Peter M. Richardson

Axonal Elongation in Peripheral and Central Nervous System Transplants

Publisher Summary This chapter discusses axonal elongation in peripheral and central nervous system (PNS/CNS) transplants. The effective regeneration of injured nerve fibers depends upon several events: the survival of the neuronal perikarya; an outgrowth of new branches from the proximal stumps of the severed axons; elongation, ensheathment, and increase in the caliber of the growing axons; the reestablishment of quantitatively and qualitatively appropriate terminal contacts; and the loss of redundant axon branches. In the peripheral nervous system (PNS), this sequence of events can lead to the restoration of nerve fiber structure and function. In the adult mammalian CNS, by contrast, neither the initial outgrowths from interrupted axons nor the collateral sprouts from intact neurons elongate for more than a few millimeters. Although several mechanisms both intrinsic and extrinsic to nerve cells must contribute to the overall failure of CNS regeneration, certain experimental evidence suggests that differences in axonal elongation after damage to the CNS and PNS are strongly influenced by the characteristics of the microenvironment that surrounds the injured fibers. The chapter discusses the grafting of Schwann cells into peripheral nerve. It also describes the transplantation of neurons and target tissues.

Endogenous interleukin‐6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice

Partial nerve injury is a potential cause of distressing chronic pain for which conventional analgesic treatment with opiates or anti‐inflammatory agents is not very effective. Constriction nerve injury, widely used to study neuropathic pain, was shown here to induce interleukin‐6 (IL‐6) mRNA in a subset of rat primary sensory neurons. When we inflicted chronic nerve constriction on mice with null mutation of the IL‐6 gene, the hypersensitivity to cutaneous heat and pressure that is induced in wild‐type mice was not evident, the loss of substance P in sensory neurons was excessive and the induction of galanin in central sensory projections was reduced. In additional experiments, intrathecal infusion of IL‐6 in rats was shown to stimulate synthesis of galanin in approximately one‐third of lumbar dorsal root ganglion neurons. The results of these experiments indicate that endogenous IL‐6 mediates some of the hypersensitive responses that characterize peripheral neuropathic pain, and influences two neuropeptides that have been implicated in pain transmission.

Influence of injury and cytokines on synthesis of monocyte chemoattractant protein-1 mRNA in peripheral nervous tissue

The signals and the source of the signals for monocyte/macrophage entry into the injured peripheral nervous tissue are not yet defined. This study was undertaken to determine the distribution of the chemokine monocyte chemoattractant protein‐1 mRNA in injured rat and mouse nerves and to investigate the mechanisms that regulate its synthesis in rat Schwann cells. Results from RNase protection assays showed that, following sciatic nerve transection in rats, mRNA for monocyte chemoattractant protein‐1 was induced at the site of lesion within 3u2003h of surgery and in more distal segments from 24u2003h for at least 8u2003days. In cultured Schwann cells, tumour necrosis factor‐α but not interleukin‐1β, interleukin‐6, transforming growth factor‐β1, platelet‐derived growth factor‐BB or nerve growth factor induced monocyte chemoattractant protein‐1 mRNA in a time‐ and dose‐dependent fashion. The induction of monocyte chemoattractant protein‐1 mRNA in Schwann cells treated with tumour necrosis factor‐α was reduced by inhibitors of nuclear factor‐κB and the p38 mitogen‐activated protein kinase. In mice that lack the two receptors for tumour necrosis factor, the message for JE, a murine homologue of monocyte chemoattractant protein‐1, was still induced within 6u2003h of injury at the lesion site. However, in more distal segments 4u2003days after transection the concentration of JE mRNA was lower than that of control mice. Tumor necrosis factor‐α is the only cytokine that was shown to induce monocyte chemoattractant protein‐1 mRNA in cultured Schwann cells and is one of the factors that regulate the synthesis of monocyte chemoattractant protein‐1 in injured nerves.

Nonpenetrating trauma to the carotid artery: seven cases and a literature review.

Nonpenetrating carotid trauma is uncommon and frequently missed on initial examination. The cases of seven patients seen over a period of 21 years are presented and 100 cases from the most recent literature are reviewed. Causes and mechanisms of injury, clinical presentation, investigations, management, and outcome are discussed. Causes of injury were three motor vehicle collisions, two falls, one sports injury, and one blow to the face. Clinical presentation was early in four and delayed in three. The earliest symptoms and signs were a change in mental status, headache, unprovoked fall, focal weakness, neglect, and dysphasia. Doppler studies may be useful in screening, but a definitive diagnosis is made with the help of angiography. Two patients were treated surgically; one died, one with delayed symptoms from a pseudoaneurysm recovered completely. Five patients were given anticoagulants; all survived with permanent deficits related to their pretreatment neurologic status. The outcome in 100 recent cases from the literature has improved compared with previous reports. The overall mortality was 12%. The outcome in our seven cases supports recent trends toward a strategy of early anticoagulation and selective surgical treatment.

