Evaluation of the neuroprotective activity of a new allylmorpholine derivative in a rat model of traumatic brain injury

Abstract

Introduction. The search for and development of new drugs capable of reducing the severity of neurological deficit in traumatic brain injury are a critical task for investigational pharmacology. Chromone-containing allylmorpholines are a new group of neuroprotective drug candidates that have been shown to inhibit acetylcholinesterase and butyrylcholinesterase, and block N-methyl-D-aspartate receptors in vitro.Aim. This study aimed to evaluate the neuroprotective activity of the allylmorpholine derivative (E)-4-[3-(8-bromo-6-methyl-4-oxo-4H-chromen- 3-yl)-1-cyclohexylallyl]morpholin-4-ium chloride (33b) in vivo using a rat model of traumatic brain injury.Materials and methods. Traumatic brain injury was induced using the controlled cortical impact model. The allylmorpholine derivative was administered intraperitoneally at 1, 10, or 50 mg × kg-1 b.w. at 1 h after trauma induction, and then daily for the next 6 d. The neurological deficit was assessed using the Limb Placing, Open Field, Elevated Plus Maze, Beam Walking, and Cylinder tests.Results and discussion. At all doses administered, the allylmorpholine derivative had no positive effect on the motor function or exploratory behavior following traumatic brain injury. In the Elevated Plus Maze, 10 mg × kg-1 b.w. of the compound further suppressed exploratory behaviour in the injured animals, which appears to be consistent with its sedative properties observed previously in zebrafish.Conclusion. Despite the previously described in vitro affinity of allylmorpholines towards several molecular targets crucial for the pathogenesis of brain trauma and posttraumatic functional recovery, an allylmorpholine derivative had no neuroprotective effect in a rat model of traumatic brain injury in this study. These results further emphasize the importance of in vivo evaluation of potential neuroprotective drug candidates.

Novel Chromone-Containing Allylmorpholines Induce Anxiolytic-like and Sedative Effects in Adult Zebrafish

“…Compound 5 has been previously evaluated as a potential neuroprotecting agent in rats with unilateral traumatic brain injury; however, it failed to demonstrate any neuroprotective activity. Nonetheless, it induced dose-dependent sedation in rats [ 18 ] and in zebrafish in our experiment. Notably, the CCAMs exerted a sedative effect over a wide range of concentrations; this could be related not only to their different inherent activities shown in vitro [ 13 ] but also to their varying solubility in water, which would affect their availability and the exposure of zebrafish to them.…”

“…As both AChE and NMDAR have long been considered viable therapeutic targets for neuroprotection and cognitive enhancement [ 14 , 15 , 16 , 17 ], CCAMs appear to be a promising group of drug candidates for the treatment of neurological disorders. In a recent study, a novel CCAM was found to exert sedation in rats with traumatic brain injury [ 18 ]. However, to the best of our knowledge, no in vivo screening of this class of compounds’ behavioral activity has been performed to date.…”