Roles of Ca Channels in Demyelinating Diseases

Since axonal degeneration is now recognized to be a prominent feature in demyelinating diseases, Ca channels might be pathologically relevant if they predispose axons to Ca-mediated damage. There are three mechanisms by which axonal Ca influx can be modulated in demyelination unmasking of existing Ca channels in the internode, changes in gene expression of other ion channels, and changes in gene expression of Ca channels. 1. Increased Ca Influx per Unit Length by Unmasking Ca Channels on the...

Experimental Models of Neurological Disorders

Animal models are essential tools in axonal injury research. There are several ways that animal models can help overcome the hurdles that arise during neuropathological studies in humans. Time course analyses can be performed, which are critical for examining mechanisms of disease. In most human studies, brain pathology investigations are limited to the end stage, because the tissue is inaccessible to direct observation. Second, the neurological diseases can take several years to develop and...

Wallerian Degeneration

After transection of an axon in the CNS, the cut ends rapidly seal and the distal axon may survive for several days before it begins to undergo wallerian degeneration, the larger axons degenerating before finer caliber axons. After the axon has degenerated, the myelin sheath begins to degenerate but in marked contrast to the rapid removal of axon and myelin debris from the PNS, the debris in the CNS is slowly cleared over a period of months (Bignami and Eng, 1973). In the human brain and spinal...

Caspases in Wallerian Degeneration

Before the observations that UPS was involved in the initial stages of wallerian degeneration, an attractive hypothesis was that members of the apoptotic pathway might be regulating or executing the axonal degeneration seen after injury akin to the apoptosis of injured cells. Similar to wal-lerian degeneration, apoptosis in the nervous system is an active process that requires energy and presence of regulatory proteins and enzymes capable of degrading cellular proteins (Yuan and Yankner, 2000)....

Apoptotic Neuronal Cell Death

In the last few years, histopathological studies of postmortem tissue of patients, as well as data from experimental animal and cell culture models, have revealed the presence of neuronal apoptosis in multiple sclerosis (MS), an autoimmune CNS disease that has long been thought to be primarily characterized by inflammation and demyelination. In human autopsy brain tissue, a limited number of apoptotic neurons could be detected in chronic active and chronic inactive lesions from patients with MS...

Guillain Barr Syndrome Variants

GBS is a prototypic autoimmune peripheral nerve disorder with acute-onset and monophasic course that is the leading cause of acute flaccid paralysis worldwide since the near eradication of polio. This syndrome of rapidly evolving flaccid paralysis and areflexia in conjunction with albumino-cytologic dissociation was described by Guillain, Barr , and Strohl in 1916. Later, pathological studies on autopsy materials obtained from GBS cases showed the presence of T-cell inflammation and...

Demyelinated Axons

Although demyelinated axons can sometimes conduct impulses successfully, they never conduct as well as normal axons. Conduction remains much slower and less secure than normal, and it is also prone to conduction failure, especially if conducting trains of impulses at higher frequencies. These conduction deficits result in a range of functional deficits in patients. Techniques that allow the progress of the action potential to be monitored as it conducts along the demyelinated axolemma (Bostock...

Identification of K Channel Subtypes and Mapping of Axonal Localization

Juxtaparanodal Tripartite of Kv1.1 Kv1.2 Kvb2 Fast, delayed rectifier is historically the first K channel to be studied in axons. This channel was first characterized in the squid giant axon in 1952 (Hodgkin and Huxley, 1952), then later in amphibian nodes of Ranvier. These channels are partially open at the resting potential, but are strongly activated by depolarization with fast activation kinetics. As shown by Hodgkin and Huxley, fast delayed rectifiers play an indispensable role in...

Molecular Mechanisms of Neuronal Apoptosis in EAE

Neurodegenerative diseases are often characterized by apoptosis of certain neuronal populations and concomitant intracellular protein depositions. In ALS, cell death of upper and lower motor neurons is associated with inclusion of proteins such as skein-like ubiquitin. In animal models of Huntington's disease, as well as in brain tissue from Huntington patients, neuronal cell death in the striatum related to intranuclear deposition of mutant huntingtin and ubiquitin was observed. Cell death in...

