Search Results (142)

Systematic Alzheimer’s disease (AD) is a neurodegenerative disease increasingly prevalent in the aging population. AD is characterized by pathological features such as β-amyloid (Aβ) plaque accumulation, tau neurofibrillary tangles formation, oxidative stress, an impaired cholinergic system, and neuroinflammation. Many therapeutic drugs have been developed to slow the progression of AD by targeting these pathological mechanisms. However, synthetic drugs, such as donepezil and memantine, can often lead to side effects. In this context, seaweeds have been drawing attention as a nutrient source and a potential source of health-improving metabolites. Studies have shown that extracts from brown macroalgae can potentially reduce the inflammation associated with neurodegenerative diseases by inhibiting proinflammatory cytokine expression. Furthermore, their bioactive compounds exhibit antioxidant properties vital in combating oxidative stress. Antioxidants, mainly carotenoids and phenolic compounds, have been linked to improved cognitive function and a reduced risk of neurodegenerative disorders by protecting neuronal cells through their ability to scavenge free radicals. In addition, omega-3 fatty acids found in certain macroalgae have the potential to support brain health and cognitive function, further enhancing their neuroprotective effects. In conclusion, this review has comprehensively evaluated the research conducted on brown macroalgae in the last five years, covering their potential bioactive compounds, methods of obtaining these compounds, and their neuroprotective properties against AD. The limited number of clinical studies in the literature highlights the need for further research. This narrative review provides a basic framework for new approaches to neuroprotective strategies, such as those associated with brown macroalgae natural resources. Furthermore, they may play an increasingly important role in developing functional foods and nutraceuticals that can support human health in preventing and managing neurodegenerative diseases. Full article

Background: Deep brain stimulation (DBS) is employed to adjust the activity of impaired brain circuits. The variability in clinical trial outcomes for treating Alzheimer’s disease with memantine is not yet fully understood. We conducted a randomized in silico study comparing virtual DBS therapies with treatment involving an NMDA antagonist combined with DBS in patients with Alzheimer’s disease. Methods: Neural network models representing Alzheimer’s disease (AD) patients were randomly assigned to four groups: AD, memantine treatment, DBS, and DBS and memantine. Out of 100 unique neural networks created to model moderate and severe AD with varying hippocampal synaptic loss, 20 were randomly selected to represent AD patients. Virtual treatments—memantine, DBS, and DBS and memantine—were applied, resulting in a total of 80 simulations. Results: The normalized mean number of spikes in the CA1 region among the virtual AD hippocampi treated with memantine, DBS therapy, and DBS and memantine differed significantly (p < 0.0001). The normalized mean number of spikes in the virtual AD hippocampi was 0.33 (95% CI, 0.29–0.36) and was significantly lower compared to the number of spikes in the virtual AD hippocampi treated with memantine, which was 0.53 (95% CI, 0.48–0.59) (p = 0.0162), and in the DBS and memantine group, which was 0.67 (95% CI, 0.57–0.78) (p = 0.0001). Conclusions: Our simulation results indicate the effectiveness of virtual memantine and DBS therapy compared to memantine monotherapy for Alzheimer’s disease. Full article

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays an important role in transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations in the glutamatergic signaling pathway are now accepted as a central element in Alzheimer’s disease (AD) pathophysiology. One of the most prevalent types of dementia in older adults is AD, a progressive neurodegenerative illness brought on by a persistent decline in cognitive function. Since AD has been shown to be multifactorial, a variety of pharmaceutical targets may be used to treat the condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists and acetylcholinesterase inhibitors (AChEIs) are two drug classes that the Food and Drug Administration has authorized for the treatment of AD. The AChEIs approved to treat AD are galantamine, donepezil, and rivastigmine. However, memantine is the only non-competitive NMDAR antagonist that has been authorized for the treatment of AD. This review aims to outline the involvement of glutamate (GLU) at the molecular level and the signaling pathways that are associated with AD to demonstrate the drug target therapeutic potential of glutamate and its receptor. We will also consider the opinion of the leading authorities working in this area, the drawback of the existing therapeutic strategies, and the direction for the further investigation. Full article

