B.1. Spinal cord injury is a devastating condition that severely affects the quality of life of an individual. In the US, it is estimated that there are approximately 250,000 individuals living with an SCI, with nearly 11,000 new cases each year. With medical costs that can approach $1,000,000 per patient in the first year alone, the impact of SCI is devastating to the individual and their family. Individuals that have SCI experience different degrees of physical disability, including loss of sensation, muscle paralysis, sexual dysfunction, as well as loss of bladder and bowel control. Depending upon the injury, the clinical manifestations of a spinal cord injury can be severe including either quadriplegia or paraplegia.
B.2. Secondary injury cascade has serious deleterious consequences both anatomically and functionally
The initial injury is acute and mainly caused by mechanical insult, such as forces of compression and displacement that rupture blood vessels and directly injure neurons and glia. The secondary injury is a subsequent degenerative response that includes edema, ischemia, inflammation, ionic imbalance (such as increased intracellular calcium), excitotoxicity, caspase and calpain activation (resulting from increased intracellular calcium), loss of energy metabolism, neurotransmitter accumulation (such as free radical production or lipid peroxidation), and apoptosis 5-7. While the severity of the initial injury is dependent on the nature of trauma and cannot be controlled, the severity of the secondary injury may be modulated through the use of pharmacological agents such as Methylprednisolone (MP) or GM-1 5. The relatively slow progression of the secondary injury response (several hours to days after the initial injury) provides a therapeutic window and forms the basis of the current clinical protocol for systemic administration of MP after SCI.
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B.3. Secondary injury starts at the time of injury, peaks 3-4 days after injury, and subsides approximately 2 weeks after injury
Shearing and death of cellular membranes and axons, myelin degradation, and the migration of immune cells are part of the acute injury. The damage that follows is referred to as secondary injury, which consists of further neuronal and axonal death and degradation around the initial lesion site. The main contributors during secondary injury are macrophages and microglia, which are activated by T cells. The number of macrophages and microglia peak within the first few days (3-4 days) after injury. Two weeks after injury, the overwhelming presence of macrophages and microglia subside. However, during the initial two weeks, these cells aid in the deleterious effects that increase lesion size through axonal and neuronal death.
B.4. MP therapy is the only clinically approved therapy to influence the extent of secondary injury
Methylprednisolone is the only FDA approved, clinically used agent for the treatment of acute SCI 2. Attempts have been made to minimize the secondary damage with neuroprotective agents. MP, a synthetic corticosteroid given in high doses during the first 8 hours post-injury, is in use clinically 2,8,9. Even though the underlying therapeutic mechanism is unclear, MP mediated inhibition of lipid peroxidation and inflammatory response are thought to offer the main therapeutic benefits after SCI 10,11. The use of MP results in blocking the formation of free radicals, reducing nerve cell damage, and decreasing inflammation near the injury by suppressing immune cells. In 1990 the results of the Second National Acute Spinal Cord Injury Study (NASCIS II) showed that the administration of a high-dose (at least 30mg/kg) regimen of the MP could reduce human neurological deficits after SCI insults 12. This positive data resulted in the registration of the high-dose MP for acute SCI treatment in several countries.
B.5. Systemic MP therapy has undesired side-effects and its efficacy is marginal
Although MP reduces neurological deficits, the use of the high-dose MP for acute SCI treatment is now controversial because it causes significant high-dose related side effects such as gastric bleeding, sepsis, pneumonia, acute corticosteroid myopathy and wound infection for a modest neurological recovery2. Therefore, while MP has promise, its unintended side effects (likely due to systemic delivery to areas other than the lesion site) have diminished its attractiveness. The Second National Acute Spinal Cord Injury Study demonstrated that the systemic administration of a high-dose (30mg/kg bolus injection followed by a 5.4 mg/kg/h infusion over 23 hours) regimen of MP during the first 8 hours post-injury can reduce human neurological deficits after SCI 9. We suggest that most of the side effects of MP therapy pertain to the high systemic dosage and associated toxicity, and that the relatively modest neurological gains are a reflection of inefficient dosing to the injury site. Therefore, while MP has promise, its delivery to the injury site is likely the major impediment for its effective and widespread clinical use.
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Olomoucine, a purine derivative, is a cyclin-dependent kinase (CDK) inhibitor. CDK is a cell-cycle promoting protein, which along with other pro-growth proteins is abnormally activated during glial scar formation. Such proteins can increase astrocyte proliferation and can also lead to cell death, thus exacerbating cellular damage at the lesion site. Administration of olomoucine peritoneally has been shown to suppress CDK function. Further, olomoucine has been shown to reduce neuronal cell death, reduce astroglial proliferation (and therefore reduce astrogliosis), and increase GAP-43 expression, a useful protein marker for neurite growth. Moreover, reduced astrocyte proliferation decreases expression of chondroitin sulfate proteoglycans (CSPGs), major extracellular matrix molecules associated with inhibition of neuroregneration after trauma to the CNS.
Recent work has also shown that olomoucine suppresses microglial proliferation within the glial scar. This is particularly important because microglia play an important role in the secondary damage following lesion to the CNS, during the time of scar formation. Microglial cells are activated via various pro-inflammatory cytokines (some discussed above). Rat spinal cord injury models have shown remarkable improvements after the administration of olomoucine. One hour-post administration, olomoucine suppressed microlgial proliferation, as well as reduced the tissue edema normally present during the early stages of glial scar formation. Further, 24 hours post-administration, a reduction in concentration of interleukin-1Î² was observed. Additionally, the administration of olomoucine has also been shown to decrease neuronal cell death.
B.6. Contusion injury best captures the complexity of clinical SCI
A number of animal models are currently available to examine the ability of axons to regenerate. These include a contusion model, a complete transection model, a lateral hemisection model, and a dorsal over-hemisection model, each with its own particular advantages. The hemisection models are useful models to study axonal regeneration and to test the efficacy of locally delivered drugs, such as MP, without any issues of access to neural tissue. In this proposal we design experiments using the contusion model because it is the most clinically relevant, since the vast majority of SCI in humans results from a â€œfracture-dislocationâ€Â of a particular vertebrae and resultant compression of the spinal cord running through the spinal canal of each vertebra. In humans and rats, this injury results in a significant amount of cell death and tissue damage leading to the formation of a fluid filled cyst within the center of the spinal cord surrounded by a rim of intact tissue. The contusion injury presents its own set of transport/diffusion challenges and we seek to study and overcome them in this proposal.
Summarizing the state-of-the-art
Injury to the spinal cord is a devastating life-altering event. Effective therapy to prevent neuronal death and axonal degeneration and promote axonal outgrowth has yet to be identified. MP, the only FDA clinically approved therapy for patients with SCI, has been shown to be modestly effective in reducing secondary injury. However, the systemic delivery of high dosage MP has lead to serious side effects that has curbed the enthusiasm for widespread clinical use for MP. Therefore, to maximize the benefits of MP and reduce the possible side effects, it would be ideal to deliver MP locally and allow for slow release at the injury site during the peak of secondary injury to reduce neuronal death and axonal degeneration.