Search Results (153)

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disease which has a rather complex pathophysiology. During its course, several neurotransmitter neuronal systems get affected such as acetylcholinergic, glutamatergic, gamma-aminobutyric acid (GABA)ergic systems, etc. Such complex physiology requires a sophisticated approach to pharmaceutical management. Therefore, multi-target drugs seem to be an appealing solution. In the present study, we designed and synthesized a hybrid molecule—N-sinapoylamide of memantine, whose parent molecules memantine (MEM) and sinapic acid have been shown in vivo to impact glutamatergic, acetylcholinergic, and GABA-ergic systems, respectively. In silico comparative testing of these molecules was performed, their patterns of interaction with the target enzymes or molecular complexes were analyzed, and some of the mechanisms of action were proposed. Consequently, in vivo testing was performed on a scopolamine mice model of AD and the results overly confirm part of the in silico findings. Therefore, the hybrid molecule (N-Sinapoyl-memantine) seems to be a potent candidate for further evaluation in the management of AD. Full article

We tried to synthesize the possibilities of predicting the response to clozapine treatment, which can significantly improve the efficacy of the active substance and reduce adverse reactions, and how the active substance acts at the D1 dopaminergic receptors D2, D3, D4, and D5, muscarinic M1, M2, M3, and M5, and the histamine and alpha 1 adrenergic receptor, as well as how it contributes to increased cerebral blood flow, the effect on ribosomal protein S6 function, or the effect on kynurenine 3-monooxygenase function. Clozapine is one of the most effective antipsychotics, and there is potential to improve performance by combining it with different compounds to limit adverse effects or by augmenting it with other antipsychotics (amisulpride, paliperidone), other active substances with different properties (minocycline, N-acetylcysteine, memantine), or alternative therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation). There are also significant steps in optimizing clozapine efficacy by predicting treatment response, which could be determined by testing the following: plasma levels of clozapine N-oxide and N-desmethylclozapine, serum levels of neurotrophins and glutamate, genetic testing, the polygenic risk score, morphometry, or even the identification and accurate determination of persistent negative symptoms. Full article

Background and Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative condition that significantly affects cognitive, emotional, and functional abilities in older adults. This study aimed to explore how demographic, clinical, and psychological factors influence the progression of cognitive decline in patients diagnosed with AD. Materials and Methods: A total of 101 patients were evaluated retrospectively and followed longitudinally at three different time points, using standardized instruments, including the MMSE, Reisberg’s GDS, clock-drawing test, MADRS, and Hamilton depression scale. Statistical methods included non-parametric tests, mixed-effect modeling, and Bayesian analysis. Results: Most patients were older women from rural areas, predominantly in moderate-to-severe stages of AD. Age showed a significant association with cognitive decline (p < 0.05), and depression—particularly in moderate and severe forms—was strongly linked to lower MMSE scores (p < 0.001). Over 70% of the participants had some degree of depression. The clock-drawing test highlighted visuospatial impairments, consistent with everyday functional loss. Although donepezil and memantine combinations appeared to be more frequently prescribed, no treatment showed a statistically significant advantage, and confidence interval overlaps suggest caution in interpreting differences between therapies. Longitudinal models confirmed a progressive and accelerated decline, with inter-individual variability becoming more pronounced in later stages. Although comorbidities, such as hypertension and diabetes, were frequent, they did not show a statistically significant effect on MMSE scores in this cohort. Conclusions: Age and depression appear to play central roles in the pace of cognitive deterioration in AD. Given the limited efficacy of most current therapies, these findings highlight the need for earlier intervention and a more personalized, integrated approach—combining cognitive care, psychiatric support, and comorbidity management—to better meet the needs of patients with AD. Full article

Introduction—Aim: Agitation and aggression are common symptoms in people with Alzheimer’s disease and other dementias. This systematic review outlines the current evidence for the effect of antidementia treatments on agitation and aggression in patients with Alzheimer’s disease. Methods: The literature search was performed by manually checking articles published since 2000 in the following databases: PubMed, ResearchGate, and Google Scholar, following the PRISMA guidelines. Results: Nineteen double blinded placebo-controlled trials were included. Treatment with galantamine seems to provide more credible evidence for treating or preventing agitation/aggression. Studies on memantine often presented with an improvement of the neuropsychiatric inventory but not specifically on agitation/aggression. The trials on donepezil and rivastigmine either did not include enough information on agitation/aggression or did not provide compelling results. The incidence of agitation as an adverse event was not higher in antidementia treatments compared to placebo. Conclusions: Agitation and aggression are common symptoms of Alzheimer’s disease and have a significant impact on the patient, caregiver, and the broader healthcare system. The current literature lacks robust evidence on which of the antidementia treatments could be used to manage or prevent agitation and aggression in Alzheimer’s disease. In most included studies, no specific scores that assess those symptoms were used. Future research that specifically focuses on different disease phenotypes and behavioral profiles to enhance and facilitate the management of these symptoms is needed. Full article