Functional Implications of Nav16

These results demonstrate the co-expression of Nav1.6 and the Na Ca exchanger at regions of axonal injury in EAE and in MS and provide, for the first time, information about the molecular identity of a sodium channel subtype that may drive reverse Na Ca exchange in neuroinflammatory disorders. Physiological data are consistent with a contribution of Nav1.6 to neuronal injury. Rapidly inactivating sodium current would not be expected to produce the sustained influx of Na that is needed to drive...

The Cerebellum and Motor Recovery

A potentially important brain region mediating recovery is the cerebellum. Contralesional cerebellar activity shows increased or sustained activity after an acute ischemic lesion associated with hemiparesis (Feydy et al., 2002 Fraser et al., 2002 Calautti and Baron, 2003). Increased cerebellar activity may distinguish patients with a more favorable outcome after stroke (Small et al., 2002). Cerebellar pathways have been implicated in circuitry mediating recovery and could be particularly...

References

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Consequences of Axonal Injury Within Demyelinated Plaques

Disruption of the axonal continuity within a demyeli-nated plaque has necessarily to result in degenerations of the distal portion of the nerve fiber. In addition, axon disruption may also lead to retrograde degeneration, affecting the proximal axon and the neuron of origin. It has thus to be expected that degenerative alterations occur in MS brain outside the classical plaques. Many studies have shown the presence of secondary (Wallerian) tract degeneration in MS brains (see Kornek and...

Clustering of Na Channels and Formation of New Nodes of Ranvier

The results described thus far suggest that after demyeli-nation conduction may be blocked, but can be restored by just the earliest and most minimal association of Schwann cells with axons (Smith et al., 1982 Shrager, 1988 Shrager and Rubinstein, 1990). The low density of Na+ channels in the internode could, in principle, participate in the restoration of conduction, but computational models confirm that without additional restructuring, the high capacitance of the demyelinated axon limits the...

Molecular Axon Components

Wallerian Degeneration Axons

Although a number of molecules, or classes of molecules, secreted by activated immune cells have been implicated in axon injury in MS, the early events leading to transection of the axon have not been studied in any depth. The appearance of the axon end-bulb already indicates that axon injury has proceeded to an irreversible state. The sealing of the ends of an injured axon involves calcium-dependent processes including activation of calpain and phospholipase A2 (Howard et al., 1999 Geddis and...

Multiple Sclerosis

MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85 of whom are between the ages of 20 and 50 years old (Mayr et al., 2003). Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000). The relapsing-remitting...

Kv1 Channel Localization and Function in Demyelinated and Remyelinating Axons

Kv1 channel localization after demyelination and during remyelination was described using the lysolecithin model of peripheral demyelination (Rasband et al., 1998). In these experiments, lysolecithin was injected directly into the sciatic nerve, resulting in activation of macrophages, and the disruption and eventual phagocytosis of myelin. In this model, complete, focal demyelination occurs at the site of injection within about 1 week. After demyelination, Schwann cells proliferate and are able...

Retinal Involvement in Optic Neuritis and Multiple Sclerosis

A large proportion of the pattern electroretinogram (PERG), which is recorded from the surface of the cornea or the infraorbital skin in response to a similar grating or checkerboard stimulus as is used to evoke the cortical VEP, is believed to be due to the activity of retinal ganglion cells. When recorded at a fast rate, the PERG is usually found to be attenuated in patients with a past history of optic neuritis (e.g., Plant et al., 1986 Bradshaw, 1992), although not significantly in every...

Ephaptic Activity

There is evidence that sometimes electrical activity in one axon can excite activity in another axon, which is presumed to lie adjacent to the first. Such cross-excitation at a Figure 11 Spike triggered bursting record exhibited by the same central demyelinated axon as shown in Fig. 5. After 30 seconds of stimulation at 200 Hz, stimulation at only 1 Hz indicated by the downward deflections of the stimulus artefacts, which are seemingly superimposed in time with the action potentials they evoked...

Local Influences of Myelin on Axon Cytoskeleton

Traditionally, changes in synthesis of cytoskeletal proteins, connection with suitable targets, patterns of activity, and availability of target-derived neurotrophic factors were thought to regulate axon diameter. From this viewpoint, the number of MTs and NFs Friede and Samorajski, 1970 supplied by slow axonal transport Hoffman et al., 1988, 1985, 1983 Lasek et al., 1983 Wujek et al., 1986 were believed to be the primary determinants of axon diameter. Synthesis of cytoskeletal and membrane...