Locally Synthetized 17-ß-Estradiol Reverses Amyloid-ß-42-Induced Hippocampal Long-Term Potentiation Deficits.

Amyloid beta 1-42 (Aß42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17ß-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17ß-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aß42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aß42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aß42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aß42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aß42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

Memantine versus Ginkgo biloba Extract: A Comparative Study on Cognitive Dysfunction Treatment in a Novel Rat Model.

Extracellular senile plaques and intraneuronal neurofibrillary tangles are two devastating brain proteinopathies that are indicative of Alzheimer's disease, the most prevalent type of dementia. Currently, no effective medications are available to stop or reverse Alzheimer's disease. Ginkgo biloba extract, commonly referred to as EGb 761, is a natural product made from the leaves of the G. biloba tree. It has long been demonstrated to have therapeutic benefits in Alzheimer's disease. The current study assessed the beneficial effects of EGb 761 against Alzheimer's disease in comparison with memantine, a standard treatment for Alzheimer's disease. The scopolamine-heavy metals mixture rat Alzheimer's disease model is a newly created model to study the effects of EGb 761 oral therapy on cognitive performance and other Alzheimer's disease-like changes over a 28-day experimental period. This new Alzheimer's disease model provides better criteria for Alzheimer's disease hallmarks than the conventional scopolamine model. The EGb 761 reversed memory and learning deficits induced by the scopolamine-heavy metals mixture. These outcomes were linked to a more pronounced inhibitory effect on acetylcholinesterase, caspase-3, hippocampal amyloid-beta protein (Aß1 - 42), phosphorylated tau protein counts, and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) compared to the memantine-treated group. Furthermore, EGb 761 treatment considerably reduced lipid peroxidation (malondialdehyde) and improved reduced glutathione levels compared to memantine. Our results suggest EGb 761's potential in treating central nervous system disorders. It's a promising candidate for future Alzheimer's disease therapeutic exploration. This study also highlights the need for future research to focus on the positive benefits of herbal medicines.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.

New bithiophene derivative attenuated Alzheimer's disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission.

BACKGROUND: One of the hypotheses that leads to an increased incidence of Alzheimer's disease (AD) is the accumulation of aluminum in the brain's frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. METHODOLOGY: Adult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3-6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. MAIN FINDINGS: Al disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-ß plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. CONCLUSION: Taking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-ß plaques and phosphorylation of tau.

Dispensing of antineoplastic medications and their impact on the dispensing of anti-dementia drugs for adults aged ≥60 years: A cohort study.

History of cancer has been associated with decreased risk of dementia, but it is unclear if this is due to the use of antineoplastic medications. Participants were 442,795 adults aged ≥60 years, of whom 235,841 (53.26 %) were women. Those dispensed antineoplastic medications during 2012-2013 had lower odds of being dispensed an anti-dementia drug between 2015 and 2021 (age/sex-adjusted OR = 0.60, 95%CI = 0.55-0.66). The dispensing of antineoplastic medications was associated with an adjusted hazard ratio of 0.72 (95%CI = 0.65-0.80) of subsequent dispensing of an anti-dementia drug. Understanding the mechanisms that support this association may contribute to the introduction of novel approaches to dementia prevention.

Acute and chronic glutamate NMDA antagonist treatment attenuates dopamine D1 antagonist-induced reduction of nicotine self-administration in female rats.

Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.

Minocycline mitigates tau pathology via modulating the TLR-4/NF-Ðºß signalling pathway in the hippocampus of neuroinflammation rat model.