Alzheimer’s disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson’s disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain. Due to its limited efficacy and side effect profile, rivastigmine is often not prescribed, leaving patients with no treatment options. PD has several derangements in neurotransmitter pathways (dopaminergic neurons in the nigrostriatal pathway, kynurenine pathway (KP), acetylcholine, α7 nicotinic receptor, and N-methyl-D-aspartate (NMDA) receptors) and rivastigmine is only partially effective as it only targets one pathway. Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, affects the pathophysiology of PDD in multiple ways. Both galantamine (α7 nicotinic receptor) and memantine (antagonist of the NMDA subtype of the glutamate receptor) are KYNA modulators. When used in combination, they target multiple pathways. While randomized controlled trials (RCTs) with each drug alone for PD have failed, the combination of galantamine and memantine has demonstrated a synergistic effect on cognitive enhancement in animal models. It has therapeutic potential that has not been adequately assessed, warranting future randomized controlled trials. In this review, we summarize the KYNA-centric model for PD pathophysiology and discuss how this treatment combination is promising in improving cognitive function in patients with PDD through its action on KYNA. Full article

Depression is a complex psychiatric disorder that has substantial implications for public health. The lateral habenula (LHb), a vital brain structure involved in mood regulation, and the N-methyl-D-aspartate receptor (NMDAR) within this structure are known to be associated with depressive behaviors. Recent research has identified transcription factor 7-like 2 (TCF7L2) as a crucial transcription factor in the Wnt signaling pathway, influencing diverse neuropsychiatric processes. In this study, we explore the role of TCF7L2 in the LHb and its effect on depressive-like behaviors in mice. By using behavioral tests, AAV-mediated gene knockdown or overexpression, and pharmacological interventions, we investigated the effects of alterations in TCF7L2 expression in the LHb. Our results indicate that TCF7L2 expression is reduced in neurons within the LHb of male ICR mice exposed to chronic mild stress (CMS), and neuron-specific knockdown of TCF7L2 in LHb neurons leads to notable antidepressant activity, as evidenced by reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). Conversely, the overexpression of TCF7L2 in LHb neurons induces depressive behaviors. Furthermore, the administration of the NMDAR agonist NMDA reversed the antidepressant activity of TCF7L2 knockdown, and the NMDAR antagonist memantine alleviated the depressive behaviors induced by TCF7L2 overexpression, indicating the involvement of NMDAR. These findings offer novel insights into the molecular mechanisms of depression, highlighting the potential of TCF7L2 as both a biomarker and a therapeutic target for depression. Exploring the relationship between TCF7L2 signaling and LHb function may lead to innovative therapeutic approaches for alleviating depressive symptoms. Full article

Neuropathic pain (NeP) is a complex and debilitating condition that impacts millions of people globally. Although various treatment options exist, their effectiveness is often limited, and they can be accompanied by significant side effects. In recent years, there has been increasing interest in targeting the N-methyl-D-aspartate receptor (NMDAR) as a potential therapeutic approach to alleviate different types of neuropathic pain. This narrative review aims to provide a comprehensive examination of NMDAR antagonists, specifically ketamine, memantine, methadone, amantadine, carbamazepine, valproic acid, phenytoin, dextromethorphan, riluzole, and levorphanol, in the management of NeP. By analyzing and summarizing current preclinical and clinical studies, this review seeks to evaluate the efficacy of these pharmacologic agents in providing adequate relief for NeP. Full article

