Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor.

N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including schizophrenia, depression, posttraumatic stress disorder, aging, mild cognitive impairment and Alzheimer's dementia, amyotrophic lateral sclerosis, and anti-NMDAR encephalitis. Several targets to "correct" or "reset" the NMDARMN in these CNS disorders have been identified and confirmed. With analogy to aminergic treatments, these targets include the glycine/d-serine co-agonist site, channel ionophore, glycine transporter-1, and d-amino acid oxidase. It is still early days in terms of developing novel therapeutics targeting the NMDAR. However, agents modulating NMDARMN hold promise as the next generation of CNS therapeutics.

[Blood supply topographic features in maxilla and mandible].

Topographic anatomical studies provide data on the characteristics of blood supply to maxilla and mandible. It is established that maxilla is supplied by the large number of major arteries which are commonly anastomosed to each other. Mandible intraosseous blood supply is by one major lower alveolar artery and a large number of small extraosseous arteries that supply blood to the bone, masticatory and facial muscles.

[Blood supply in maxilla after segmental osteotomy].

Anthropometric measurements allowed us to obtain anatomical data on the topography of large and small palatine canals, sprouts sphenoid bone pterygoid, pterygopalatine and pterygomaxillary sutures. These structures are important because they contain blood vessels and nerves located in the area of jaw osteotomy. A study of maxilla blood supply sources after segmental osteotomy found that the descending palatine artery, the pterygopalatine artery, the upper posterior alveolar and infraorbital arteries usually remain intact by osteotomy. There are numerous anastomoses between all the arteries supplying the maxilla.

Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior.

A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

[Computer modelling and topographo-anatomic substantiation of TMJ ankylosis surgical treatment].

Results of topographo-anatomic research of lateral and deep area of face with the use of three-dimensional computer modelling was presented. Application of the received data at operations of patients with ankilosis of the temporomandibular joint gave good results. It allows to draw a conclusion of possibility of this technique in a wide clinical practice.

[Side face part computer modelling use as background for low invasive access for TMJ puncture].

Computer modelling of the anatomic structures of different parts of maxillofacial region helps to widen surgeon's possibilities when planning and carrying out operative interventions, to improve doctor's training and to optimize students education in medical institutions. The use of 3D computer modeling for side face parts as the background for low invasive access for TMJ puncture. Results of the practical use of the worked off access (on 3D modell) to the upper part of TMJ confirm the practical efficacy of computer modelling.

D-serine added to clozapine for the treatment of schizophrenia.

OBJECTIVE: D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed. METHOD: In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week. RESULTS: The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine. CONCLUSIONS: The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.

Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment.

OBJECTIVE: Glutamatergic neurotransmission is important for memory and cognition and is severely affected in Alzheimer's disease. D-Cycloserine exhibits partial agonist activity at the glycine site of N-methyl-D-aspartate subtype glutamate receptor, facilitating activation of the receptor and improving cognition and memory. METHOD: Seventeen patients with Alzheimer's disease received a three-phase, double-blind, placebo-controlled trial of 50 mg and 100 mg/day of D-cycloserine. RESULTS: D-Cycloserine was associated with significant improvement in scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (improvement of 3.0 points) when given at a dose of 100 mg/day. CONCLUSIONS: D-Cycloserine has cognitive benefits for patients with Alzheimer's disease.

A preliminary study of D-cycloserine treatment in Alzheimer's disease.

D-cycloserine is a partial agonist on the glycine site of the N-methyl-D-aspartate glutamate receptor. This double-blind crossover study of 15 mg D-cycloserine in Alzheimer's disease patients did not demonstrate clinical benefit. Higher medication dosage or long-term treatment may be required.

Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal.

OBJECTIVE: Neurophysiological and pathological effects of ethanol may be mediated, to an important extent, via the glutamatergic system. Animal studies indicate the acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Persistent attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in the compensatory up-regulation of NMDA receptors. Whether glutamatergic neurotransmission and oxidative stress are enhanced during ethanol withdrawal in humans is unknown. METHOD: CSF was obtained from 18 matched comparison subjects and from 18 patients with alcohol dependence 1 week and 1 month after cessation of ethanol ingestion. CSF samples were analyzed for excitatory neurotransmitters, gamma-aminobutyric acid (GABA), and markers for oxidative stress. RESULTS: The alcohol-dependent patients' CSF levels of aspartate, glycine, and N-acetylaspartylglutamate were all higher than those of the comparison subjects, and their concentration of GABA was lower. In addition, there were significant correlations between excitatory neurotransmitters and oxidative stress markers, which suggest that the two mechanisms may play an interactive role in neurotoxicity mediated by ethanol withdrawal. CONCLUSIONS: The data suggest that augmentation of excitatory neurotransmission may lead to enhanced oxidative stress, which, in concert with reduced inhibitory neurotransmission, may contribute to the symptoms of ethanol withdrawal and associated neurotoxicity in humans. Whether these abnormalities represent a trait- or state-dependent marker of ethanol dependence remains to be resolved.

A glutamatergic model of ECT-induced memory dysfunction.

Electroconvulsive therapy (ECT) is an efficacious treatment for a variety of neuropsychiatric conditions including major depression, mania, catatonia, Parkinson's disease, and neuroleptic malignant syndrome. However, ECT-induced memory dysfunction complicates the treatment and is a major concern for both patients and providers. We briefly review ECT-induced memory dysfunction and propose a glutamatergic model for it. (Articles examined were retrieved by a Medline search on the terms electroconvulsion and glutamate, with language limited to English.) Specifically, we hypothesize that ECT-induced memory dysfunction results from neuronal insults due to excessive release of excitatory amino acids and activation of their receptors, which produce cation and water flux and reversible oxidative stress. This model offers multiple testable hypotheses; exploring them may help to identify the risk factors for this significant side effect of ECT treatment and may thus yield effective agents for its prevention and treatment.

[Structural changes of blood vessels and bile ducts in pathology]. / Izmeneniia arkhitektoniki krovenosnykh sosudov i zhelchnykh protokov pri patologicheskikh protsessakh.

Examination of 305 liver specimens of human cadavers of various age and study of the findings of intravital contrast examination of the duct and vascular system in 130 patients aged from 22 to 84 years revealed changes in the architectonics of the vessels and bile ducts in pathological processes. In healthy individuals the enlargement of the length and diameter of the vessels and ducts and increase in the depth of distribution of their intrahepatic branches from the surface of the liver ware regular in character and depended on the size of the liver and the age; they were marked by a straight linear course without sharp bends and dilatations. The length, diameter, the angles at the junction, and the direction of the course of the vessels and ducts changed sharply in inflammatory processes in the liver and bile ducts, focal lesions, and cirrhosis. Irregular enlargement of the diameter of the vessels and ducts and their marked tortousness were noted. The changes in the duct system were in direct dependence on the pressure in the biliary tract, the higher the pressure, the greater was the dilatation of the ducts at all levels.

[Changes in the architectonics of the bile ducts in inflammatory processes]. / Izmenenie arkhitektoniki zhelchnykh protokov pri vospalitel'nykh protsessakh.

A study of 156 preparations of the liver of adults, and as well examination of 62 patients has shown, that in inflammatory processes in the liver and bile ducts, the considerable changes in the length, diameter, angles of the confluence of the bile ducts occurred. With increase in the pronouncement of biliary hypertension, their diameter increases.