INTRODUCTION: The neuroinflammatory response was seen to impact the formation of phosphorylated tau protein in Alzheimer's disease (AD). This study aims to investigate the molecular mechanism of minocycline in reducing phosphorylated tau protein formation in the hippocampus of lipopolysaccharide (LPS)-induced rats. METHODS: Fifty adult male Sprague Dawley (SD) rats were randomly allocated to 1 of 5 groups: control, LPS (5 mg/kg), LPS + minocycline (25 mg/kg), LPS + minocycline (50 mg/kg) and LPS + memantine (10 mg/kg). Minocycline and memantine were administered intraperitoneally (i.p) for two weeks, and LPS was injected i.p. once on day 5. ELISA was used to determine the level of phosphorylated tau protein in SD rats' hippocampal tissue. The density and expression of Toll-like receptor-4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кß), tumour necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2 were determined using Western blot and immunohistochemistry. RESULTS: Minocycline, like memantine, prevented LPS-induced increasein phosphorylated tau protein level suggested via reduced density and expression of TLR-4, NF-кß, TNF-αand COX-2 proteins in rat hippocampal tissue. Interestingly, higher doses were shown to be more neuroprotective than lower doses. CONCLUSION: This study suggests that minocycline suppresses the neuroinflammation signalling pathway and decreased phosphorylated tau protein formation induced by LPS in a dose-dependent manner. Minocycline can be used as a preventative and therapeutic drug for neuroinflammatory diseases such as AD.

Effect of Cerebralcare Granule® combined with memantine on Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: In elderly people, Alzheimer's disease (AD) is the most common form of dementia. It has been shown that traditional Chinese medicine (TCM) based on phytomedicines enhances the therapeutic effects of modern medicine when taken in conjunction with them. Modern medicine N-methyl-D-aspartate receptor (NMDA) antagonist memantine (Mm) are mainly used in the clinical treatment of AD. TCM Cerebralcare Granule® (CG) has long been an effective treatment for headaches, dizziness, and other symptoms. In this study, we employ a blend of CG and Mm to address Alzheimer's disease-like symptoms and explore their impacts and underlying mechanisms. AIM OF THE STUDY: The objective of our study was to observe the effects of CG combined with Memantine (Mm) on learning and memory impairment of AD mice induced by D-galactose and to explore the mechanism at work. MATERIALS AND METHODS: CG and Mm were combined to target multiple pathological processes involved in AD. For a thorough analysis, we performed various experiments such as behavioral detection, pathological detection, proteomic detection, and other experimental methods of detection. RESULTS: It was found that the combination of CG and Mm was significantly effective for improving learning and memory in AD mice as well as brain pathology. The serum and hippocampal tissue of AD mice were significantly enhanced with catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were decreased with this treatment. In AD mice, a combination of Mm and CG (CG + Mm) significantly increased the levels of the anti-inflammatory factors IL-4 and IL-10, decreased the levels of pro-inflammatory factors (IL-6, IL-1ß) and tumor necrosis factor-alpha (TNF-α), improved synaptic plasticity by restoring synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) expression in the hippocampus, enhanced Aß phagocytosis of microglia in AD mice, and increased mitochondrial respiratory chain enzyme complexes I, II, III, and IV, lead to an increase in the number of functionally active NMDA receptors in the hippocampus. Proteomic analysis GO analysis showed that the positive regulation gene H3BIV5 of G protein coupled receptor signal pathway and synaptic transmission was up-regulated, while the transsynaptic signal of postsynaptic membrane potential and regulation-related gene Q5NCT9 were down-regulated. Most proteins showed significant enriched signal transduction pathway profiles after CG + Mm treatment, based on the KEGG pathway database. CONCLUSION: The data supported the idea that CG and Mm could be more effective in treating AD mice induced by D-galactose than Mm alone. We provided a basis for the clinical use of CG with Mm.

Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AßO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (90 µM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AßO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AßO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

Development of a Novel Co-processed Excipitient Comprising of Xylitol, Mannitol, Microcrystalline Cellulose, and Crospovidone for the Compounding of Memantine Hydrochloride Orally Disintegrating Tablet.

