Paranodal Myelin Damage after Acute Stretch in Guinea Pig Spinal Cord

Abstract

Mechanical injury causes myelin disruption and subsequent axonal conduction failure in the mammalian spinal cord. However, the underlying mechanism is not well understood. In mammalian myelinated axons, proper paranodal myelin structure is crucial for the generation and propagation of action potentials. The exposure of potassium channels at the juxtaparanodal region due to myelin disruption is thought to induce outward potassium currents and inhibit the genesis of the action potential, leading to conduction failure. Using multimodal imaging techniques, we provided anatomical evidence demonstrating paranodal myelin disruption and consequent exposure and redistribution of potassium channels following mechanical insult in the guinea pig spinal cord. Decompaction of paranodal myelin was also observed. It was shown that paranodal demyelination can result from both an initial physical impact and secondary biochemical reactions that are calcium dependent. 4-Aminopyridine (4-AP), a known potassium channel blocker, can partially restore axonal conduction, which further implicates the role of potassium channels in conduction failure. We provide important evidence of paranodal myelin damage, the role of potassium channels in conduction loss, and the therapeutic value of potassium blockade as an effective intervention to restore function following spinal cord trauma.

Development of the central nervous system in guinea pig (Cavia porcellus, Rodentia, Caviidae)

“…This fact enables a more detailed study of the disease, particularly regarding to cholesterol, a substance proven important in the production of a protein which destroys neurons. This feature also allows the use of this rodent for evaluation of traumatic injuries to the spinal cord (Ouyang et al 2008, Sun et al 2012) and development of effective therapeutic and clinical interventions in pathologies associated with acute spinal cord injuries.…”

Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease

“…Given that this structure is vital for maintaining neuronal function, morphological studies have demonstrated significant demyelination in animal models of both SCI [4, 5] and MS [6–8], implicating myelin injury as a common feature of CNS trauma and disease. For example, compression and stretch SCI have shown immediate myelin damage such as elongation of the nodes of Ranvier and separation of the myelin and axolemma [9–11]. Such demyelination has been shown to progress with graded lengthening of the nodes two and five hours post stretch SCI in rats [11].…”

“…For example, compression and stretch SCI have shown immediate myelin damage such as elongation of the nodes of Ranvier and separation of the myelin and axolemma [9–11]. Such demyelination has been shown to progress with graded lengthening of the nodes two and five hours post stretch SCI in rats [11]. Furthermore, strikingly similar damage was also observed upon morphological analysis of excised spinal cords of experimental autoimmune encephalomyelitis (EAE) mice, a well-established model of MS, in which nodal lengthening and myelin retraction were also observed (unpublished observation, Shi).…”

“…Myelin enhances axonal conduction by both inhibiting ionic exchange across the membrane and increasing transverse resistance at the internodal region [12]. Accordingly, compromise of the structural integrity of myelin elicits significant conduction loss in spinal cord tissue partly due to the exposure and consequential activation of voltage-gated K + channels typically residing in the juxtaparanodal region [1, 10, 11, 13–15]. Ex vivo studies of spinal cord tissue have demonstrated that myelin damage and subsequent exposure of K + channels impaired signal propagation, indicated by a reduction of compound action potential (CAP) amplitude [10, 11, 14].…”

“…Accordingly, compromise of the structural integrity of myelin elicits significant conduction loss in spinal cord tissue partly due to the exposure and consequential activation of voltage-gated K + channels typically residing in the juxtaparanodal region [1, 10, 11, 13–15]. Ex vivo studies of spinal cord tissue have demonstrated that myelin damage and subsequent exposure of K + channels impaired signal propagation, indicated by a reduction of compound action potential (CAP) amplitude [10, 11, 14]. In fact, diminished CAP amplitudes were detected at the precise moment of physical damage indicating that a number of axons were not capable of signal transduction, likely due to immediate myelin injury [9, 10].…”