Nerve Degeneration and Regeneration - Nerve Muscle Physiology (1st Year MBBS)

Overview

Part 1: Changes After Nerve Injury

A. At the Cell Body - Chromatolysis

• The cell body swells
• The nucleus shifts to an eccentric position (away from center)
• The rough endoplasmic reticulum (Nissl substance) fragments and disperses - this is called the chromatolytic reaction or chromatolysis

"The cell body of the injured neuron swells, the nucleus moves to an eccentric position, and the rough endoplasmic reticulum gets fragmented (chromatolytic reaction)." - Ganong's Review of Medical Physiology, 26th Ed., p. 143

Part 2: Nerve Degeneration

B. Orthograde (Wallerian) Degeneration - Distal to Injury

• Disconnection from the cell body cuts off axonal transport of essential materials
• Calcium influx triggers activation of proteases (calpain) that degrade the axon cytoskeleton
• Distal axon and its myelin sheath undergo complete destruction

"Orthograde degeneration (Wallerian degeneration) occurs from the point of injury to the nerve terminal, interrupting neural transmission. Distal to the injury, the membrane breaks down and the myelin sheath degenerates." - Ganong's Review of Medical Physiology, 26th Ed., p. 143

C. Retrograde Degeneration - Proximal to Injury

• Retrograde degeneration extends from the injury site back to the nearest node of Ranvier
• In severe injuries, the entire proximal segment or even the cell body may die (retrograde cell death)

"The proximal axon also is affected and may undergo retrograde degeneration and die." - Ganong, p. 143 "Proximally, the nerve suffers degeneration as far as the nearest node of Ranvier." - Bailey & Love's Short Practice of Surgery, 28th Ed.

Part 3: Nerve Regeneration

D. Preparation for Regeneration

1. Schwann cells proliferate and align inside the empty endoneurial tubes
2. They form bands of Bungner - longitudinal columns that act as a scaffold and guide for regenerating axons
3. Macrophages recruited by Schwann cells scavenge remaining myelin debris
4. Schwann cells secrete neurotrophins (NGF, BDNF, NT-3) that attract and support axon growth

E. Regenerative Sprouting

• From the proximal stump, the axon sprouts multiple small growth cones (regenerative sprouting)
• These grow along the bands of Bungner at a rate of approximately 1-4 mm/day (roughly 1 inch/month)
• Multiple sprouts form; only the one that successfully enters the distal endoneurial tube survives; the others retract

"The nerve then starts to regrow, with multiple small branches projecting along the path the axon previously followed (regenerative sprouting)." - Ganong, p. 143

F. Neurotropism - Target-Directed Growth

• Neurotrophins (growth factors) released by target tissues act as chemical attractants
• The extracellular matrix and hormones also contribute
• Axons can sometimes grow back to their original motor or sensory endings, especially at the neuromuscular junction

"Axons sometimes grow back to their original targets, especially in locations like the neuromuscular junction. However, nerve regeneration is generally limited because axons often become entangled in the area of tissue damage at the site where they were disrupted." - Ganong, p. 143

"The regenerating nerve fibres are attracted to their receptors by neurotropism, which is mediated by growth factors, hormones and the extracellular matrix." - Bailey & Love, 28th Ed.

G. Remyelination

• Schwann cells wrap around the new axon to restore the myelin sheath
• The new myelin is initially thinner and shorter internodal segments compared to the original
• Conduction velocity is lower than normal initially but may improve over months

Part 4: Denervation Hypersensitivity (Supersensitivity)

In Skeletal Muscle:

• Normally, nicotinic ACh receptors are concentrated only at the motor end plate (neuromuscular junction)
• When the motor nerve is cut and degenerates, the muscle becomes extremely sensitive to acetylcholine - called denervation hypersensitivity or denervation supersensitivity
• There is a marked proliferation of nicotinic receptors over the entire muscle fiber surface (not just the end plate)

In Smooth Muscle:

• Smooth muscle does not atrophy when denervated (unlike skeletal muscle)
• But it becomes hyperresponsive to the chemical mediator that normally activates it
• The same phenomenon occurs at autonomic junctions

Mechanism of Denervation Hypersensitivity:

1. Upregulation of receptors - loss of the chemical messenger leads to upregulation of its receptors (receptor supersensitivity)
2. Lack of reuptake - when the nerve terminal degenerates, there is no longer reuptake of secreted neurotransmitters, so even small amounts cause exaggerated effects

"When the motor nerve to skeletal muscle is cut and allowed to degenerate, the muscle gradually becomes extremely sensitive to acetylcholine... Normally nicotinic receptors are located only in the vicinity of the motor endplate... When the motor nerve is severed, there is a marked proliferation of nicotinic receptors over a wide region of the neuromuscular junction." - Ganong, 26th Ed., p. 143-144

Part 5: Factors Affecting Successful Regeneration

"Nerve regeneration is generally limited because axons often become entangled in the area of tissue damage at the site where they were disrupted. This difficulty has been reduced by administration of neurotrophins." - Ganong, p. 143

Part 6: Complications of Failed Regeneration

• Neuroma formation: When axons cannot reach their target and grow in a disorganized, coiled mass at the injury site. Neuromas are painful and can cause hypersensitivity.
• Denervation atrophy: Skeletal muscle fibers progressively atrophy without motor nerve input.
• Misdirected reinnervation: Axons may reinnervate wrong targets (e.g., a motor axon growing to a sensory receptor), leading to abnormal function.

Summary Table

Quick Mnemonics for 1st Year MBBS

• Ganong's Review of Medical Physiology, 26th Edition - Chapter 6: "Axonal Injury & Denervation Supersensitivity," pp. 143-144 (Figure 6-14)
• Guyton and Hall Textbook of Medical Physiology - Chapter 7: Neuromuscular Junction and context of nerve-muscle physiology
• Bailey & Love's Short Practice of Surgery, 28th Edition - Figure 3.4: Peripheral nerve degeneration and regeneration