Spinal cord injury : Mechanical and molecular aspects

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Neuroscience

Sammanfattning: Traumatic spinal cord injury leads to full or partial paralysis and loss of sensation below the level of injury. The annual incidence of spinal cord injury in the United States is 3-5 per 100,000 and in Sweden is 1.5-2 per 100,000. This translates to 11,000 new cases of traumatic spinal cord injury in the US and 150 in Sweden each year. Axon regeneration takes place in peripheral nerves but is limited in the central nervous system. The lack of regenerative capacity in the spinal cord is not an inherent property of the neurons. It is rather the sum of posttraumatic events such as the formation of a glial scar and cysts, a lack of sufficient trophic support and the presence of growth-inhibitory proteins, such as myelin- associated glycoproteins, Nogo and chondroitin sulphate proteoglycans. As the regenerative capacity of the adult injured spinal cord in itself is minor and does not lead to any regain of function, it offers an important field of research. Posttraumatic cystic myelopathy is a devastating problem secondary to spinal cord injury. It is an expansive process that gives rise to loss of sensory and motor function, increasing spasticity, pain, autonomic system dysfunction and bladder disorders. We have developed a new experimental model (thecal sac constriction model) which has given us a wider understanding of the formation of posttraumatic cysts. Thecal sac constriction was achieved by extradural silk ligature at the spinal cord level Th8. Rats with complete spinal cord transection served as a second model for comparison. Animals were investigated using high-resolution magnetic resonance imaging (MRI) and histology. MRI offered the specific advantage of enabling characterisation of the course of events occurring in the spinal cord of individual living animals repeatedly over time. We conclude that induced intramedullary pressure gradients originating from the cerebrospinal fluid pulse pressure may underlie cyst formation in the vicinity of obstructions of the spinal canal and that cysts are preceded by edema. Functional magnetic resonance imaging (fMRI) is based on observations that neural activation leads to alter- ations of local cerebral metabolism, coupled to changes in local cerebral blood flow. We performed fMRI at 4.7 Tesla of the rat brain during electric stimulation of forepaw, hindpaw or tail. The tail is an important organ of the rat involved in sensation, temperature control, balance and movement. The tail is also of great interest in pain research taking advantage of standardized tail flick tests to monitor pain and measure the effects of pain modulating drugs. Repeated stimulation of the right and left forepaws and hindpaws leads to robust activation of the contralateral sensorimotor cortex. Tail stimulation give' rise to a strikingly extended bilateral cortical activation, localized along the midline. This presents possibilities for using fMRI as a tool in future research involving the rodent tail in studies of pain, as well as generally in studying changes of sensorimotor cortical representations during learning, plasticity and lesion or repair tasks. The neurotrophin and glial cell-derived neurotrophic factor (GDNF) families of ligands have important roles during nervous system development and are potent endogenous stimulators of neuron survival and nerve fiber growth. Expression of ligands and functional receptors depends on the specific cell type, and may change during development, aging and after injury. It is therefore crucial to closely map ligands and receptors of trophic factors in tissues in order to identify potential biological activities and to develop therapeutic regimens. Because there are similarities and dissimilarities in the expression of ligands and receptors between species, we have determined to which extent data obtained in rodents are applicable to humans. Studies of the GDNF family and neurotrophin receptors and ligands expressed in adult and fetal human dorsal root ganglion and spinal cord has shown expressions in humans to be remarkably similar to that in rodents, supporting the usefulness of rodents in studies of neurotrophic mechanisms. Nevertheless, certain specific differences were also noted. The bovine myelin-associated neurite growth-inhibitory protein N1220 has been characterized; the gene has been identified and cloned and termed nogo. Three different transcripts are generated from the nogo gene by alternative promoter usage and splicing and the resulting proteins (termed Nogo-A, Nogo-B and Nogo-C) differ in the length of a presumed intracellular domain. An important contribution to the understanding of the physiological role of this protein has been the mapping of the protein and its receptor in humans, rodents and mice. Together, our data show that Nogo-R levels in adult neurons are regulated in vivo. Strong, rapid and transient downregulation of Nogo-R mRNA in response to kainic acid in cortex, hippocampus and amygdala suggests a role for Nogo-A and Nogo-R in plasticity; learning and memory. The ability to reconnect neural pathways proximal and distal to a spinal cord lesion, while limiting the extent of primary and secondary injury by using a combinition of neuroprotectivive and reparative methods, will play an important role in achieving functional recovery.

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