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico. Full article

Background: Neuroenhancement in sports, through pharmacological and non-pharmacological methods, is a complex and highly debated topic with no definitive regulatory framework established by the World Anti-Doping Agency (WADA). The hypothesis that dermatological changes could serve as observable biomarkers for neurodoping introduces a novel and promising approach to detecting and understanding the physiological impacts of cognitive enhancers in athletes. As neurodoping methods become increasingly sophisticated, developing objective, reliable, and non-invasive detection strategies is imperative. Utilizing dermatological signs as a diagnostic tool for internal neurophysiological changes could offer critical insights into the safety, fairness, and ethical considerations of cognitive enhancement in competitive sports. A systematic correlation between skin manifestations, the timeline of neurodoping practices, and the intensity of cognitive enhancement methods could provide healthcare professionals valuable tools for monitoring athletes’ health and ensuring strict compliance with anti-doping regulations. Methods: Due to the limited body of research on this topic, a systematic review of the literature was conducted, spanning from 2010 to 31 December 2024, using databases such as PubMed, Science Direct, and Google Scholar. This study followed the 2020 PRISMA guidelines and included English-language articles published within the specified period, focusing on skin lesions as adverse reactions to pharmacological and non-pharmacological neuroenhancement methods. The research employed targeted keywords, including “skin lesions AND rivastigmine”, “skin lesions AND galantamine”, “skin lesions AND donepezil”, “skin lesions AND memantine”, and “skin lesions AND transcranial direct electrical stimulation”. Given the scarcity of studies directly addressing neurodoping in sports, the search criteria were broadened to include skin reactions associated with cognitive enhancers and brain stimulation. Eighteen relevant articles were identified and analyzed. Results: The review identified rivastigmine patches as the most used pharmacological method for neuroenhancement, with pruritic (itchy) skin lesions as a frequent adverse effect. Donepezil was associated with fewer and primarily non-pruritic skin reactions. Among non-pharmacological methods, transcranial direct current stimulation (tDCS) was notably linked to skin burns, primarily due to inadequate electrode–skin contact, prolonged exposure, or excessive current intensity. These findings suggest that specific dermatological manifestations could serve as potential indicators of neurodoping practices in athletes. Conclusions: Although specific neuroenhancement methods demonstrate distinctive dermatological side effects that might signal neurodoping, the current lack of robust clinical data involving athletes limits the ability to draw definitive conclusions. Athletes who engage in neurodoping without medical supervision are at an elevated risk of adverse dermatological and systemic reactions. Skin lesions, therefore, could represent a valuable early diagnostic marker for the inappropriate use or overuse of cognitive-enhancing drugs or neuromodulation therapies. The findings emphasize the need for focused clinical research to establish validated dermatological criteria for detecting neurodoping. This research could contribute significantly to the ongoing neuroethical discourse regarding the legitimacy and safety of cognitive enhancement in sports. Full article