Orally disintegrating tablets, which were originally developed in the pharmaceutical field to improve the compliance of patients who had difficulty swallowing tablets, have become a preferable choice in solid dosage forms since it brings advantages to the patients and consumers in the healthcare system. Among the advantages of this novel dosage form are a faster onset of action, improved bioavailability, and the ease of administration as it can be taken without water. However, there are still some limitations of orally disintegrating tablets that need to be overcome, including a lack of mechanical strength, an unpleasant taste of the drug in the mouth, and a stability issue due to its hygroscopicity nature. This objective of this study was to identify the composition of co-processed excipients comprising of mannitol, microcrystalline cellulose, xylitol, and crospovidone or croscarmellose sodium in order to formulate orally disintegrating tablets containing memantine hydrochloride. This study was carried out in two stages. Firstly, orally disintegrating tablets containing memantine hydrochloride with 6 different formulations, which differed in the percentage of crospovidone or croscarmellose sodium, were formulated and manufactured. Secondly, the orally disintegrating tablets obtained were evaluated through pre- and post-compression tests based on the standard for orally disintegrating tablets. Formulation 3, which consisted of 10% xylitol, 10% mannitol, 72% microcrystalline cellulose, and 8% crospovidone, was chosen as the optimum formulation for the co-processed excipient since it was the fastest disintegration process among all the formulations in the study. In addition, Formulation 3 also showed the acceptable and satisfying results in other evaluation tests such as - weight variation test, hardness test, and friability test. The co-processed excipient comprising of 10% xylitol, 10% mannitol, 72% microcrystalline cellulose, and 8% crospovidone, which is characterized by improved functionalities such as a fast disintegration process, plays a crucial role in the application of orally disintegrating tablets.

NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages.

Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.

In Vitro Permeability Study of Homotaurine Using a High-Performance Liquid Chromatography with Fluorescence Detection Pre-Column Derivatization Method.

Homotaurine (HOM) is considered a promising drug for the treatment of Alzheimer's and other neurodegenerative diseases. In the present work, a new high-performance liquid chromatography with fluorescence detection (HPLC-FLD) (λex. = 340 nm and λem. = 455 nm) method was developed and validated for the study of substance permeability in the central nervous system (CNS). Analysis was performed on a RP-C18 column with a binary gradient elution system consisting of methanol-potassium phosphate buffer solution (pH = 7.0, 0.02 M) as mobile phase. Samples of homotaurine and histidine (internal standard) were initially derivatized with ortho-phthalaldehyde (OPA) (0.01 M), N-acetylcysteine (0.01 M) and borate buffer (pH = 10.5; 0.05 M). To ensure the stability and efficiency of the reaction, the presence of different nucleophilic reagents, namely (a) 2-mercaptoethanol (2-ME), (b) N-acetylcysteine (NAC), (c) tiopronin (Thiola), (d) 3-mercaptopropionic acid (3-MPA) and (e) captopril, was investigated. The method was validated (R2 = 0.9999, intra-day repeatability %RSD < 3.22%, inter-day precision %RSD = 1.83%, limits of detection 5.75 ng/mL and limits of quantification 17.43 ng/mL, recovery of five different concentrations 99.75-101.58%) and successfully applied to investigate the in vitro permeability of homotaurine using Franz diffusion cells. The apparent permeability (Papp) of HOM was compared with that of memantine, which is considered a potential therapeutic drug for various CNSs. Our study demonstrates that homotaurine exhibits superior permeability through the simulated blood-brain barrier compared to memantine, offering promising insights for enhanced drug delivery strategies targeting neurological conditions.

Palliative whole brain radiation therapy: an international state of practice.

