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Publication Date

2008-06-11

Availability

UM campus only

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2008-05-12

First Committee Member

Ellen Barrett - Committee Chair

Second Committee Member

Robert Keane - Committee Member

Third Committee Member

W. Dalton Dietrich - Committee Member

Fourth Committee Member

Damien Pearse - Mentor

Abstract

The extent of damage in animal models of spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of the second messenger, cyclic adenosine monophosphate (cAMP), via administration of the phosphodiesterase 4 inhibitor, Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following thoracic contusive SCI injury in rat. Rolipram or vehicle control (10% ethanol) was given daily for 2 weeks post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons (CMAs) was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (2 h PI) increased neuronal survival; 0.5 mg- 1.0 mg/kg protected oligodendrocytes, 1.0 mg/kg produced optimal preservation of CMAs. Administration of 1.0 mg/kg Rolipram via different routes (intravenous [i.v.], subcutaneous [s.c.] or oral, 2 h PI) demonstrated that all routes allowed for significant protection following SCI; the i.v. route provided the best clinical translation. Examination of delayed treatment, initiated 1-48 h after SCI, revealed protective efficacy of Rolipram even when administered up to 48 h PI. With the optimal therapeutic protocol (1.0 mg/kg, i.v.), Rolipram reduced the levels of the chemokine, monocyte chemoattractant protein acutely post-injury and elevated the levels of the anti-inflammatory cytokine, interleukin-10, based on Enzyme-Linked ImmunoSorbent Assay (ELISA) results. Rolipram, when delivered within 48 h PI, was also able to significantly reduce the number of ED1-positive mononuclear phagocytes compared to vehicle-treated controls. This work supports the use of Rolipram as an acute neuroprotectant following SCI, defines an administration protocol, and investigates a potential mechanism for Rolipram-mediated protection.

Keywords

CAMP; Oligodendrocyte; Neuron; Myelination; Ethanol; Phosphodiesterase; Trauma; Neuroprotection

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