Background/Objectives: Over the past 25 years, numerous biological molecules, like recombinant lysosomal enzymes, neurotrophins, receptors, and therapeutic antibodies, have been tested in clinical trials for neurological diseases. However, achieving significant success in clinical applications has remained elusive. A primary challenge has been the inability of these molecules to traverse the blood–brain barrier (BBB). Recognizing this hurdle, our study aimed to utilize niosomes as delivery vehicles, leveraging the “molecular Trojan horse” technology, to enhance the transport of molecules across the BBB. Methods: Previously synthesized memantine derivatives (MP1–4) were encapsulated into niosomes for improved BBB permeability, hypothesizing that this approach could minimize peripheral drug toxicity while ensuring targeted brain delivery. Using the human neuroblastoma (SH-SY5Y) cell line differentiated into neuron-like structures with retinoic acid and then exposed to amyloid beta 1–42 peptide, we established an in vitro Alzheimer’s disease (AD) model. In this model, the potential usability of MP1–4 was assessed through viability tests (MTT) and toxicological response analysis. The niosomes’ particle size and morphological structures were characterized using scanning electron microscopy (SEM), with their loading and release capacities determined via UV spectroscopy. Crucially, the ability of the niosomes to cross the BBB and their potential anti-Alzheimer efficacy were analyzed in an in vitro transwell system with endothelial cells. Results: The niosomal formulations demonstrated effective drug encapsulation (encapsulation efficiency: 85.3% ± 2.7%), controlled release (72 h release: 38.5% ± 1.2%), and stable morphology (PDI: 0.22 ± 0.03, zeta potential: −31.4 ± 1.5 mV). Among the derivatives, MP1, MP2, and MP4 exhibited significant neuroprotective effects, enhancing cell viability by approximately 40% (p < 0.05) in the presence of Aβ1-42 at a concentration of 47 µg/mL. The niosomal delivery system improved BBB permeability by 2.5-fold compared to free drug derivatives, as confirmed using an in vitro bEnd.3 cell model. Conclusions: Memantine-loaded niosomes provide a promising platform for overcoming BBB limitations and enhancing the therapeutic efficacy of Alzheimer’s disease treatments. This study highlights the potential of nanotechnology-based delivery systems in developing targeted therapies for neurodegenerative diseases. Further in vivo studies are warranted to validate these findings and explore clinical applications. Full article

Aging and age-related neurodegenerative disorders are characterized by the dysfunction or loss of brain nicotinic acetylcholine receptors (nAChRs), and these changes may be related to other senescence markers, such as oxidative stress and DNA repair dysfunction. However, the mechanism of nAChR loss in the aging brain and the modification of this process by drugs (e.g., memantine, Mem) are not yet fully understood. To study whether the differences in nAChR expression in the rat brain occur due to aging or oxidative stress and are modulated by Mem, we analyzed nAChR subunits (at RNA and protein levels) and other biomarkers by real-time quantitative polymerase chain reaction (RQ-PCR) and Western blot validation. Twenty-one female Wistar rats were divided into four groups, depending on age, and the oldest group received injections of Mem or water with the use of intragastric catheters. We studied the cerebral grey matter (CGM), subcortical white matter (SCWM), and cerebellum (Ce). Results showed an age-related decrease of α7 nAChR mRNA level in SCWM. The α7 nAChR mRNA loss was accompanied by reduced expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and an increased tumor necrosis factor alpha (TNFα) level. In the water group, we observed a higher level of α7 nAChR protein in the SCWM and Ce. Biomarker levels changed, but to a different extent depending on the brain area. Importantly, the dysfunction in antioxidative status was stopped and even regressed under Mem treatment. After two weeks of treatment, an increase in TP53 protein level and a decrease in 8-oxo-2′deoxyguanosine (8-oxo-2′dG) level were observed. We conclude that Mem administration may be protective against the senescence process by antioxidative mechanisms. Full article

Alzheimer’s and Parkinson’s are the most common neurodegenerative diseases (NDDs). The development of aberrant protein aggregates and the progressive and permanent loss of neurons are the major characteristic features of these disorders. Although the precise mechanisms causing Alzheimer’s disease (AD) and Parkinson’s disease (PD) are still unknown, there is a wealth of evidence suggesting that misfolded proteins, accumulation of misfolded proteins, dysfunction of neuroreceptors and mitochondria, dysregulation of enzymes, and the release of neurotransmitters significantly influence the pathophysiology of these diseases. There is no effective protective medicine or therapy available even with the availability of numerous medications. There is an urgent need to create new and powerful bioactive compounds since the number of people with NDDs is rising globally. Heterocyclic compounds have consistently played a pivotal role in drug discovery due to their exceptional pharmaceutical properties. Many clinically approved drugs, such as galantamine hydrobromide, donepezil hydrochloride, memantine hydrochloride, and opicapone, feature heterocyclic cores. As these heterocyclic compounds have exceptional therapeutic potential, heterocycles are an intriguing research topic for the development of new effective therapeutic drugs for PD and AD. This review aims to provide current insights into the development and potential use of heterocyclic compounds targeting diverse therapeutic targets to manage and potentially treat patients with AD and PD. Full article

Alzheimer’s disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer’s disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions. Full article

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