Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms

Abstract

Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.

Keywords: neuro-regeneration; neurodegeneration; neuroprotection; primary injury; secondary injury; spinal cord injury.

Figure 1

Spinal cord injury (SCI) (a) phases of SCI, (b) sub-classification of secondary injury depending on duration of injury and (c) pathophysiological events according to SCI phases.

Figure 2

Pathophysiology, clinical manifestations, and phases of SCI.

Figure 3

Stages of axon degeneration, (A) acute injury responses, (B) acute axonal degeneration (AAD) and (C) Wallerian degeneration.

Figure 4

(A) Healthy spinal cord and (B) an injured spinal cord with three lesion compartments, showing inner non-viable small lesion compartment, compact astrocyte core, and perilesion perimeters with multicellular and multi-molecular components (astrocytes, neurons, macrophages, microglia, NG2-OPC, fibrocytes, oligodendrocytes, fibroblast, nerve cells and activated astrocytes) regulating gliosis (gliosis scar formation) post SCI.

Figure 5

Molecular interactions balancing inflammatory responses, debris clearance and phagocytosis regulators following SCI with left showing hydrophobic intercellular molecular interactions controlling harmful signal while right cycle reflect neuro-inflammatory molecular interaction controlling phagocytosis while center portion show multimolecular interactions to clear cellular phagocytic debris.

Figure 6

Neuroprotective pathways and different neuroprotective approaches with centre portion showing neuroprotective pathways (i) neurotransmitter agonist/antagonist, (ii) channel blockers, (iii) anti-oxidative pathways, (iv) apoptotic pathway (v) herbal and natural agents, (vi) cellular and genetic agents, while various agents acting on specific pathways are shown by pointed arrows.

Figure 7

Apoptotic pathway (i) intrinsic pathway and (ii) extrinsic pathway with anti-apoptotic inhibitors, i.e., calpain and caspase that act on specific target molecule and retard apoptosis.

Figure 8

Immuno-modulatory (neuro-inflammatory) pathway following spinal cord injury and specific immuno-modulatory agents.

Figure 9

Neuroregenerative pathway (RhoA/Rho and Rock pathway) and underlying neuroregenerative approaches (i) enhancement of remyelination and (ii) enhancement of neuronal and axonal regeneration strategies.