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New Strategies for Brain Protection Including NMDA Receptor Antagonists
Published in Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin, Brain Injury and Pediatric Cardiac Surgery, 2019
Data from our experiments demonstrate that dizocilpine reduces neuropathologic injury following two hours of hypothermic circulatory arrest in the canine model and also promotes functional recovery. Pretreatment and weaning of the drug reduced neuronal injury and preserved both NMDA and non-NMDA glutamate receptor expression in vulnerable regions. The use of NMDA receptor antagonists clearly has promise as a neuroprotective strategy. The fact that dizocilpine and related agents are effective in animal models provides a starting point for the design of clinical protocols. Although dizocilpine may not prove to be the specific drug that is tested clinically, these animal studies provide evidence that excitotoxicity is an important step in the injury that can occur during and after hypothermic circulatory arrest.
Metabolic Mapping with Deoxyglucose Autoradiography as an Approach for Assessing Drug Action in the Central Nervous System
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Akeo Kurumaji, Deborah Dewar, James McCulloch
Data such as these suggest that the activation and hypermetabolism seen in some limbic areas after dizocilpine can only be observed in the functionally intact CNS of the conscious animals and not with electrophysiology in anesthetized animals or in brain slices in vitro. Moreover, these data indicate that the limbic activation after dizocilpine can be readily controlled by light anesthesia, potentially of critical importance to the clinical use of noncompetitive NMDA receptor antagonists.
Third Histamine Receptor: From Discovery to Clinics, Long-Lasting Love Story at INSERM and Bioprojet
Published in Divya Vohora, The Third Histamine Receptor, 2008
First, tiprolisant shows some efficacy in various models of schizophrenia. For instance, it partially reduces the hyperlocomotor and stereotypic behaviors of direct or indirect dopaminergic agonists, as do, with higher potencies, the antipsychotic drugs; the hyperlocomotor activity of dizocilpine is also partially reversed, indicating that the drug affects the dopamine—NMDA imbalances. The mechanism of these actions, although not well understood, is not related to the blockade of dopaminergic receptors. Interestingly enough, Aude Burban and Jean-Michel Arrang have also recently shown that the drug almost completely reverses the deficit of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine in mice; the low dosage of tiprolisant that was required, together with similar effects on gating deficit reported by the Abbott group with another compound, indicates that this is a drug class effect. Reversal of PPI inhibition is probably one of the best predictors of antipsychotic potential for nondopaminergic drug candidates, inasmuch as it explores a sensorimotor gating deficit, which is considered as a cardinal sign of schizophrenia. Second, drugs showing, such as H3-receptor inverse agonists, a large spectrum of procognitive efficacy are actively explored for improvement of the cognitive deficits in remaining of the schizophrenic patients, even treated with antipsychotic drugs of the second generation.
Beneficial effects of atypical antipsychotics on object recognition deficits after adolescent toluene exposure in mice: involvement of 5-HT1A receptors
Published in The American Journal of Drug and Alcohol Abuse, 2022
Mei-Yi Lee, Chung-Pin Hsieh, Ming-Huan Chan, Hwei-Hsien Chen
To test whether activation of 5-HT1A receptors is involved in the beneficial effects of aripiprazole, clozapine, and buspirone to restore the toluene-induced recognition memory deficits, 3 separate experiments were performed. WAY-100635, a 5-HT1A receptor antagonist, was administered 30 min prior to aripiprazole, clozapine, or buspirone in toluene-exposed mice for subsequent NORT. Each experiment included at least 4 groups (oil+vehicle+vehicle, toluene+vehicle+vehicle, toluene+ vehicle+drug, toluene+WAY-100635+drug). WAY-100635 has been reported to alleviate cognitive impairments induced by a fornix lesion (18) or dizocilpine (19). Therefore, the toluene+WAY-100635+vehicle group was included in the experiment of aripiprazole to determine if WAY-100635 alone could restore the detrimental effect of toluene. The numbers of mice used in each experiment were 34 (aripiprazole), 32 (clozapine), and 26 (buspirone).
N-Methyl-D-Aspartate (NMDA) receptor modulators: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Hazem Ahmed, Ahmed Haider, Simon M. Ametamey
Takeda Pharmaceutical Company recently filed two patents disclosing two novel series of heterocycles as GluN1/GluN2B subunit antagonists for prophylaxis or therapy of major depression, bipolar disorder, migraine, pain, sleeping disorders, respiratory depression, hearing loss, traumatic brain injury, peripheral symptoms of dementia and other related neurological diseases [179,180]. A total number of 99 compounds were provided together with synthetic procedures and 95 compounds were biologically evaluated applying GluN1/GluN2B Ca2+ influx assay and human GluN1/GluN2B expressing HEK293 cells. The results were presented as a relative activity value that inhibits 100% of the cumulative fluorescence resulting from a well that is devoid of glutamic acid and glycine. A capsule and a tablet formulation were disclosed with the excipients and their respective percentages were defined. The second patent reported 85 compounds, which were similarly evaluated using the GluN1/GluN2B Ca2+ influx assay. Furthermore, functional antagonism in vivo using [3H]dizocilpine was evaluated in Sprague Dawley rats for three compounds, taking into account the fact that dizocilpine binds selectively to the PCP-binding site of the open NMDA ion channels. There is, however, an inherent bias in this assay given that dizocilpine does not bind selectively to GluN2B subunit-containing NMDA receptors. The same three compounds were also subjected to the hERG manual patch-clamp assay. Two compounds, 16 and 17, that showed notable performance in their respective biological testing are shown in Figure 17.
Pharmacokinetic and pharmacodynamic studies of iloperidone-loaded lipid nanoemulsions via oral route of administration
Published in Drug Development and Industrial Pharmacy, 2021
Arjun Narala, Dinesh Suram, Kishan Veerabrahma
Dinesh et al. [5] developed IL SMEDDS and liquisolid formulation. PD study was performed by inducing hyperlocomotion in wistar rats. MK-801 (Dizocilpine) at a dose of 0.5 mg/kg was used to induce hyperlocomotion. MK-801 treated rats showed maximum locomotor response after 15 min and locomotion response was decreased to base level after 60 min. Comparatively, SMEDDS and liquisolid formulation (LS) showed similar reduction in locomotor response after 15 min.