BACKGROUND: Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers preferentially use stereotactic radiotherapy (SRT) and reserve WBRT for those with >15 lesions, leptomeningeal presentation, rapidly progressive disease, or limited estimated survival. Despite regional differences among preferred dose, fractionation, and treatment technique, we predict survival post-WBRT will remain poor-indicating appropriate application of WBRT in this era of SRT and improved systemic therapies. METHODS: A multi-center, international retrospective analysis of patients receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. De-identified data were analyzed centrally. Patients receiving WBRT as part of a curative regimen, prophylactically, or as bridging therapy were excluded. The collected data consisted of patient parameters including prescription dose and fractionation, use of neurocognitive sparing techniques and survival after WBRT. Survival was calculated via the Kaplan-Meier method. RESULTS: Of 29,943 international RT prescriptions written at ten participating centers in 2022, 462 (1.5%) were for palliative WBRT. Participating centers were in the United States (n=138), the United Kingdom (n=111), Hong Kong (n=72), Italy (n=49), Belgium (n=45), Germany (n=27), Ghana (n=15), and Cyprus (n=5). Twenty-six different dose regimens were used. The most common prescriptions were for 3,000 cGy over 10 fractions (45.0%) and 2,000 cGy over 5 fractions (43.5%) with significant regional preferences (P<0.001). Prior SRT was delivered in 32 patients (6.7%), hippocampal avoidance (HA) was used in 44 patients (9.5%), and memantine was prescribed in 93 patients (20.1%). Survival ranged from 0 days to still surviving at 402 days post-treatment. The global median overall survival (OS) was 84 days after WBRT [95% confidence interval (CI): 68.0-104.0]. Actuarial survival at 7 days, 1 month, 3 months, and 6 months were 95%, 78%, 48%, and 32%, respectively. Twenty-seven patients (5.8%) were unable to complete their prescribed WBRT. CONCLUSIONS: This moment-in-time analysis confirms that patients with poor expected survival are being appropriately selected for WBRT-illustrating the dwindling indications for WBRT-and demonstrates the variance in global practice. Since poor survival precludes patients from deriving benefit, memantine and HA are best suited in carefully selected cases.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

BACKGROUND: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. OBJECTIVE: To evaluate psychopharmacological medication use at the time of FTD diagnosis. METHODS: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. RESULTS: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. CONCLUSION: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001.

PURPOSE: Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT + memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 year. METHODS AND MATERIALS: Adult patients with brain metastases were randomized to HA-WBRT + memantine or WBRT + memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. RESULTS: Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT + memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P = .016) and was associated with less deterioration in TMT-B at 4 months (P = .012) and HVLT-R recognition at 4 (P = .055) and 6 months (P = .011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT + Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P = .026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P = .003 using complete-case data; P = .0016 using imputed data) and 12 months (P = .0027 using complete-case data; P = .0014 using imputed data), and fewer cognitive symptoms over time (P = .043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. CONCLUSIONS: With median follow-up exceeding 1 year, HA during WBRT + memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference, and cognitive symptoms with no difference in survival or toxicity.

Synthesis and Biological Evaluation of a Library of Sulfonamide Analogs of Memantine to Target Glioblastoma.

A library of 34 lipophilic sulfonamides based upon the memantine core has been synthesized to identify potential drug candidates to cross the blood-brain barrier and target glioblastoma. The library was screened for in vitro activity against 4 mammalian cell lines, including U-87 (glioblastoma). Additional synthetic variation of the active compounds has validated the importance of specific regions of the pharmacophore, with the sulfonamide functionality and S-aryl unit displaying the most significant impact. In silico investigations suggest the active compounds might target DDR1 or RET proteins. The investigation has resulted in several compounds that warrant further development for lead optimization.

Unfavorable effects of memantine on the skeletal system in female rats.

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used in the treatment of Alzheimer's disease (AD). NMDA receptors are expressed on bone cells. The aim of the present study was to investigate the effects of memantine on the rat musculoskeletal system. Taking into account that most of female AD patients are postmenopausal, the study was carried out on intact and ovariectomized (estrogen-deficient) rats. Mature Wistar rats were divided into following groups: non-ovariectomized (NOVX) control rats, NOVX rats treated with memantine, ovariectomized (OVX) control rats, and OVX rats treated with memantine. Memantine (2 mg/kg p.o.) was administered once daily for four weeks, starting one week after ovariectomy. The serum bone turnover marker and cytokine levels, bone density, mass, mineralization, mechanical properties, histomorphometric parameters of compact and cancellous bone, skeletal muscle mass and grip strength were determined. In NOVX rats, memantine slightly decreased the strength of compact bone of the femoral diaphysis (parameters in the yield point) and unfavorably affected histomorphometric parameters of cancellous bone (the femoral epiphysis and metaphysis). In OVX rats, in which estrogen deficiency induced osteoporotic changes, memantine increased the phosphorus content in the femoral bone mineral. No other effects on bone were observed in the memantine-treated OVX rats. In conclusion, the results of the present study indicated slight damaging skeletal effects of memantine in rats with normal estrogen levels.

