The emergence of advanced systemic therapies added to the use of cranial radiation techniques has significantly improved outcomes for cancer patients with multiple brain metastases (BM), leading to a considerable increase in long-term survivors. In this context, the rise of radiation-induced cognitive toxicity (RICT) has become increasingly relevant. In this critical narrative review, we address the controversies arising from clinical trials aimed at mitigating RICT. We thoroughly examine interventions such as memantine, hippocampal avoidance irradiation during BM treatment or in a prophylactic setting, and the assessment of cognitive safety in stereotactic radiosurgery (SRS). Our focus extends to recent neuroscience research findings, emphasizing the importance of preserving not only the hippocampal cortex but also other cortical regions involved in neural dynamic networks and their intricate role in encoding new memories. Despite treatment advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain areas requiring further elucidation. Future trials are required to delineate optimal indications and ensure SRS safety. Additionally, the impact of new systemic therapies and the potential effects of delaying irradiation on cognitive functioning also need to be addressed. Inclusive trial designs, encompassing patients with multiple BM and accounting for diverse treatment scenarios, are essential for advancing effective strategies in managing RICT and the treatment of BM patients.

β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer\'s disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease\'s development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.

BACKGROUND: We aimed to assess the impact of cholinesterase inhibitors (ChEIs) and memantine on cognition, major adverse cardiovascular events (MACE) and mortality in dementia with Lewy bodies (DLB).
METHODS: A total of 1,095 incident DLB patients from the Swedish Registry on cognitive/dementia disorders were included. Using an inverse probability of treatment weighting, the effect of initiating ChEI or memantine within 90 days of DLB diagnosis and nonuse was evaluated on cognitive trajectories and risks of MACE and death.
RESULTS: The use of ChEIs significantly slowed cognitive decline at follow-ups (Mini-Mental State Examination [MMSE] -0.39 points/y; 95% confidence interval [CI], -0.96 to 0.18) compared to memantine (-2.49 points/y; -4.02 to -0.97) and nonuse (-2.50 points/y; -4.28 to -0.73). Treatment groups did not differ in MACE events. ChEI use was associated with lower risk of death in the first year after DLB diagnosis (adjusted hazard ratio [HR] 0.66, 95% CI 0.46, 0.94).
CONCLUSIONS: Our findings illuminate the potential benefits of ChEI treatment in DLB patients.
CONCLUSIONS: Cholinesterase inhibitors slow cognitive decline over a 5-year follow-up period when compared to both memantine treatment and nonuse in patients with dementia with Lewy bodies. Cholinesterase Inhibitors reduce risk of mortality within the initial year, but this effect is not sustained after 1 year in patients with dementia with Lewy bodies.

The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer\'s disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.

UNASSIGNED: This systematic review and meta-analysis aimed to assess the efficacy of NMDA antagonists in ASD (Autism Spectrum Disorder) on the core (communication and social interaction, repetitive behavior) and associated symptoms (irritability) of ASD, as well as their safety.
UNASSIGNED: PubMed, CENTRAL, CINHAL, EMBASE, and PsycINFO databases were searched until November 2023. Two authors independently selected the studies and extracted data. Randomized controlled trials assessing the efficacy of NMDA receptor antagonists in participants with ASD aged <18 years were included. The quality of the studies was assessed using the Risk of Bias-2 tool. A random-effect meta-analysis model was used to calculate standardized mean differences (SMD) or odds ratios (OR) using meta package in R.
UNASSIGNED: This systematic review included ten studies (588 participants). Most studies did not report scales assessing core symptoms of ASD. Meta-analysis of efficacy on ASD core symptoms included three studies (248 participants). NMDA antagonists were not superior to placebo [SMD = 0.29; CI 95% (-1,94; 1.35); I2 = 0%]. NMDA antagonists was not superior to placebo concerning response (four studies, 189 participants) [OR = 2.4; CI 95% (0.69; 8.38); I2 = 35%]. Meta-analysis of efficacy on irritability included three studies (186 participants); NMDA antagonists were not superior to placebo [MD irritability = -1.94; CI 95% (-4.66; 0.77); I2 = 0%]. Compared with placebo, significantly more participants in the NMDA antagonist group reported at least one adverse event (five studies, 310 participants) [OR = 2.04; CI 95% (1.17; 3.57); I2 = 0%].
UNASSIGNED: Current evidence does not support the effectiveness of NMDA antagonists in the treatment of ASD symptoms or irritability. Further research is needed due to the limited and low quality data available.
UNASSIGNED: PROSPERO CRD42018110399.

