cx717 and Disease-Models--Animal

Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea.. The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats.. In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg).. Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

Topics: Anesthetics, Intravenous; Animals; Animals, Newborn; Apnea; Disease Models, Animal; Drug Therapy, Combination; Isoxazoles; Male; Mice; Plethysmography; Propofol; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency

Ampakines are a class of putative nootropic drug designed to positively modulate the AMPA receptor and have been investigated as a potential treatment for cognitive disorders such as Alzheimer's Disease. Nonetheless, some ampakines such as CX717 have been incompletely characterized in behavioural pharmacological studies. Therefore, in this study, we attempted to further characterize the effects of the ampakine, CX717 (20 mg/kg s.c), on the performance of rats in a 5 choice serial reaction time (5CSRTT) and object recognition memory task, using rats with cognitive deficits caused by bilateral vestibular deafferentation (BVD) as a model. In the 5CSRTT, when the stimulus duration was varied from 5 to 2 sec, the number of incorrect responses was significantly greater for the BVD group compared to sham controls, but significantly less for the CX717 groups, with no significant interaction. With changes in inter-trial interval (ITI), there was a significant effect of surgery/drug and a significant effect of ITI on premature responses, and the BVD group treated with CX717 showed significantly fewer premature responses than the other groups. In the object recognition memory task, CX717 significantly reduced total exploration time and the exploration towards the novel object in both sham and BVD animals. These results suggest that CX717 can reduce the number of incorrect responses in both sham and BVD rats and enhance inhibitory control specifically in BVD rats, in the 5CSRTT. On the other hand, CX717 produced a detrimental effect in the object recognition memory task.

Topics: Animals; Attention; Cognition; Cognition Disorders; Disease Models, Animal; Isoxazoles; Male; Memory; Memory Disorders; Neural Inhibition; Nootropic Agents; Rats; Rats, Wistar; Reaction Time; Recognition, Psychology; Time Factors; Treatment Outcome; Vestibular Diseases

Opioid analgesics are the most widely used and effective pharmacological agents for the treatment of acute, postoperative and chronic pain. However, activation of opiate receptors leads to significant depression of respiratory frequency in a subpopulation of patients. Here we test the hypothesis that the AMPAKINE CX717 is effective for alleviating fentanyl-induced respiratory depression without interfering with analgesia. Ampakines are a relatively new class of compounds that are in Phase II clinical trials as potential treatments for cognitive disorders and the enhancement of memory and attentiveness. They function by allosterically binding to amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA)-type glutamate receptors and modulating the kinetics of channel closing, transmitter dissociation and desensitization. AMPA receptor mediated conductances play a central role in controlling respiratory rhythmogenesis and drive to motoneurons. Here, we demonstrate that CX717 counters fentanyl-induced respiratory depression without significantly altering analgesia and sedation, or noticeably affecting the animals' behavior. Collectively, the preclinical data demonstrate the significant potential for the use of ampakines in respiratory medicine.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Drug Administration Schedule; Fentanyl; Heart Rate; Hyperalgesia; Isoxazoles; Male; Pain Measurement; Phrenic Nerve; Plethysmography; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Respiratory Insufficiency; Time Factors