Nerve Injury, Degeneration, and Regeneration PDF

Nerve Injury, Degeneration, and Regeneration L. Gilchrist DPT 5035 Objectives Using knowledge of the classification of a nerve injury create a prognosis and appropriate timeframe for functional recovery. Describe the stages of nerve degeneration and regeneration that...

Nerve Injury, Degeneration, and Regeneration L. Gilchrist DPT 5035 Objectives Using knowledge of the classification of a nerve injury create a prognosis and appropriate timeframe for functional recovery. Describe the stages of nerve degeneration and regeneration that follow peripheral nerve injury. Compare and contrast the cellular responses to nerve injury in the CNS and PNS. AXON DEGENERATION (in the PNS) If an axon is cut (axotomy), the result is two axon segments: Proximal segment Separately from one another Distal segment 3 & sealed from extracellular matrix Immediate Effects Ends seal themselves off & retract from each other, widening the gap. enzymesteaks Calcium that entered the cut ends activating proteases that down protein peripheral Gap becomes infiltrated by glial cells, creating a scar. helpful especially in segment - = or harmful  a * has nosuppl Distal Segment Degeneration Distal segment is completely cut off from the soma does not receive the supplies that it needs to survive → eventually completely degenerates Called anterograde or Wallerian degeneration Terminal endings show signs of early (1 day) degeneration Completely disintegrate (by 2 weeks). Terminal Endings retract from post-synaptic cell Synaptic cleft is invaded by glial cells Distal segment of axon and its myelin sheath also degenerate Axon swells and breaks into bead-like fragments Myelin sheath retracts from axon surface & disintegrates DURATION: takes days to weeks in PNS, but months in the CNS Proceeds in an anterograde degeneration, moving from cut end toward the terminal endings Anterograde Degeneration Proximal Axon Degeneration The proximal segment of the axon does NOT degenerate completely. Begins to degenerate at the cut end, proceeding backward up the axon toward the soma (retrograde degeneration). Stops degenerating when it reaches the 1st node of Ranvier.  " time to Soma Degeneration Gives Rebuilt a new 11 Axon Changes appear in the cell body ↳ swell be up purple and Axotomy reaction changes color (purple) Cell body swells, doubling its size 3 Retraction of pre-synaptic terminals from dendrites 4 Axon Regeneration - PNS Soma Changes: Increased synthesis of proteins for use in rebuilding the neuron axon Axon Regeneration Begins Macrophages infiltrate the injury: Phagocytose the myelin and axon debris. Secrete growth factors that facilitate Schwann cell proliferation. ~myelin more > - the Noexon growth PNS Regeneration cont. Schwann cells become active: Secrete chemicals that facilitates axon sprouting (Laminin) Secrete nerve cell adhesion molecules serving to guide axon growth The cut end of the proximal segment sprouts new axon processes, called "growth cones" These axon growth processes grow out in random directions. Rate of axon growth is 3.5-4.0 mm/day However, rate of functional re-innervation is only 1.0-1.5 mm/day (allowing time for synapses to be reestablished) LD Take 3- Month  - Axon attempts path-finding to its original target If cut axon, but intact myelin sheath → sheath can guide axon re-growth to its original target, resulting in re-innervation "bad" Those axon growth processes that do NOT find their way into a sheath will usually grow in the wrong direction, forming a tangle, called a neuroma "ugly Only those axons that find their original target survive Better the alignment of the axon ends = greater chance for axon sprouts to find their sheath → better functional recovery Growth Cones Neuroma → provoked painful when Re-innervation Re-establishment of synaptic connections get incoming signaly Once an axon finds its correct target, recognition chemicals signal back up to the soma Myelination is restored. Re-establishment of function of target cells *However, conduction velocity only recovers to about 80% of its original speed.  Central Nervous System Axon Regeneration Regeneration is less successful than in the PNS. Proximal axon segment sends out growth nuveramany processes for a brief time (2wk) called 1) don't e gliahua "abortive regeneration" > - unsuccessful Usually unable to cross the gap created by the injury & by the glial scar do not find their way into the distal segment's myelin sheath do not find their way to their original targets ↓ don't send Thus CNS neurons do NOT regenerate & out their somas eventually die. CNS Recovery Structural recovery - Re-connection does NOT occur Functional recovery - Partially occurs after incomplete lesion by compensation provided via other remaining neural pathways that may spread influence *PT teaches patient to use these other intact pathways other pathway take can of sypanses other pathway to compensate Possible reasons for failure of CNS growth processes: Non-permissive environment Gliosis Glia cells fill as scar tissue →mechanical barrier Gliosis is more extensive in the CNS than the PNS Growth Inhibiting Factors CNS Glial cells secrete of toxic chemicals → reducing growth of new axon sprouts Absence of chemical "growth enhancing factors" Schwann cells secrete growth enhancing factors NOT secreted by oligodendrocytes in CNS PNS Repair If peripheral nerve sheath intact, re- growth likely If complete transection: Approximation and suturing of CT Nerve Autograft - non-essential cutaneous nerve Engineered nerve repair conduits https://onlinelibrary.wiley.com/doi/10.1002/adhm.201500864 Research on Enhancing Axon Re-growth in CNS Nerve growth factors Transplanting PNS tissue grafts to repair CNS lesions. Transplanting embryonic or neonatal nerve tissue to repair lesion Cultured neural stem cells Re-Starting Brain Cell Proliferation Impact on Remote Neurons the in neuron Remote effects are called trans-neuronal degeneration kill off 2 - > - neuron middle a Effects cross synapses, from an injured neuron to other neurons gives autner to grow Retrograde Trans-neuronal Degeneration Degenerative changes in the neurons that are pre-synaptic to the injured cell Degeneration occurs across the synapse, in a direction opposite to that of normal signals Mechanism for retrograde changes: Normally, trophic factors are secreted by the target neuron and passed back to the pre- synaptic neuron to keep it healthy An injured neuron may be unable to secrete this trophic factor → pre-synaptic neurons then also become damaged Anterograde Trans-neuronal Degeneration Degenerative changes in the neurons that are post-synaptic to the injured cell Possible explanations for these trans-neuronal changes: Neuron somas require a minimal level of electrical stimulation to survive. Neurons require some trophic factor (nutritive chemical) from the pre- synaptic cell. Amount of trophic factor released may be regulated by electrical activity Clinical Consequences of Anterograde Degeneration Denervation hypersensitivity The post-synaptic cell loses its normal innervation Synaptic sites vacated by the injured neurons are taken over by axons from healthy ones. Post-synaptic cell becomes “hyper-sensitive” with additional receptors. 2 Affectinga Additional responsiveness to remaining inputs Compression Injuries Local ischemia to axon either by pressure of fluid (edema) or anat. structure Small arteries bring blood supply to each portion of the axon Neurons require ATP for maintaining ion concentrations → decreased function of axon Larger axons are more susceptible to compression effects than small fibers Ischemia causes release of chemical signals from nearby cells to promote increased blood supply also activates nearby chemically gated nociceptors Compression Injuries cont. Local demyelination at site of compression Early: Compression leads to Schwann cell death near site Later: Remyelination occurs, but: Shorter internode intervals Thinner myelination → slowed conduction velocity (Gupta et al, 2004) Changed concentration of sodium channels Increased numbers of Na channels → ectopic discharges(Chen et al, 2004)