Metabolic Mapping with Deoxyglucose Autoradiography as an Approach for Assessing Drug Action in the Central Nervous System
Edythe D. London in Imaging Drug Action in the Brain, 2017
The investigations with NMDA receptor antagonists highlight one of the strengths of the 14C-2-deoxyglucose functional mapping strategy, namely, that the investigations are normally performed in conscious animals. In halothane-anesthetized rats, the pattern of altered glucose use after dizocilpine differs qualitatively and quantitatively from that observed in conscious rats (Kurumaji and McCulloch, 1989). In anesthetized rats, significant reductions in glucose use are noted after dizocilpine in 19 of the 28 regions examined, with no area displaying significantly increased glucose use after administration of the drug. In halothane-anesthetized rats, dizocilpine fails to change the rates of glucose use in the olfactory areas, hippocampus molecular layer, and dentate gyrus (Figure 6). In the subicular complex, posterior cingulate cortex, and mamillary body, the pattern of the metabolic response to dizocil pine is reversed with halothane anesthesia, with significant reductions in glucose use being observed. In the cerebral cortices (particularly the auditory, sensory-motor, and frontal cortex), the decreases in glucose use following dizocilpine in anesthetized animals are qualitatively similar but quantitatively less marked than those in conscious animals (Kurumaji and McCulloch, 1989).
New Strategies for Brain Protection Including NMDA Receptor Antagonists
Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin in Brain Injury and Pediatric Cardiac Surgery, 2019
Our laboratory has studied the effect of dizocilpine in a perinatal rat model.2,5 In the model, one carotid artery of a 7-day-old rat is ligated, and the pup is exposed to hypoxia (8% oxygen) for two hours. Over an hour, areas of low flow appear in the periventricular white matter. A 70% reduction in blood flow combined with the hypoxemia leads to a substantial loss of brain tissue in the ipsilateral hemisphere with preservation of the other hemisphere. The fine lamellar organization of the corpus striatum is disrupted in the basal ganglia, and large infarcted areas can often be seen within the smaller hemisphere.10
Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders
Published in Expert Opinion on Drug Discovery, 2021
At the behavioral level, S1R agonists are potent antidepressant and anti-amnesic drugs. In particular, in line with the potentiating effect on [Ca2+]i mobilization and on NMDA-evoked responses in the hippocampus, the effects of the ligands on the learning impairments provoked by the NDMAR noncompetitive antagonist dizocilpine (MK-801) were extensively examined. DTG, [2S-(2α, 6α,11 R*)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (Alazocine, (+)-N-allylnormetazocine hydrochloride, (+)-SKF-10,047; Figure 1), PRE-084 (Figure 2f), cutamesine, or blarcamesine attenuated dizocilpine-induced spontaneous alternation or passive avoidance deficits with a bi-phasic dose response [57,104–107]. Furthermore, S1R ligands attenuated the learning deficits induced by cholinergic blockade. (+)-Pentazocine, cutamesine, or ANAVEX1-41 prevented the learning deficits induced by the mAChR antagonist scopolamine in a haloperidol-, NE-100-, or BD10,047-sensitive manner and with a bell-shaped dose-response curve [108,109]. Similar bi-phasic effects were observed in pathological models of amnesia, including pathological aging as observed in senescence-accelerated mice (SAM) [110], basal forebrain lesions [108,111] or the pharmacological AD model induced by intracerebroventricular injection of oligomerized Aß25-35 amyloid peptide [57,112].
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies
Published in Expert Opinion on Drug Discovery, 2018
Bence Szilágyi, György G. Ferenczy, György M. Keserű
D-serine is a co-agonist of the NMDA receptor whose hypofunction contributes to the pathophysiology of schizophrenia [76]. D-serine oxidative deamination is catalyzed by DAAO and thus the involvement of DAAO in schizophrenia is widely hypothesized. This possibility is supported by association between schizophrenia and single nucleotide polymorphisms in DAAO and its regulator (G72) [16,17] and by increased DAAO expression and enzyme activity in schizophrenia [18]. Indeed, several experiments showed that administration of DAAO inhibitors alone or together with D-serine to rodents significantly increases D-serine levels in the plasma [56,58–60,64,67,77] and in the brain [56,58,59,67,77]. DAAO inhibitors were also evaluated in animal behavior assays and several experiments suggested that they have the potential to improve psychosis or cognitive deficits associated with schizophrenia. Notably, acute and oral administration of mice with 4 was reported to normalize phencyclidine (PCP)-induced prepulse inhibition [56] and oral chronic treatment with 4 normalized the locomotor activity in PCP treated mice [56]. It was also shown that 18 ameliorated the cognitive deficit induced by MK-801 [67] and the co-administration of 9 with D-serine significantly reduced dizocilpine-induced prepulse inhibition deficits [64]. These results show that DAAO inhibitors are effective in rodent models predictive of antipsychotic activity.
Overexpression of NaV1.6 in the rostral ventrolateral medulla in rats mediates stress-induced hypertension via glutamate regulation
Published in Clinical and Experimental Hypertension, 2022
Lei Tong, Mengyu Xing, Jiaxiang Wu, Shuai Zhang, Dechang Chu, Haili Zhang, Fuxue Chen, Dongshu Du
For intra-nuclear administration in RVLM, each animal was placed in prone with the was mounted in a stereotaxic instrument (RWD, China) to ensure that the bregma and lambda were positioned on the same horizontal plane. RVLM microinjections were performed with a glass micropipette (tip diameter is 50–70 microns) by using the following coordinates: 3.7–4.0 mm caudal to lambdoid suture, 2 mm lateral to the midline, and 8.0 mm ventral to the surface of the dura (28). The amount of microinjection drug was glutamate receptor antagonist (Dizocilpine 20 pmoles & CNQX 150 pmoles) or GABA receptor antagonist (Bicuculline 5 pmoles) (MCE, China), and the volume was controlled at 1 μL/side. After each microinjection, the micropipette was left in place for approximately 3 minutes (23,29). The rats were anesthetized with urethane (1–1.5 g/kg iv) at supplemental doses as required (0.1–0.3 g/kg iv). The right femoral artery was cannulated using polyethylene catheters filled with heparinized saline (50 U/mL) (30). The distal end of the arterial cannula was attached to a pressure transducer to directly monitor the blood pressure (BP). Systolic blood pressure (SBP) and heart rate (HR) were simultaneously measured.