Neurotrophic factors in regeneration

Nerve growth factor, fibroblast growth factor, and ciliary neurotrophic factor can protect selected populations of neurons from some of the degenerative changes that otherwise follow axonal injury or other insults. The function of diffusible neurotrophic factors in axonal regeneration is still unclear, however. Knowledge of the nerve growth factor congeners, brain-derived neurotrophic factor and neurotrophin-3, is advancing rapidly as is the identification of neurotrophin receptors, several of which are membrane-bound tyrosine kinases.

Galanin Expression in Neuropathic Pain: Friend or Foe?a

Abstract: We investigated a possible link between galanin expression and evoked pain accompanying painful partial sciatic nerve lesions. Increased galanin immunoreactivity (IR) in the dorsal horn, in gracile nucleus, and in sensory neurons following chronic constriction injury (CCI) compared to complete sciatic transection suggested a facilitatory role in thermal and mechanical hypersensitivity (allodynia). We therefore investigated the effects of endogenous interleukin‐6 (IL‐6) and nerve growth factor (NGF) on allodynia and neuropeptide expression. IL‐6 knockout mice showed decreased allodynia and galanin‐IR compared to wild‐type mice, but also decreased substance P (SP)‐IR in the dorsal horn. Anti‐NGF‐treated rats with CCI also showed decreased allodynia and SP‐IR, but increased galanin‐IR in the dorsal horn. These results suggest that evoked pain is more tightly linked to SP than to galanin expression. If galanins effects are inhibitory as the bulk of the literature suggests, its effects are subordinate to those of SP and to other changes following CCI.

Visual abnormalities with multiple trauma.

Abstract The diversity of pathogenetic mechanisms involved in posttraumatic visual impairment was reviewed in a study of the hospital records of 24 patients admitted with multiple injuries. Most major visual abnormalities occurred in young people (average age 33 years) who presented with a wide range of overall severity of injury (injury severity score 13–47) and involvement of the central nervous system (Glasgow coma scale 5–15). Bilateral or monocular blindness developed in 63% of patients. Seventy percent of the injuries involved the anterior visual pathways with damage to the optic nerve alone accounting for 35%. Fractures of the sphenoid bone, particularly of the body, accompanied optic nerve and chiasmal injuries and some cases of traumatic carotid-cavernous fistulas. Pathogenetic mechanisms varied according to the site of injury and included vitreous hemorrhage and optic atrophy secondary to raised intracranial pressure, retinal hypoxia from carotid-cavernous fistulas, shearing and compression injuries of the optic nerve, traumatic chiasmal syndrome, temporoparietal and occipital contusions, and transtentorial herniation with occipital infarction. Visual abnormalities varied in severity from moderately reduced visual acuity and diverse hemianopias and scotomas to blindness. The incidence of posttraumatic residual visual abnormalities is likely to increase in the wake of improved acute care of the traumatized victim.

Influences of peripheral nerve components on axonal growth.

One function of sheath cells (Schwann cells and endoneurial fibroblasts) is to promote the regeneration of injured axons. Sheath cells are associated with several molecules that support neurite extension in vitro including one agent very similar to classical nerve growth factor (NGF)..* In this essay, evidence will be summarized that NGF is normally synthesized by sheath cells and acts on receptors along the course of axons in nerve trunks. Two types of action of sheath cells on regenerating neurons will be described with the suggestion that two classes of molecules are involved.

Proximal median neuropathy secondary to humeral neck fracture

Median neuropathies proximal to the wrist are uncommon and usually result from penetrating injuries, fracture dislocation of the distal humerus, or compressioin by fibrous bands. A 66‐year‐old man suffered a comminuted fracture of the proximal humerus after a fall. Electrodiagnostic studies revealed a severe proximal median neuropathy and a mild distal radial mononeuropathy. Proximal median neuropathy rarely occurs in humeral neck fracture, mostly because the median nerve is not in close contact with the humerus proximally.

VISUAL ABNORMALITIES IN MULTIPLE TRAUMA

The diversity of pathogenetic mechanisms involved in posttraumatic visual impairment was reviewed in a study of the hospital records of 24 patients admitted with multiple injuries. Most major visual abnormalities occurred in young people (average age 33 years) who presented with a wide range of overall severity of injury (injury severity score 13-47) and involvement of the central nervous system (Glasgow coma scale 5-15). Bilateral or monocular blindness developed in 63% of patients. Seventy percent of the injuries involved the anterior visual pathways with damage to the optic nerve alone accounting for 35%. Fractures of the sphenoid bone, particularly of the body, accompanied optic nerve and chiasmal injuries and some cases of traumatic carotid-cavernous fistulas. Pathogenetic mechanisms varied according to the site of injury and included vitreous hemorrhage and optic atrophy secondary to raised intracranial pressure, retinal hypoxia from carotid-cavernous fistulas, shearing and compression injuries of the optic nerve, traumatic chiasmal syndrome, temporoparietal and occipital contusions, and transtentorial herniation with occipital infarction. Visual abnormalities varied in severity from moderately reduced visual acuity and diverse hemianopias and scotomas to blindness. The incidence of posttraumatic residual visual abnormalities is likely to increase in the wake of improved acute care of the traumatized victim.