and no changes in catalase and glutathione (GSH), cell death by elevation of Bax and caspase-3 and reduced Bcl-2, and increase lipid peroxidation, impaired mitochondrial function. When GLN is administered alongside DXR, it has been observed to positively impact various biological markers, including COX-2, NF-κB, MDA, SOD, Bax, Bcl-2, and caspase-3 levels. Additionally, GLN improves lipid peroxidation and mitochondrial activity. CONCLUSIONS: DXR therapy in rats results in the development of neurotoxicity, and a combination of GLN can recover these toxicities, suggesting GLN promising evidence for mitigating the neurotoxic effects induced by DXR.

The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice.

BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice. MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration. RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101). CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.

Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study.

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.

The effects of different acetylcholinesterase inhibitors on EEG patterns in patients with Alzheimer's disease: A systematic review.

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The early diagnosis of AD is an important factor for the control of AD progression. Electroencephalography (EEG) can be used for early diagnosis of AD. Acetylcholinesterase inhibitors (AChEIs) are also used for the amelioration of AD symptoms. In this systematic review, we reviewed the effect of different AChEIs including donepezil, rivastigmine, tacrine, physostigmine, and galantamine on EEG patterns in patients with AD. METHODS: PubMed electronic database was searched and 122 articles were found. After removal of unrelated articles, 24 articles were selected for the present study. RESULTS: AChEIs can decrease beta, theta, and delta frequency bands in patients with AD. However, conflicting results were found for alpha band. Some studies have shown increased alpha frequency, while others have shown decreased alpha frequency following treatment with AChEIs. The only difference was the type of drug. CONCLUSIONS: We found that studies reporting the decreased alpha frequency used donepezil and galantamine, while studies reporting the increased alpha frequency used rivastigmine and tacrine. It was suggested that future studies should focus on the effect of different AChEIs on EEG bands, especially alpha frequency in patients with AD, to compare their effects and find the reason for their different influence on EEG patterns. Also, differences between the effects of AChEIs on oligodendrocyte differentiation and myelination may be another important factor. This is the first article investigating the effect of different AChEIs on EEG patterns in patients with AD.

Galantamine mitigates testicular injury and disturbed spermatogenesis in adjuvant arthritic rats via modulating apoptosis, inflammatory signals, and IL-6/JAK/STAT3/SOCS3 signaling.

Rheumatoid arthritis (RA) affects the joints and the endocrine system via persistent immune system activation. RA patients have a higher frequency of testicular dysfunction, impotence, and decreased libido. This investigation aimed to evaluate the efficacy of galantamine (GAL) on testicular injury secondary to RA. Rats were allocated into four groups: control, GAL (2 mg/kg/day, p.o), CFA (0.3 mg/kg, s.c), and CFA + GAL. Testicular injury indicators, such as testosterone level, sperm count, and gonadosomatic index, were evaluated. Inflammatory indicators, such as interleukin-6 (IL-6), p-Nuclear factor kappa B (NF-κB p65), and anti-inflammatory cytokine interleukin-10 (IL-10), were assessed. Cleaved caspase-3 expression was immunohistochemically investigated. Protein expressions of Janus kinase (JAK), signal transducers and activators of transcription (STAT3), and Suppressors of Cytokine Signaling 3 (SOCS3) were examined by Western blot analysis. Results show that serum testosterone, sperm count, and gonadosomatic index were increased significantly by GAL. Additionally, GAL significantly diminished testicular IL-6 while improved IL-10 expression relative to CFA group. Furthermore, GAL attenuated testicular histopathological abnormalities by CFA and downregulated cleaved caspase-3 and NF-κB p65 expressions. It also downregulated JAK/STAT3 cascade with SOCS3 upregulation. In conclusion, GAL has potential protective effects on testicular damage secondary to RA via counteracting testicular inflammation, apoptosis, and inhibiting IL-6/JAK/STAT3/SOCS3 signaling.

Galantamine ameliorates experimental pancreatitis.

BACKGROUND: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. METHODS: The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. RESULTS: Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. CONCLUSION: Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.

Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. OBJECTIVE: To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. METHODS: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. RESULTS: Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. CONCLUSION: In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.