Central pattern generators in the brainstem and spinal cord: an overview of basic principles, similarities and differences.

Central pattern generators (CPGs) are generally defined as networks of neurons capable of enabling the production of central commands, specifically controlling stereotyped, rhythmic motor behaviors. Several CPGs localized in brainstem and spinal cord areas have been shown to underlie the expression of complex behaviors such as deglutition, mastication, respiration, defecation, micturition, ejaculation, and locomotion. Their pivotal roles have clearly been demonstrated although their organization and cellular properties remain incompletely characterized. In recent years, insightful findings about CPGs have been made mainly because (1) several complementary animal models were developed; (2) these models enabled a wide variety of techniques to be used and, hence, a plethora of characteristics to be discovered; and (3) organizations, functions, and cell properties across all models and species studied thus far were generally found to be well-preserved phylogenetically. This article aims at providing an overview for non-experts of the most important findings made on CPGs in in vivo animal models, in vitro preparations from invertebrate and vertebrate species as well as in primates. Data about CPG functions, adaptation, organization, and cellular properties will be summarized with a special attention paid to the network for locomotion given its advanced level of characterization compared with some of the other CPGs. Similarities and differences between these networks will also be highlighted.

Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury.

BACKGROUND: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. METHODS: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. RESULTS: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. CONCLUSION: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.

Pharmacological approaches to chronic spinal cord injury.

Although research on neural tissue repair has made enormous progress in recent years, spinal cord injury remains a devastating condition for which there is still no cure. In fact, recent estimates of prevalence in the United States reveal that spinal cord injury has undergone a five-fold increase in the last decades. Though, it has become the second most common neurological problem in North America after Alzheimer's disease. Despite modern trauma units and intensive care treatments, spinal cord injury remains associated with several comorbid conditions and unbearable health care costs. Regular administration of a plethora of symptomatic drug treatments aimed at controlling related-secondary complications and life-threatening problems in chronic spinal cord-injured patients has recently been reported. This article provides a thorough overview of the main drug classes and products currently used or in development for chronic spinal cord injury. Special attention is paid to a novel class of drug treatment designed to provide a holistic solution for several chronic complications and diseases related with spinal cord injury. There is clear evidence showing that new class can elicit 'on-demand' episodes of rhythmic and stereotyped walking activity in previously completely paraplegic animals and may consequently constitute a simple therapy against several physical inactivity-related comorbid problems. Understanding further pharmacological approaches to chronic spinal cord injury may improve both life expectancy and overall quality of life while reducing unsustainable cost increases associated with this debilitation condition.

Effects on locomotion, muscle, bone, and blood induced by a combination therapy eliciting weight-bearing stepping in nonassisted spinal cord-transected mice.

BACKGROUND: The health benefits associated with physical activity-based rehabilitation in patients with no lower-extremity motor function after a spinal cord injury (SCI) is uncertain. METHODS: The authors assessed signs of efficacy, safety, and utility associated with a novel pharmacological combination therapy to activate central pattern generator (CPG) activity and corresponding locomotor activity in complete thoracic Th9/10-transected mice. RESULTS: Subcutaneous administration 4 times per week for 1 month of 1.5 mg/kg buspirone, 1.5 mg/kg apomorphine, 12.5 mg/kg benserazide, and 50 mg/kg L-DOPA induced episodes of weight-bearing stepping on a treadmill in nonassisted paraplegic mice for 45-minute sessions. Hindlimb muscle cross-sectional area and fiber area values as well as several blood cell constituent levels assessed at 30 days postinjury were positively affected by the combination therapy, as compared with controls. Episodes of locomotion remained effective on each treatment. Femoral bone mineral density loss was not prevented by triple therapy. CONCLUSION: Although translation of these findings needs further experimentation, similar pharmacological activation of the CPG offers a novel therapeutic target to provide some health benefits in motor-complete SCI patients.

Spinal cord injury research in mice: 2008 review.

Spinal cord injury (SCI) is an irreversible condition causing damage to myelinated fiber tracts that carry sensation and motor signals to and from the brain. SCI is also associated with gray matter damage and often life-threatening secondary complications. This mini-review aims to provide the nonspecialist reader with a comprehensive description of recent advances made in 2008 using murine models of SCI. A variety of approaches, including advanced genetics and molecular techniques, have allowed a number of key findings in the field of secondary degeneration, repair, regeneration (including insights from peripheral nerve lesion models), metabolic dysfunctions, and pharmacological neuromodulation.

Key central pattern generators of the spinal cord.

In the central nervous system (CNS), central pattern generators (CPGs) are generally considered as specialized networks that can produce oscillatory motor output in the absence of any oscillatory input. For instance, respiration and mastication are among the critical biological functions well known to be controlled by such specialized networks. Several other CPGs have also been found specifically in the spinal cord. Among them, the CPG for locomotion is probably the most extensively studied rhythm- and pattern-generating network of the CNS. Other, less completely understood CPGs have also been associated with the control of scratching, micturition, and ejaculation. This review provides a brief update on CPG organization and function in the spinal cord and focuses on similarities and differences between these networks and their pharmacological modulation.

Ionotropic 5-HT3 receptor agonist-induced motor responses in the hindlimbs of paraplegic mice.

Centrally expressed 5-HT3 receptors (5-HTR3) are well known for their role in wakefulness, cognition, and nociception. However, clear evidence of their participation in motor control is still lacking despite specific 5-HTR3 expression in hindlimb motor areas of the spinal cord (i.e., lumbar laminae VII-IX). Here, we studied the acute effects of 4-amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride (SR 57227A), a potent and selective 5-HTR3 agonist, on hindlimb movement generation in complete paraplegic mice. The induced movements were assessed in open-field, air-stepping, and treadmill conditions using a combination of qualitative and quantitative methods. The results revealed that SR 57227A (1-4 mg/kg ip) produced hindlimb movements corresponding to scores ranging from 1 to 5 on the motor scales of Basso, Beattie, and Bresnahan and of Antri, Orsal, and Barthe. Additional analyses revealed that one-third of the movements displayed on a treadmill were "locomotor-like" (i.e., bilateral alternation), whereas only nonlocomotor movements were observed in the other testing conditions suggesting a task-dependent contribution of peripheral afferent inputs to these effects. Locomotor-like movements could also be induced in open field and air stepping if SR 57227A was combined with subthreshold doses of 5-carboxytryptamine (5-HT1A/7 receptor agonist), suggesting synergistic actions of these drugs on central neurons. These results demonstrate that 5-HTR3 activation can induce motor activity and, under some conditions, rhythmic locomotor-like movements in the hindlimbs of paraplegic mice providing evidence of an unsuspected role for this receptor subtype in hindlimb motor control.