Molecular and Anatomic Mechanisms of Nerve Root, Spinal Nerve, and Peripheral Nerve Injury

Cellular and Molecular Biology: Brief Review

Axonal myelination is established by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). The transition zone between the two is known as the Obersteiner–Redlich Zone, and is commonly discussed in connection with schwannomas arising from the cranial nerves. This transition, present at the junction of spinal nerves and peripheral nerves, has been implicated in mechanisms of iatrogenic nerve injury. A brief overview of both oligodendrocytes and Schwann cells is provided here.

Oligodendrocytes

Oligodendrocytes are responsible for creating and maintaining myelin sheaths within axons of the CNS; a single oligodendrocyte may be affiliated with multiple axons. These cells play a pivotal role in several other complex biological processes, including development, injury repair, and disease process modulation. Alterations in the myelin basic protein produced by oligodendrocytes lead to a variety of demyelinating disease processes with significant clinical implications. Studies suggest that the oligodendrocyte is particularly sensitive to a wide range of oxidative, chemical, radiation-induced, and mechanical injuries. ^,

Schwann Cells

Schwann cells are the PNS correlate of oligodendrocytes, albeit with some notable distinctions. Unlike oligodendrocytes, each Schwann cell myelinates only a single axon. They also provide support to unmyelinated axons in the periphery. Myelin protein zero forms the majority of the myelin sheath in the PNS; alterations in this protein or to Schwann cells lead to a variety of peripheral neuropathies.

Motor Exit Point Glia

Recent research in zebrafish has demonstrated the presence of motor exit point (MEP) glia. These cells are believed to be derived from the CNS, but provide myelination to spinal motor nerve roots. The establishment of the MEP is the result of contact inhibition between the peripheral MEP glial cells and CNS oligodendrocyte progenitor cells.

Transition From Dura to Perineurium

The transition from CNS to PNS is marked at the transition zone as described earlier. The cellular changes at this transition (oligodendrocytes to Schwann cells) are accompanied by macroanatomic changes as well. The dura and arachnoid surrounding the spinal cord are replaced by the perineurium and epineurium encasing the peripheral nerves. In this transition zone, the perineurium enters the subarachnoid space, terminating in an open-ended perineurial extension; the exiting nerve roots are encased by the nerve root sleeve, with an ultrastructure distinct from both perineurium and dura.

Apoptosis

Apoptosis is often described as “programmed cell death.” It plays a role in developmental pruning, and is signaled from within the cell. It involves a cascade of intracellular events wherein chromatin aggregates, internucleosomal DNA is fragmented, and the cell nucleus shrinks (pyknosis), with subsequent phagocytic destruction of cells without an inflammatory response.

There are three major pathways for apoptosis: intrinsic, extrinsic, and endoplasmic reticulum (ER)–mediated. All have been described in postinjury cell death in the spinal cord, dorsal root ganglion (DRG), and peripheral nerves. Briefly, the intrinsic pathway is mediated by proapoptotic Bax and antiapoptotic Bcl-2; the extrinsic pathway is mediated by death receptors such as Fas and their ligands, and the ER-mediated pathway involving intracellular Ca ²⁺ . Other effector molecules, including caspases and tumor necrosis factor-α, are involved in a variety of apoptosis-related cascades.

Necrosis

Necrosis is distinct from apoptosis. It is signaled by external factors within the cellular environment, does not have a role in normal development, and leads to significant local and systemic inflammation.