Background and Objectives: Alzheimer’s disease is a global health concern, with a rising prevalence among the elderly. Current pharmacological treatments, including acetylcholinesterase inhibitors (AChEIs) and N-Methyl D-Aspartate (NMDA) receptor antagonists, are associated with adverse events (AEs), particularly in the context of polypharmacy. This study aimed to investigate the relationship between Alzheimer’s disease treatment combinations, the number of concomitant medications, and the occurrence of AEs. Materials and Methods: Data from the Japanese Adverse Drug Event Report database, spanning from April 2004 to June 2020, were analyzed. Patients aged 60 and older with Alzheimer’s disease treated with AChEIs (donepezil, galantamine, and rivastigmine) or the NMDA receptor antagonist memantine were included. Logistic regression models were employed to assess the association between AEs and Alzheimer’s disease drug combinations, as well as the number of concomitant medications. Results: Among 2653 patients, 47.7% were prescribed five or more drugs. The frequency of AEs was 6.4% for bradycardia, 4.6% for pneumonia, 3.6% for altered state of consciousness, 3.5% for seizures, 3.5% for decreased appetite, 3.5% for vomiting, 3.4% for loss of consciousness, 3.4% for fracture, 3.2% for cardiac failure, and 3.0% for falls. The combination of memantine with AChEIs was associated with a higher risk of bradycardia, whereas donepezil alone was linked to a reduced risk of fractures and falls. Polypharmacy was significantly correlated with an increased incidence of AEs, particularly altered state of consciousness, decreased appetite, vomiting, and falls. The adjusted odds ratios for using five or more drugs compared to no drugs was 10.45 for altered state of consciousness, 7.92 for decreased appetite, 4.74 for vomiting, and 5.95 for falls. Conclusions: In the treatment of Alzheimer’s disease, the occurrence of AEs is associated with the number of concurrent medications, independently of the known AEs of Alzheimer’s disease drugs and their combination patterns. Full article

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a “triple-drug therapy” in treating Alzheimer’s disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aβ) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer’s disease treatment and nose-to-brain delivery. Full article

Glaucoma is a major global health concern and the leading cause of irreversible blindness worldwide, characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons. This review focuses on the need for neuroprotective strategies in glaucoma management, addressing the limitations of current treatments that primarily target intraocular pressure (IOP) reduction. Despite effective IOP management, many patients continue to experience RGC degeneration, leading to irreversible blindness. This review provides an overview of both pharmacological interventions and emerging technologies aimed at directly protecting RGCs and the optic nerve, independent of IOP reduction. Pharmacological agents such as brimonidine, neurotrophic factors, memantine, Ginkgo biloba extract, citicoline, nicotinamide, insulin, and resveratrol show promise in preclinical and early clinical studies for their neuroprotective properties. Emerging technologies, including stem cell therapy, gene therapy, mitochondrial-targeted therapies, and nanotechnologies, offer innovative approaches for neuroprotection and regeneration of damaged RGCs. While these interventions hold significant potential, further research and clinical trials are necessary to confirm their efficacy and establish their role in clinical practice. This review highlights the multifaceted nature of neuroprotection in glaucoma, aiming to guide future research and clinical practice toward more effective management of glaucoma-induced neurodegeneration. Full article

Background: Potentially inappropriate medication prescribing is prevalent and well studied in older adults. However, limited data are available on inappropriate drug dosing in those with dementia or cognitive impairment and renal impairment. Objectives: We aimed to examine the prevalence of, and factors associated with, inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment. Methods: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the Cochrane Handbook for Systematic Reviews of Interventions. We searched Medline, Embase, CINAHL, and PubMed for studies on inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment, published from 1 January 2000 to 31 August 2024, with English language restriction following the PICOS search strategy. Two reviewers independently screened all titles and abstracts, extracted data from included studies, and undertook quality assessment using the Joanna Briggs Institute (JBI) tool. Descriptive statistics were used to summarise and present findings. Results: In total, eight retrospective cohort studies were included. Of the total number of patients with dementia who had renal impairment (n = 5250), there were 2695 patients (51.3%; range: 0–60%) who had inappropriate drug dosing. Drugs commonly prescribed in inappropriate doses in patients with dementia who had renal impairment included memantine, baclofen, nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, digoxin, morphine, and allopurinol. The studies did not identify statistically significant risk factors for inappropriate drug dosing. Conclusions: Inappropriate drug dosing among older adults with dementia or cognitive impairment and renal impairment appears to occur frequently. While our findings should be interpreted with caution owing to the small number of studies and substantial heterogeneity, proactive prevention, recognition, and management of inappropriate drug dosing in this population is warranted. Full article

