dextrorphan and Paraplegia

We investigated the effect of dextrorphan, an N -methyl-D -aspartate receptor antagonist, on the reduction of ischemic spinal cord injury and the safe clamping time after various methods of administration.. Spinal cord ischemia was induced in New Zealand White rabbits by infrarenal aortic clamping and animals were divided into 5 groups. Group A (n = 15) received simple clamping. Groups B (n = 20) and C (n = 35) received dextrorphan pretreatment (10 mg/kg), followed by continuous intravenous or intra-aortic infusion (1 mg/min), respectively. Group D (n = 25) received the same dextrorphan pretreatment and bolus intra-aortic injection at clamping (1 mg per minute of clamping time). Group E (n = 15) received bolus intrathecal injection of dextrorphan (0.2 mg/kg). Each dextrorphan-treated group had a small group of control animals (n = 5). The neurologic status was assessed by the Johnson score (5 = normal, 0 = paraplegic) 48 hours after unclamping, and animals were put to death for histopathologic examination.. All dextrorphan-treated groups showed better neurologic function than the respective control animals (P <.001 vs groups B, C, and D; P =.014 vs group E). The order of efficacy of dextrorphan (as revealed by the average of neurologic status) was as follows: group C > group D (P =.017, after 50 minutes of clamping), group D > group B (P =.014, after 45 minutes of clamping), and group B > group E (P <.001, after 40 minutes of clamping). Histopathologic findings did not necessarily correspond with hind-limb neurologic function.. Dextrorphan reduced the physical findings associated with ischemic spinal cord injury, and continuous intra-aortic infusion prolonged the safe clamping time significantly more than delivery by other routes.

Topics: Animals; Aorta, Abdominal; Constriction; Dextrorphan; Male; Neuroprotective Agents; Paraplegia; Rabbits; Receptors, N-Methyl-D-Aspartate; Spinal Cord Ischemia; Time Factors

We examined the characteristics of neuronal cell death after transient spinal cord ischemia in the rat and the effects of an N-methyl-D-aspartate antagonist, dextrorphan, and a protein synthesis inhibitor, cycloheximide.. Spinal cord ischemia was induced for 15 minutes in Long-Evans rats with use of a 2F Fogarty catheter, which was passed through the left carotid artery and occluded the descending aorta, combined with a blood volume reduction distal to the occlusion. The rats were killed after 1, 2, and 7 days. Other groups of rats were pretreated with dextrorphan (30 mg/kg, intraperitoneally, n = 7), cycloheximide (30 mg, intrathecally, n = 7), or vehicle (saline solution, n = 12) and killed after 2 days.. This model reliably produced paraplegia and histopathologically distinct morphologic changes consistent with necrosis or apoptosis by light and electron microscopic criteria in different neuronal populations in the lumbar cord. Scattered necrotic neurons were seen in the intermediate gray matter (laminae 3 to 7) after 1, 2, and 7 days, whereas apoptotic neurons were seen in the dorsal horn laminae 1 to 3 after 1 and 2 days. Deoxyribonucleic acid extracted from lumbar cord showed internucleosomal fragmentation (laddering) on gel electrophoresis indicative of apoptosis. The severity of paraplegia in the rats treated with dextrorphan and cycloheximide was attenuated 1 day and 2 days after ischemia. The numbers of both necrotic and apoptotic neurons were markedly reduced in both dextrorphan- and cycloheximide-treated rats.. The results suggest that both N-methyl-D-aspartate receptor-mediated excitotoxicity and apoptosis contribute to spinal cord neuronal death after ischemia and that pharmacologic treatments directed at blocking both of these processes may have therapeutic utility in reducing spinal cord ischemic injury.

Topics: Animals; Apoptosis; Cycloheximide; Dextrorphan; Excitatory Amino Acid Antagonists; Male; Microscopy, Electron; N-Methylaspartate; Necrosis; Neurons; Paraplegia; Premedication; Protein Synthesis Inhibitors; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Spinal Cord; Time Factors