A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

Companys-Alemany, Júlia; Turcu, Andreea L.; Bellver-Sanchis, Aina; Loza, Marı́a Isabel; Brea, José; Canudas, Anna Maria; Leiva, Rosana; Vázquez, Santiago; Pallàs, Mercè; Griñán-Ferré, Christian

doi:10.3390/pharmaceutics12030284

Cited by 50 publications

(37 citation statements)

References 65 publications

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“…Several NMDAR uncompetitive antagonists have been developed and entered clinical trials, however, most of them failed due to low efficacy and side effects. Memantine ( 5 , Figure 4 ) is the only approved drug in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive antagonist compounds are being developed, such as RL-208 (3,4,8,9-tetramethyltetracyclo [4.4.0.0 3,9 .0 4,8 ]dec-1-yl)methylamine hydrochloride), a polycyclic amine compound that may possess a promising therapeutic effect in age-related cognitive problems and AD [ 115 , 116 , 117 ].…”

Section: Treatmentmentioning

confidence: 99%

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

2020

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Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N-methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

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Section: Treatmentmentioning

confidence: 99%

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

2020

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“…All procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Soochow University (ethical code:SUDA20201020A01). We took adequate measures to minimize animal suffering, and the sample size is based on the sample size used in our group’s previous publications and other similar studies ( 31 ).…”

Section: Methodsmentioning

confidence: 99%

Effects of Melatonin on Neurobehavior and Cognition in a Cerebral Palsy Model of plppr5−/− Mice

Sun

Jin

et al. 2021

Front. Endocrinol.

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Cerebral palsy (CP), a group of clinical syndromes caused by non-progressive brain damage in the developing fetus or infant, is one of the most common causes of lifelong physical disability in children in most countries. At present, many researchers believe that perinatal cerebral hypoxic ischemic injury or inflammatory injury are the main causes of cerebral palsy. Previous studies including our works confirmed that melatonin has a protective effect against convulsive brain damage during development and that it affects the expression of various molecules involved in processes such as metabolism, plasticity and signaling in the brain. Integral membrane protein plppr5 is a new member of the plasticity-related protein family, which is specifically expressed in brain and spinal cord, and induces filopodia formation as well as neurite growth. It is highly expressed in the brain, especially in areas of high plasticity, such as the hippocampus. The signals are slightly lower in the cortex, the cerebellum, and in striatum. Noteworthy, during development plppr5 mRNA is expressed in the spinal cord, i.e., in neuron rich regions such as in medial motor nuclei, suggesting that plppr5 plays an important role in the regulation of neurons. However, the existing literature only states that plppr5 is involved in the occurrence and stability of dendritic spines, and research on its possible involvement in neonatal ischemic hypoxic encephalopathy has not been previously reported. We used plppr5 knockout (plppr5−/−) mice and their wild-type littermates to establish a model of hypoxicischemic brain injury (HI) to further explore the effects of melatonin on brain injury and the role of plppr5 in this treatment in an HI model, which mainly focuses on cognition, exercise, learning, and memory. All the tests were performed at 3–4 weeks after HI. As for melatonin treatment, which was performed 5 min after HI injury and followed by every 24h. In these experiments, we found that there was a significant interaction between genotype and treatment in novel object recognition tests, surface righting reflex tests and forelimb suspension reflex tests, which represent learning and memory, motor function and coordination, and the forelimb grip of the mice, respectively. However, a significant main effect of genotype and treatment on performance in all behavioral tests were observed. Specifically, wild-type mice with HI injury performed better than plppr5−/− mice, regardless of treatment with melatonin or vehicle. Moreover, treatment with melatonin could improve behavior in the tests for wild-type mice with HI injury, but not for plppr5−/− mice. This study showed that plppr5 knockout aggravated HI damage and partially weakened the neuroprotection of melatonin in some aspects (such as novel object recognition test and partial nerve reflexes), which deserves further study.

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“…Antagonists selectively inhibiting extrasynaptic NMDA receptors may have neuroprotective effects [ 113 ]. Recently, a new NMDA receptor blocker, RL-208, has been tested on a mouse model of late-onset AD, showing cognitive function improvement in terms of increased synaptic protein density, increased phosphorylation of NMDA2B, reduced protein-related apoptosis, as well as decreased phosphorylated tau levels [ 114 ]. This study points out that this novel neuroprotective drug may be valuable for treating AD.…”

Section: Therapeutic Approaches Targeting Molecular/cellular Signamentioning

confidence: 99%

Critical Molecular and Cellular Contributors to Tau Pathology

2021

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Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

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A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

Cited by 50 publications

References 65 publications

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

Effects of Melatonin on Neurobehavior and Cognition in a Cerebral Palsy Model of plppr5−/− Mice

Critical Molecular and Cellular Contributors to Tau Pathology

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