NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide] is a novel -methyl-d-aspartate (NMDA) receptor modulator that is currently being investigated in phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies demonstrated that NYX-2925 is a member of a novel class of NMDA receptor-specific modulators that affect synaptic plasticity processes associated with learning and memory. Studies here examined NYX-2925 administration in rat peripheral chronic constriction nerve injury (CCI) and streptozotocin-induced diabetic mechanical hypersensitivity. Additionally, NYX-2925 was examined in formalin-induced persistent pain model and the tail flick test of acute nociception. Oral administration of NYX-2925 resulted in rapid and long-lasting analgesia in both of the neuropathic pain models and formalin-induced persistent pain, but was ineffective in the tail flick model. The analgesic effects of NYX-2925 were blocked by the systemic administration of NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid. Microinjection of NYX-2925 into the medial prefrontal cortex of CCI rats resulted in analgesic effects similar to those observed following systemic administration, whereas intrathecal administration of NYX-2925 was ineffective. In CCI animals, NYX-2925 administration reversed deficits seen in a rat model of rough-and-tumble play. Thus, it appears that NYX-2925 may have therapeutic potential for the treatment of neuropathic pain, and the data presented here support the idea that NYX-2925 may act centrally to ameliorate pain and modulate negative affective states associated with chronic neuropathic pain.
HighlightsDirect injection of the NMDAR modulator NYX-2925 in the mPFC, reverses allodynia.Src activity is downregulated in the mPFC of a CCI neuropathic pain model.NYX-2925 restores pain induced decrease of phosphorylated NMDAR’s.NYX-2925 restores pain induced decrease of Src-mediated intracellular signaling.
An assist device was developed which is able to support the pumping function of the heart by direct application of pressure to the left ventricle. The goal of this animal study in pigs was to determine whether it is possible to maintain sufficient blood circulation with the aid of the new system when the heart is fibrillating or its capacity has been greatly reduced. Following sternotomy complete invasive monitoring was installed. The intrathoracic implantable mechanical multi-chamber pump system (IMPS) was placed around the left ventricle. By means of the beta-blocker carazolol, systolic left-ventricular pressure (LVPsys), cardiac output, heart rate, and left-ventricular dp/dtmax (LVdp/dtmax) were gradually lowered and the pump system was tested intermittently. Then the heart was fibrillated and the system was tested again. When cardiac output, LVdp/dtmax, and systolic blood pressure were reduced by approximately 50% IMPS was able to increase LVPsys by 83% (IMPS) on: 96 +/- 9 mmHg vs. IMPS off: 63 +/- 6 mmHg), and the blood pressure in the carotid artery by 86% (IMPS on: 95/40 +/-15 mmHg vs. IMPS off: 69/38 +/- 9 mmHg). The mean cardiac output was 64% (IMPS on: 4.3 L/min vs. IMPS off: 3.9L/min); in most cases a great variability could be observed depending on the preload, the heart rate, and the mode of pressure application. When the heart was fibrillating, IMPS was able to maintain adequate circulatory conditions with LVPsys = 88%, blood pressure in the carotid artery = 85%, and LVdp/dtmax = 57% of the control values measured before fibrillation and beta-blockade. The system presented here is able to support the impaired left ventricle and to replace its pumping function. The advantages of the system are its efficiency and the lack of contact of the circulating blood with foreign surfaces. Whether the system is suited for bridging and recovery support shall be clarified in further studies.
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