Phenytoin Protects Spinal Cord Axons and Preserves Axonal Conduction and Neurological Function in a Model of Neuroinflammation In Vivo

2003 ◽  
Vol 90 (5) ◽  
pp. 3566-3571 ◽  
Author(s):  
Albert C. Lo ◽  
Carl Y. Saab ◽  
Joel A. Black ◽  
Stephen G. Waxman
Keyword(s):  
Spinal Cord ◽  
Sodium Channels ◽  
Action Potentials ◽  
Axonal Degeneration ◽  
Corticospinal Tract ◽  
Calcium Influx ◽  
Clinical Status ◽  
Channel Blockers ◽  
Sodium Influx

Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.

scholarly journals Alterations of action potentials and the localization of Nav1.6 sodium channels in spared axons after hemisection injury of the spinal cord in adult rats

2011 ◽  
Vol 105 (3) ◽  
pp. 1033-1044 ◽  
Author(s):  
Arsen S. Hunanyan ◽  
Valentina Alessi ◽  
Samik Patel ◽  
Damien D. Pearse ◽  
Gary Matthews ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sodium Channels ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Input Resistance ◽  
Ultrastructural Changes ◽  
Resting Membrane Potential ◽  
Adult Rats ◽  
Cord Injury

Previously, we reported a pronounced reduction in transmission through surviving axons contralateral to chronic hemisection (HX) of adult rat spinal cord. To examine the cellular and molecular mechanisms responsible for this diminished transmission, we recorded intracellularly from lumbar lateral white matter axons in deeply anesthetized adult rats in vivo and measured the propagation of action potentials (APs) through rubrospinal/reticulospinal tract (RST/RtST) axons contralateral to chronic HX at T10. We found decreased excitability in these axons, manifested by an increased rheobase to trigger APs and longer latency for AP propagation passing the injury level, without significant differences in axonal resting membrane potential and input resistance. These electrophysiological changes were associated with altered spatial localization of Nav1.6 sodium channels along axons: a subset of axons contralateral to the injury exhibited a diffuse localization (>10 μm spread) of Nav1.6 channels, a pattern characteristic of demyelinated axons (Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Proc Natl Acad Sci USA 101: 8168–8173, 2004b). This result was substantiated by ultrastructural changes seen with electron microscopy, in which an increased number of large-caliber, demyelinated RST axons were found contralateral to the chronic HX. Therefore, an increased rheobase, pathological changes in the distribution of Nav1.6 sodium channels, and the demyelination of contralateral RST axons are likely responsible for their decreased conduction chronically after HX and thus may provide novel targets for strategies to improve function following incomplete spinal cord injury.

Praziquantel and the benzodiazepine Ro 11-3128 do not compete for the same binding sites in schistosomes

Parasitology ◽  
2007 ◽  
Vol 135 (1) ◽  
pp. 47-54 ◽  
Author(s):  
L. PICA-MATTOCCIA ◽  
A. RUPPEL ◽  
C. M. XIA ◽  
D. CIOLI
Keyword(s):  
Calcium Channel ◽  
Binding Sites ◽  
Calcium Influx ◽  
Cytochalasin D ◽  
The Other ◽  
Channel Blockers ◽  
Spastic Paralysis ◽  
Receptor Sites

SUMMARYThe benzodiazepine Ro 11-3128 (methyl-clonazepam) presents several similarities with praziquantel with regard to its anti-schistosomal mode of action, since both drugs cause spastic paralysis, calcium influx and tegumental disruption in the parasites. In order to know whether the two compounds share the same binding sites in the schistosomes, we performed in vivo and in vitro competition experiments. We took advantage of the fact that Ro 11-3128 is active against immature Schistosoma mansoni (whereas praziquantel is inactive), and praziquantel is active against S. japonicum (which is insensitive to Ro 11-3128). An excess of praziquantel did not inhibit the activity of Ro 11-3128 against immature S. mansoni and an excess of Ro 11-3128 did not inhibit the activity of praziquantel against S. japonicum, suggesting that the schistosome binding sites of the two drugs are different. On the other hand, cytochalasin D, an agent known to perturb – among other things – calcium channel function, was capable of inhibiting the schistosomicidal activity of both praziquantel and Ro 11-3128, thus adding another element of similarity between the two anti-schistosomal agents. A similar, albeit partial, inhibition of the schistosomicidal activity of the two drugs was exerted by some of the classical calcium channel blockers. Taken together, these results suggest that praziquantel and Ro 11-3128, although binding to different schistosome receptor sites, may use the same basic anti-schistosomal effector mechanisms.

