The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
Plasmodium berghei is a single-celled parasite causing rodent malaria. It is in the Plasmodium subgenus Vinckeia.
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.
WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.
The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.
Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.
Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.
Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.
Dedicator of cytokinesis protein 3 (Dock3), also known as MOCA and PBP, is a large protein encoded in the human by the DOCK3 gene, involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock3 specifically activates the small G protein Rac.
The Alzheimer type II astrocyte is thought to be a pathological type of cell in the brain; however, its exact pathology remains unknown. Like other astrocytes, it is a non-neuronal glial cell. It's mainly seen in diseases that cause increased levels of ammonia (hyperammonemia), such as chronic liver disease and Wilson's disease.
In biochemistry, the glutamate–glutamine cycle is a cyclic metabolic pathway which maintains an adequate supply of the neurotransmitter glutamate in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.
Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.
6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist, which was isolated originally from Streptomyces in a sample of Peruvian soil. This diazo compound is biosynthesized from lysine by three enzymes in bacteria. It is one of the most famous non-proteinogenic amino acid and was characterized in 1956 by Henry W Dion et al., who suggested a possible use in cancer therapy. This antitumoral efficacy was confirmed in different animal models. DON was tested as chemotherapeutic agent in different clinical studies, but was never approved. In 2019, DON was shown to kill tumor cells while reversing disease symptoms and improve overall survival in late-stage experimental glioblastoma in mice, when combined with calorie-restricted ketogenic diet.
Positron emission tomography–magnetic resonance imaging (PET–MRI) is a hybrid imaging technology that incorporates magnetic resonance imaging (MRI) soft tissue morphological imaging and positron emission tomography (PET) functional imaging.
PIEZO1 is a mechanosensitive ion channel protein that in humans is encoded by the gene PIEZO1. PIEZO1 and its close homolog PIEZO2 were cloned in 2010, using an siRNA-based screen for mechanosensitive ion channels.
PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs), which is being researched as a potential anti-cancer therapeutic agent. It is a phosphate ester “pre-prodrug” that is rapidly converted to the HAP PR-104A in the body. PR-104A is in turn metabolised to reactive nitrogen mustard DNA crosslinking agents in hypoxic tissues such as found in solid tumours. Following initial clinical studies, it was discovered that PR-104A is also activated by the enzyme AKR1C3, independently of hypoxia. Hypoxia in the bone marrow of patients with leukaemia, and high activity of AKR1C3 in some leukaemia subtypes has led to interest in clinical trials of PR-104 in relapsed refractory acute leukaemias.
Julie C. Price is an American medical physicist and professor of radiology at Massachusetts General Hospital (MGH), Harvard Medical School (HMS), as well as the director of PET Pharmacokinetic Modeling at the Athinoula A. Martinos Center at MGH. Price is a leader in the study and application of quantitative positron emission tomography (PET) methods. Prior to this, Price worked with Pittsburgh colleagues to lead the first fully quantitative pharmacokinetic evaluations of 11C-labeled Pittsburgh compound-B (PIB), one of the most widely used PET ligands for imaging amyloid beta plaques. As a principal investigator at MGH, Price continues work to validate novel PET methods for imaging biological markers of health and disease in studies of aging and neurodegeneration, including studies of glucose metabolism, protein expression, neurotransmitter system function, and tau and amyloid beta plaque burden.
HC-067047 is a drug which acts as a potent and selective antagonist for the TRPV4 receptor. It has been used to investigate the role of TRPV4 receptors in a number of areas, such as regulation of blood pressure, bladder function and some forms of pain, as well as neurological functions.
The neurovascular unit (NVU) comprises the components of the brain that collectively regulate cerebral blood flow in order to deliver the requisite nutrients to activated neurons. The NVU addresses the brain's unique dilemma of having high energy demands yet low energy storage capacity. In order to function properly, the brain must receive substrates for energy metabolism–mainly glucose–in specific areas, quantities, and times. Neurons do not have the same ability as, for example, muscle cells, which can use up their energy reserves and refill them later; therefore, cerebral metabolism must be driven in the moment. The neurovascular unit facilitates this ad hoc delivery and, thus, ensures that neuronal activity can continue seamlessly.