Memantine, a non-competitive NMDA receptor antagonist, is used to treat Alzheimer’s disease. Therefore, loading memantine in nanoparticles (NPs) could be an essential tool to improve the treatment effectiveness while reducing drug toxicity. Even though some approaches have been described to quantify memantine, none reported optimized methods using high-performance liquid chromatography resorting to ultraviolet detection (UV–HPLC) to determine encapsulation in NPs. The present research developed a HPLC method using pre-column derivatization for quantitatively analyzing memantine hydrochloride in NPs. Memantine was derivatized using 9-fluorenylmethyl chloroformate (FMOC). The developed method was fully validated regarding suitability, specificity, linearity, sensitivity, precision, accuracy, and robustness according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The retention time of memantine was 11.393 ± 0.003 min, with a mean recovery of 92.9 ± 3.7%. The new chromatographic method was validated and found to respond linearly over 5–140 μg/mL, with a high coefficient of determination. Intraday precision lay between 3.6% and 4.6%, and interday precision between 4.2% and 9.3%. The stability of memantine was also tested at 4 °C and −20 °C, and no signs of decay were found for up to 6 months. The new method was properly validated and proved simple, sensitive, specific, accurate, and precise for determining memantine encapsulation efficiency in lipid NPs. Greenness was evaluated, presenting a final score of 0.45. In the future, this methodology could also be applied to quantify memantine in different nanoformulations. Full article

Cytoprotective and neurotoxic kynurenines formed along the kynurenine pathway (KP) were identified as possible therapeutic targets in various neuropsychiatric conditions. Memantine, an adamantane derivative modulating dopamine-, noradrenaline-, serotonin-, and glutamate-mediated neurotransmission is currently considered for therapy in dementia, psychiatric disorders, migraines, or ischemia. Previous studies have revealed that memantine potently stimulates the synthesis of neuroprotective kynurenic acid (KYNA) in vitro via a protein kinase A-dependent mechanism. Here, the effects of acute and prolonged administration of memantine on brain kynurenines and the functional changes in the cerebral KP were assessed in rats using chromatographic and enzymatic methods. Five-day but not single treatment with memantine selectively activated the cortical KP towards neuroprotective KYNA. KYNA increases were accompanied by a moderate decrease in cortical tryptophan (TRP) and L-kynurenine (L-KYN) concentrations without changes in 3-hydroxykynurenine (3-HK) levels. Enzymatic studies revealed that the activity of cortical KYNA biosynthetic enzymes ex vivo was stimulated after prolonged administration of memantine. As memantine does not directly stimulate the activity of KATs’ proteins, the higher activity of KATs most probably results from the increased expression of the respective genes. Noteworthy, the concentrations of KYNA, 3-HK, TRP, and L-KYN in the striatum, hippocampus, and cerebellum were not affected. Selective cortical increase in KYNA seems to represent one of the mechanisms underlying the clinical efficacy of memantine. It is tempting to hypothesize that a combination of memantine and drugs could strongly boost cortical KYNA and provide a more effective option for treating cortical pathologies at early stages. Further studies should evaluate this issue in experimental animal models and under clinical scenarios. Full article

Arguably, the most important parameter in treating cognitive decline associated with Alzheimer’s disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy, resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvements in patients with cognitive decline, but long-term follow-up (>5 years) has not been reported previously. Therefore, here, we report sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols. Full article

Addressing the dysfunctions of all brain cell types in Alzheimer’s disease (AD) should cure the dementia, an objective that might be achieved by GLP-1 agonist drugs, because receptors for GLP-1 are present in all of the main brain cell types, i.e., neurons, oligodendroglia, astroglia, microglia, endothelial cells and pericytes. This article describes the benefits provided to all of those brain cell types by GLP-1 agonist drugs. The article uses studies in humans, not rodents, to describe the effect of GLP-1 agonists upon cognition, because rodents’ brains differ from those of humans in so many ways that results from rodent studies may not be totally transferable to humans. Commercially available GLP-1 agonists have mostly shown either positive effects upon cognition or no effects. One important reason for no effects is a reduced rate of entering brain parenchyma. Dulaglutide has the greatest entry to brain, at 61.8%, among the available GLP-1 agonists, and seems to offer the best likelihood for cure of AD. Although there is only one study of cognition that used dulaglutide, it was randomized, placebo controlled, and very large; it involved 8828 participants and showed significant benefit to cognition. A clinical trial to test the hypothesis that dulaglutide may cure AD should have, as its primary outcome, a 30% greater cure rate of AD by dulaglutide than that achieved by an equipoise arm of, e.g., lithium plus memantine. Full article