This study examines pharmaceutically acceptable inorganic salts of memantine, specifically focusing on hydrogen sulfate, sulfate, and dihydrogen phosphate salts, with the aim of finding alternatives to the commonly used chloride salt in the treatment of Alzheimer\'s disease. Through comprehensive solid-state characterization, including powder X-ray diffraction, thermal analysis, and solubility testing, we unveil complex polymorphic behaviors, reversible solid-state transitions, and significant differences in solubility and stability among the salts. Notably, the hydrogen sulfate salt emerges as a promising candidate for drug formulations, offering improved solubility, nonhygroscopic nature, and favorable morphological characteristics compared to the existing chloride salt. This work establishes a foundation for further investigation into memantine salts as potential therapeutics with improved efficacy.

UNASSIGNED: Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy.
UNASSIGNED: We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age.
UNASSIGNED: Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65 years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18 years, 16 in patients between 18 and 65 years, and 113 in patients older than 65 years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19 days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment.
UNASSIGNED: Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets. We previously reported non-conventional intracellular signaling triggered by which, upon activation, promotes the interaction between JNK2 and STX1A which enhances the rate of vesicular secretion. We developed a cell-permeable peptide, named JGRi1, able to disrupt such interaction, thus reducing vesicular secretion. In this work, to selectively study the effect of JGRi1 in a much simpler system, we employed neuroblastoma cells, SH-SY5Y. We found that SH-SY5Y cells express the components of the NMDA receptor-JNK2 axis and that the NMDA stimulus increases the rate of vesicle release. Both JGRi1 and memantine protected SH-SY5Y cells from NMDA toxicity, but only JGRi1 reduced the interaction between JNK2 and STX1A. Both drugs successfully reduced NMDA-induced vesicle release, although, unlike memantine, JGRi1 did not prevent calcium influx. NMDA treatment induced JNK2 expression, but not JNK1 or JNK3, which was prevented by both JGRi1 and memantine, suggesting that JNK2 may be specifically involved in the response to NMDA. In conclusion, being JGRi1 able to protect cells against NMDA toxicity by interfering with JNK2/STX1A interaction, it could be considered a novel pharmacological tool to counteract excitotoxicity.

N-methyl-D-aspartate receptors (NMDARs) play a significant role in developing several central nervous system (CNS) disorders. Currently, memantine, used for treating Alzheimer\'s disease, and ketamine, known for its anesthetic and antidepressant properties, are two clinically used NMDAR open-channel blockers. However, despite extensive research into NMDAR modulators, many have shown either harmful side effects or inadequate effectiveness. For instance, dizocilpine (MK-801) is recognized for its powerful psychomimetic effects due to its high-affinity and nearly irreversible inhibition of the GluN1/GluN2 NMDAR subtypes. Unlike ketamine, memantine and MK-801 also act through a unique, low-affinity \"membrane-to-channel inhibition\" (MCI). We aimed to develop an open-channel blocker based on MK-801 with distinct inhibitory characteristics from memantine and MK-801. Our novel compound, K2060, demonstrated effective voltage-dependent inhibition in the micromolar range at key NMDAR subtypes, GluN1/GluN2A and GluN1/GluN2B, even in the presence of Mg2+. K2060 showed reversible inhibitory dynamics and a partially trapping open-channel blocking mechanism with a significantly stronger MCI than memantine. Using hippocampal slices, 30 µM K2060 inhibited excitatory postsynaptic currents in CA1 hippocampal neurons by ∼51 %, outperforming 30 µM memantine (∼21 % inhibition). K2060 exhibited No Observed Adverse Effect Level (NOAEL) of 15 mg/kg upon intraperitoneal administration in mice. Administering K2060 at a 10 mg/kg dosage resulted in brain concentrations of approximately 2 µM, with peak concentrations (Tmax) achieved within 15 minutes. Finally, applying K2060 with trimedoxime and atropine in mice exposed to tabun improved treatment outcomes. These results underscore K2060\'s potential as a therapeutic agent for CNS disorders linked to NMDAR dysfunction.

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff\'s syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine\'s capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.