Modeling and treatment of rat cervical spinal cord injury

by 1977- Gensel, John Carib

Spinal cord injury (SCI) is a long lasting, debilitating condition with no cure and highest incidence in young adults. Cervical SCI is the most common form of human SCI. It is also the most devastating, often leaving patients paralyzed with a 15-20 year decrease in life expectancy. The majority of animal SCI contusion models are focused on thoracic injury. This spinal cord level is easy to access for surgery and the resulting deficits are almost entirely due to white matter damage that disconnects the rostral nervous system from the caudal spinal cord. Damage at the cervical level is different; in addition to the disconnection, the gray matter damage affects the neurons controlling the upper extremities and diaphragm. To investigate injury at the most common level of injuries for humans, we characterized a unilateral C5 cervical contusion injury model in rats. By examining six-week behavioral recovery after SCI in rats, we demonstrated that functional deficits are dependent upon the severity of injury. Analysis of the histopathology revealed that behavioral consequences are a result of damage to both the gray and white matter. Unilateral injury provides within-subject controls and preserves bladder and respiratory function. ii Many treatments for experimental rat SCI improve behavioral and histological outcomes but have yet to be implemented after human SCI. Treatments must be safe and tested in clinically relevant models to move from animals to humans. We examined the effects of three different clinically acceptable drugs. The first, methlyprednisolone, has anti-inflammatory effects if given after injury and is currently the only drug approved for treatment of acute SCI. The second, minocycline, is a semi-synthetic, tetracycline derivative with anti-inflammatory properties. The third, topiramate, blocks glutamate receptors and hence excitotoxicity, an important component of secondary injury. Minocycline and methylprednisolone were tested after moderate-severe unilateral cervical contusion injury. Neither treatment yielded significant behavioral improvements compared to control over a 6-week period. There were also no significant effects on histopathological measures. Topiramate was first tested in a model of excitotoxicity and then after cervical contusion. Topiramate treatment was compared to NBQX, a standard AMPA-receptor antagonists used in animal models of disease. Both drugs preserved neuron numbers after excitotoxic injury compared to controls, but only topiramate was found to protect neurons after SCI. More small and medium sized neurons were spared in the topiramate treated group compared to control 48 hours after moderate-severe cervical contusion SCI. NBQX treatment increased white matter sparing compared to control, but resulted in worse motor function compared to topiramate. Both treatments were only effective when applied after moderatesevere injury and not after mild injury. iii This dissertation is dedicated to my parents John A. Gensel and Elizabeth “Betty” Gensel and my fiancé Heather C. Dunfee who have supported me unconditionally in all my endeavors. iv