Memantine, an NMDA receptor antagonist, protected the brain against the long-term consequences of sepsis in mice.

AIMS: Long-term neuroinflammation and brain dysfunction have frequently been reported in sepsis survivors. In this study, the protective effect of memantine (an NMDA receptor antagonist) on the long-term consequences of sepsis on the brain was investigated in mice. MATERIALS AND METHODS: Eighty-five male C57 mice were included. Memantine was administrated through gavage at 5, 10, and 20 mg/kg three days before sepsis and continued for three days after sepsis induction. Sepsis was induced by intraperitoneal injection of 5 mg/kg LPS. A cohort of mice was sacrificed on the 4th day post sepsis to measure NF-κB, TNF-α, and IL-1ß mRNA expression and oxidative stress markers in the brain. The second cohort was used for behavioral tests one month after sepsis induction and then sacrificed for oxidative stress markers and acetylcholinesterase (AChE) activity measurement. KEY FINDINGS: MDA levels and mRNA expression of NF-κB, TNF-α, and IL-1ß ameliorated by memantine at the early days of sepsis induction, and total thiol content and SOD activity were increased. Post-septic mice showed significant disruption of recognition memory in novel object recognition (NOR) and depressive and anxiety-like behaviors in tail suspension test, elevated plus maze (EPM), and open field tests one month after sepsis. Memantine at 10 and 20 mg/kg dose-dependently ameliorated behavioral abnormalities, reduced AChE activity and MDA levels, and enhanced SOD activity and thiol content one month after sepsis. SIGNIFICANCE: These findings suggest that early treatment of septic mice with memantine could ameliorate brain inflammation and oxidative damage and prevent long-term behavioral consequences of sepsis.

Cognitive impairment of MRL mice is related to NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived micro-vascular endothelial cells.

Systemic lupus erythematosus (SLE) is a chronic recurrent autoimmune disease affecting almost all organs. This study was conducted to investigate cognitive impairment of SLE mice (MRL/lpr mice), and explore associated pathological mechanism. Behavior tests (open-field test, elevated plus-maze test, forced swimming test, sucrose preference test, and Morris water maze test) were conducted in MRL/MPJ and MRL/lpr mice. ELISA test was performed to determine levels of antibodies (anti-dsDNA, anti-RPA, anti-ACA, and anti-NR2a/b) and inflammatory factors [tumour necrosis factor a (TNF-a), interleukin (IL)-6, IL-8, and IL-10]. Micro-vascular endothelial cells (MVECs) were isolated, identified, and divided into MVECs (NC), anti-NR2a/2b, memantine, glycine, dexamethasone, and IL-1b groups. Cell proliferation was measured using cell counting kit-8 (CCK-8) assay, and Western blotting was applied to evaluate ELAM-1, VCAM-1, ICAM-1, IKBa, p-IKBa expression. MRL/lpr mice demonstrated lower locomotion/exploration ability, higher anxiety, obvious depression symptoms, lower learning/memory capability compared with MRL/MPJ mice. MRL/lpr mice demonstrated high levels of anti-NR2a/b antibody and auto-antibodies. NMDA receptor antagonist (memantine) significantly increased, and NMDA receptor agonist (glycine) significantly decreased MVECs proliferation compared with NC group ( p < 0.05). Memantine significantly reduced and glycine predominantly enhanced TNF-a, IL-6, IL-8, and IL-10 levels compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist modulated adhesion molecules expression in MVECs. ELAM-1, VCAM-1, and ICAM-1 expressions were significantly down-modulated in memantine group, and remarkably up-modulated in glycine group compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist regulated phosphorylation of p-IKBa. The above effects of memantine evenly equaled to dexamethasone, and glycine evenly equaled to IL-1b. In conclusion, cognitive impairment of MRL mice might be associated with NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived MVECs.