Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model.

Several neurologic diseases including spinal cord injury, Parkinson's disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

Changes in Brain Electrical Activity after Transient Middle Cerebral Artery Occlusion in Rats.

Objectives. Ischemic stroke is a leading cause of death and disability worldwide. To search for new therapeutic and pharmacotherapeutic strategies, numerous models of this disease have been proposed, the most popular being transient middle cerebral artery occlusion. Behavioral and sensorimotor testing, biochemical, and histological methods are traditionally used in conjunction with this model to assess the effectiveness of potential treatment options. Despite its wide overall popularity, electroencephalography/electrocorticography is quite rarely used in such studies. Materials and methods. In the present work, we explored the changes in brain electrical activity at days 3 and 7 after 30- and 45-min of transient middle cerebral artery occlusion in rats. Results. Cerebral ischemia altered the amplitude and spectral electrocorticogram characteristics, and led to a reorganization of inter- and intrahemispheric functional connections. Ischemia duration affected the severity as well as the nature of the observed changes. Conclusions. The dynamics of changes in brain electrical activity may indicate a spontaneous partial recovery of impaired cerebral functions at post-surgery day 7. Our results suggest that electrocorticography can be used successfully to assess the functional status of the brain following ischemic stroke in rats as well as to investigate the dynamics of functional recovery.

Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury.

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain's electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg-1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 µg∙kg-1 did not affect the brain's electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

Site-Specific Neuromodulation of Detrusor and External Urethral Sphincter by Epidural Spinal Cord Stimulation.

Impairments of the lower urinary tract function including urine storage and voiding are widely spread among patients with spinal cord injuries. The management of such patients includes bladder catheterization, surgical and pharmacological approaches, which reduce the morbidity from urinary tract-related complications. However, to date, there is no effective treatment of neurogenic bladder and restoration of urinary function. In the present study, we examined neuromodulation of detrusor (Detr) and external urethral sphincter by epidural electrical stimulation (EES) of lumbar and sacral regions of the spinal cord in chronic rats. To our knowledge, it is the first chronic study where detrusor and external urethral sphincter signals were recorded simultaneously to monitor their neuromodulation by site-specific spinal cord stimulation (SCS). The data obtained demonstrate that activation of detrusor muscle mainly occurs during the stimulation of the upper lumbar (L1) and lower lumbar (L5-L6) spinal segments whereas external urethral sphincter was activated predominantly by sacral stimulation. These findings can be used for the development of neurorehabilitation strategies based on spinal cord epidural stimulation for autonomic function recovery after severe spinal cord injury (SCI).

Attenuation of neurological deficit by a novel ethanolamine derivative in rats after brain trauma.

Objectives: To prove that our novel ethanolamine derivative (FDES) can normalize overall movement and exploratory activity of rats with traumatic brain injury (TBI) owing to its peculiar properties. Materials and methods: TBI was modeled using controlled cortical impact injury (CCI) model method. The resulting neurological deficit, efficacy of the novel agent and other reference agents used were assayed in tests which evaluated overall movements and exploratory behavior of the rats. Finally, scopolamine in equimolar dose was used to estimate the role of cholinergic system in the efficacy of our agent. The tests included: limb-placing, open field, elevated plus maze, cylinder, and beam walking tests. Results: Intraperitoneal administration of FDES at a dose of 10 mg/kg led to improvement of fore- and hind-limb functions of rats with traumatic brain injury as was shown in "Limb placing", "Open field" "Cylinder" and "Beam walking" tests. The new agent had no effects on traumatized rats behavior in the "Elevated Plus Maze" test. Simultaneous co-administration of scopolamine with FDES reduced the beneficial effects of the latter in rats with trauma. Conclusion: The neuroprotective effects of new agent were manifested in the reduction of motor deficiencies, and exploratory activity in the CCI model rats. In comparison with choline alfoscerate and citicoline, FDES showed more beneficial effects as were observed in most of the tests, and did not negatively influence the traumatized rats psychologically. Notably, it is possible that the neuroprotective influence of the new agent is mediated by its actions on the cholinergic system.

Pharmacological screening of a new alpha-2 adrenergic receptor agonist, mafedine, in zebrafish.

Pharmacological agents acting at alpha-2 adrenergic receptors are widely used in physiology and neuroscience research. Mounting evidence of their potential utility in clinical and experimental psychopharmacology, necessitates new models and novel model organisms for their screening. Here, we characterize behavioral effects of mafedine (6-oxo-1-phenyl-2- (phenylamino)-1,6-dihydropyrimidine-4-sodium olate), a novel drug with alpha-2 adrenergic receptor agonistic effects, in adult zebrafish (Danio rerio) in the novel tank test of anxiety and activity. Following an acute 20-min exposure, mafedine at 60 mg/L produced a mild psychostimulant action with some anxiogenic-like effects. Repeated acute 20-min/day administration of mafedine for 7 consecutive days at 1, 5 and 10 mg/L had a similar action on fish behavior as an acute exposure to 60 mg/L. Since mafedine demonstrated robust behavioral effects in zebrafish - a sensitive vertebrate aquatic model, it is likely that it may modulate rodent and human behavior as well. Thus, further studies are needed to explore this possibility in detail, and whether it may foster clinical application of mafedine and related alpha-2 adrenergic agents.