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4-Aminopyridine derivatives enhance impulse conduction in guinea-pig spinal cord following traumatic injury

Department of Basic Medical Sciences, Center for Paralysis Research, Purdue University, 408 South University Street, West Lafayette, IN 47907, USA.
Neuroscience (Impact Factor: 3.33). 09/2007; 148(1):44-52. DOI: 10.1016/j.neuroscience.2007.05.039
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ABSTRACT 4-Aminopyridine (4-AP), a potassium channel blocker, is capable of restoring conduction in the injured spinal cord. However, the maximal tolerated level of 4-AP in humans is 100 times lower than the optimal dose in in vitro animal studies due to its substantially negative side effects. As an initial step toward the goal of identifying alternative potassium channel blockers with a similar ability of enhancing conduction and with fewer side effects, we have synthesized structurally distinct pyridine-based blockers. Using isolated guinea-pig spinal cord white matter and a double sucrose gap recording device, we have found three pyridine derivatives, N-(4-pyridyl)-methyl carbamate (100 microM), N-(4-pyridyl)-ethyl carbamate (100 microM), and N-(4-pyridyl)-tertbutyl (10 microM) can significantly enhance conduction in spinal cord white matter following stretch. Similar to 4-AP, the derivatives did not preferentially enhance conduction based on axonal caliber. Unlike 4-AP, the derivatives did not change the overall electrical responsiveness of axons to multiple stimuli, indicating the axons recruited by the derivatives conducted in a manner similar to healthy axons. These results demonstrate the ability of novel constructs to serve as an alternative to 4-AP for the purpose of reversing conduction deficits.

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    • "Guinea pigs are frequently used as laboratory animals in studies of ischemic spinal cord injury (Duerstock and Borgens 2002; Luo et al. 2002; McBride et al. 2007). The arterial supply of the thoracolumbar part of the spinal cord in guinea pigs has only been described in a few studies (Knox-Macaulay et al. 1960; Soutoul et al. 1964). "
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    ABSTRACT: Guinea pigs are frequently used as experimental models in studies of ischemic spinal cord injury. The aim of this study was to describe the arterial blood supply to the thoracolumbar spinal cord in 20 adult English self guinea pigs using the corrosion and dissection techniques. The dorsal intercostal arteries arising from the dorsal surface of the thoracic aorta were found as follows: in eight pairs in 70 % of cases, in seven pairs in 20 % of cases and in nine pairs in 10 % of cases. Paired lumbar arteries were present as seven pairs in all the cases. The occurrence of the ventral and dorsal branches of the spinal rami observed in the thoracic and lumbar region was higher on the left than on the right. The artery of Adamkiewicz was present in 60 % of cases as a single vessel and in 40 % of cases as a double vessel. On the dorsal surface of the spinal cord, we found two dorsal spinal arteries in 60 % of cases and three in 40 % of cases. The presence of the artery of Adamkiewicz and nearly regular segmental blood supplying the thoracolumbar part of the spinal cord in all our studied animals is the reason for using guinea pigs as a simple model of ischemic damage to the thoracolumbar part of the spinal cord.
    Anatomical Science International 06/2014; DOI:10.1007/s12565-014-0245-y · 0.84 Impact Factor
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    • "A plot of the injured CAP versus the uninjured CAP revealed a linear trend (Fig. 5C). The congruence of slopes and the similarity in activation thresholds suggest both large and small axons were equally affected by compression (McBride et al., 2007). "
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    ABSTRACT: Crush to the mammalian spinal cord leads to primary mechanical damage followed by a series of secondary biomolecular events. The chronic outcomes of spinal cord injuries have been well detailed in multiple previous studies. However, the initial mechanism by which constant displacement injury induces conduction block is still unclear. We therefore investigated the anatomical factors that may directly contribute to electrophysiological deficiencies in crushed cord. Ventral white matter strips from adult guinea pig spinal cord were compressed 80%, either briefly or continuously for 30 min. Immunofluorescence imaging and coherent anti-Stokes Raman spectroscopy (CARS) were used to visualize key pathological changes to ion channels and myelin. Compression caused electrophysiological deficits, including compound action potential (CAP) decline that was injury-duration-dependent. Compression further induced myelin retraction at the nodes of Ranvier. This demyelination phenomenon exposed a subclass of voltage-gated potassium channels (K(v)1.2). Application of a potassium channel blocker, 4-aminopyridine (4-AP), restored the CAP to near pre-injury levels. To further investigate the myelin detachment phenomenon, we constructed a three-dimensional finite element model (FEM) of the axon and surrounding myelin. We found that the von Mises stress was highly concentrated at the paranodal junction. Thus, the mechanism of myelin retraction may be associated with stress concentrations that cause debonding at the axoglial interface. In conclusion, our findings implicate myelin disruption and potassium channel pathophysiology as the culprits causing compression-mediated conduction block. This result highlights a potential therapeutic target for compressive spinal cord injuries.
    Journal of neurotrauma 04/2010; 27(6):1109-20. DOI:10.1089/neu.2010.1271 · 3.97 Impact Factor
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    • "Our previous studies demonstrated these three derivatives, N-(4-pyridyl) methyl, N-(4-pyridyl) ethyl and N-(4-pyridyl) t-butyl carbamates, significantly enhance action potential conductance following mechanical stretch injury in guinea pig spinal cord both in vitro and in vivo [19] [20] [21]. More importantly however, we noted axons rescued by a 4- AP derivative conduct an action potential in a manner more like healthy axons than those rescued by 4-AP [10] [21]. "
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    ABSTRACT: Axonal demyelination is a critical pathological phenomenon associated with spinal cord injury and multiple sclerosis (MS). Previous studies demonstrated that 4-Aminopyridine, a fast potassium channel blocker, enhances impulse conduction on damaged and/or demyelinated axons, allowing for functional recovery in spinal cord injuries and MS, but with severe therapeutic limitations. To continue to explore the therapeutic value of blocking fast potassium channels while circumventing the side effects of 4-AP, we have developed three novel 4-AP derivatives that enhance impulse conduction in spinal cord trauma. In the current study, we have shown that one of these three derivatives, N-(4-pyridyl) methyl carbamates (MC), significantly inhibits a fast, I(A) like potassium current in guinea pig dorsal root ganglion cells in a whole cell patch clamp configuration. This inhibition of I(A) likely plays a critical role in MC's ability to restore conduction in mechanically injured spinal cord axons and may present a viable alternative to 4-AP for individuals with spinal cord injury or MS. From this, compounds with greater efficacy and perhaps less side effects will likely emerge in the near future, which will greatly enhance the functional restoration and lessen the suffering of SCI and MS patients.
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