In vivo imaging of axonal degeneration and regeneration in the injured spinal cord

2005 ◽  
Vol 11 (5) ◽  
pp. 572-577 ◽  
Author(s):  
Martin Kerschensteiner ◽  
Martin E Schwab ◽  
Jeff W Lichtman ◽  
Thomas Misgeld
Keyword(s):  
Spinal Cord ◽  
In Vivo Imaging ◽  
Axonal Degeneration ◽  
Injured Spinal Cord

scholarly journals Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study

2019 ◽  
Vol 9 (10) ◽  
pp. 268 ◽  
Author(s):  
List ◽  
Kohl ◽  
Winkler ◽  
Marxreiter ◽  
Doerfler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Corpus Callosum ◽  
Hereditary Spastic Paraplegia ◽  
Axonal Degeneration ◽  
Corticospinal Tract ◽  
Disease Duration ◽  
Cervical Spinal Cord ◽  
Internal Capsule ◽  
Healthy Controls ◽  
Spastic Paraplegia

Objective: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). Methods: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. Results: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. Conclusion: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.

Sodium- and Calcium-Dependent Mechanisms in the Action Potential of the Secretory Epithelium of a Clam Mantle

1989 ◽  
Vol 145 (1) ◽  
pp. 395-402
Author(s):  
PAULO S. BEIRÃO ◽  
JOSÉ HAMILTON M. NASCIMENTO
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Calcium Channel Blockers ◽  
Local Anesthetics ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Basolateral Membrane ◽  
Channel Blockers ◽  
Calcium Dependent ◽  
Repolarization Phase

The secretory epithehum of the mantle of the clam Anomalocardia brasiliana is excitable. The ionic dependence of its action potentials was investigated. Two distinct phases could be recognized by their ionic dependences. The early spike phase, that appeared in all action potentials, was dependent on the Na+ concentration of the solution in the interstitial space and was insensitive to tetrodotoxin (TTX) at concentrations as high as 36μmol l−1. It was inhibited by local anesthetics, and its repolarization was inhibited by veratrine. The data show this electrogenesis is caused by TTX-insensitive sodium channels located at the basolateral membrane of this epithelium. Cardiac-like action potentials were recorded in several specimens: the rapid Na+-dependent spike was followed by a slower repolarization phase that formed a plateau and increased the action potential duration. The plateau amplitude was markedly increased when the external Ca2+ concentration was increased to (60 mmol l−1 and it was inhibited by the addition of inorganic calcium channel blockers such as Mn2+ and Cd2+. These observations suggest that inward Ca2+ currents cause the sustained depolarization during the plateau.

scholarly journals SK Channels Gate Information Processing In Vivo by Regulating an Intrinsic Bursting Mechanism Seen In Vitro

2009 ◽  
Vol 102 (4) ◽  
pp. 2273-2287 ◽  
Author(s):  
Natalia Toporikova ◽  
Maurice J. Chacron
Keyword(s):  
Action Potentials ◽  
Time Course ◽  
Sensory Input ◽  
Calcium Influx ◽  
Fundamental Problem ◽  
Pyramidal Cells ◽  
Dendritic Morphology ◽  
Weakly Electric Fish

Understanding the mechanistic substrates of neural computations that lead to behavior remains a fundamental problem in neuroscience. In particular, the contributions of intrinsic neural properties such as burst firing and dendritic morphology to the processing of behaviorally relevant sensory input have received much interest recently. Pyramidal cells within the electrosensory lateral line lobe of weakly electric fish display an intrinsic bursting mechanism that relies on somato-dendritic interactions when recorded in vitro: backpropagating somatic action potentials trigger dendritic action potentials that lead to a depolarizing afterpotential (DAP) at the soma. We recorded intracellularly from these neurons in vivo and found firing patterns that were quite different from those seen in vitro: we found no evidence for DAPs as each somatic action potential was followed by a pronounced afterhyperpolarization (AHP). Calcium chelators injected in vivo reduced the AHP, thereby unmasking the DAP and inducing in vitro-like bursting in pyramidal cells. These bursting dynamics significantly reduced the cell's ability to encode the detailed time course of sensory input. We performed additional in vivo pharmacological manipulations and mathematical modeling to show that calcium influx through N-methyl-d-aspartate (NMDA) receptors activate dendritic small conductance (SK) calcium-activated potassium channels, which causes an AHP that counteracts the DAP and leads to early termination of the burst. Our results show that ion channels located in dendrites can have a profound influence on the processing of sensory input by neurons in vivo through the modulation of an intrinsic bursting mechanism.

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